SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression
Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Her...
Ausführliche Beschreibung
Autor*in: |
Yan, Weiwei [verfasserIn] Xie, Chengmei [verfasserIn] Sun, Sijun [verfasserIn] Zheng, Quan [verfasserIn] Wang, Jingyi [verfasserIn] Wang, Zihao [verfasserIn] Man, Cheuk-Him [verfasserIn] Wang, Haiyan [verfasserIn] Yang, Yunfan [verfasserIn] Wang, Tianshi [verfasserIn] Shi, Leilei [verfasserIn] Zhang, Shengjie [verfasserIn] Huang, Chen [verfasserIn] Xu, Shuangnian [verfasserIn] Wang, Yi-Ping [verfasserIn] |
---|
Format: |
E-Artikel |
---|---|
Sprache: |
Englisch |
Erschienen: |
2024 |
---|
Schlagwörter: |
---|
Anmerkung: |
© The Author(s) 2024 |
---|
Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 43(2024), 12 vom: 22. Apr., Seite 2337-2367 |
---|---|
Übergeordnetes Werk: |
volume:43 ; year:2024 ; number:12 ; day:22 ; month:04 ; pages:2337-2367 |
Links: |
---|
DOI / URN: |
10.1038/s44318-024-00101-9 |
---|
Katalog-ID: |
SPR05627646X |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | SPR05627646X | ||
003 | DE-627 | ||
005 | 20240618064810.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240618s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s44318-024-00101-9 |2 doi | |
035 | |a (DE-627)SPR05627646X | ||
035 | |a (SPR)s44318-024-00101-9-e | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Yan, Weiwei |e verfasserin |0 (orcid)0009-0007-8744-3275 |4 aut | |
245 | 1 | 0 | |a SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a Computermedien |b c |2 rdamedia | ||
338 | |a Online-Ressource |b cr |2 rdacarrier | ||
500 | |a © The Author(s) 2024 | ||
520 | |a Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. | ||
520 | |a Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. | ||
520 | |a Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. | ||
650 | 4 | |a FMS-like Tyrosine Kinase 3 |7 (dpeaa)DE-He213 | |
650 | 4 | |a Lysine Succinylation |7 (dpeaa)DE-He213 | |
650 | 4 | |a Mitochondrial Biogenesis |7 (dpeaa)DE-He213 | |
650 | 4 | |a Mitochondrial RNA Polymerase |7 (dpeaa)DE-He213 | |
650 | 4 | |a Succinate-CoA Ligase |7 (dpeaa)DE-He213 | |
700 | 1 | |a Xie, Chengmei |e verfasserin |4 aut | |
700 | 1 | |a Sun, Sijun |e verfasserin |4 aut | |
700 | 1 | |a Zheng, Quan |e verfasserin |0 (orcid)0000-0002-4512-9233 |4 aut | |
700 | 1 | |a Wang, Jingyi |e verfasserin |4 aut | |
700 | 1 | |a Wang, Zihao |e verfasserin |0 (orcid)0009-0007-5065-8897 |4 aut | |
700 | 1 | |a Man, Cheuk-Him |e verfasserin |4 aut | |
700 | 1 | |a Wang, Haiyan |e verfasserin |4 aut | |
700 | 1 | |a Yang, Yunfan |e verfasserin |0 (orcid)0000-0002-5266-7208 |4 aut | |
700 | 1 | |a Wang, Tianshi |e verfasserin |0 (orcid)0000-0001-8676-0737 |4 aut | |
700 | 1 | |a Shi, Leilei |e verfasserin |4 aut | |
700 | 1 | |a Zhang, Shengjie |e verfasserin |0 (orcid)0000-0003-4158-9010 |4 aut | |
700 | 1 | |a Huang, Chen |e verfasserin |0 (orcid)0009-0003-5547-5951 |4 aut | |
700 | 1 | |a Xu, Shuangnian |e verfasserin |0 (orcid)0000-0002-4041-9039 |4 aut | |
700 | 1 | |a Wang, Yi-Ping |e verfasserin |0 (orcid)0000-0002-3130-0386 |4 aut | |
773 | 0 | 8 | |i Enthalten in |t The EMBO Journal |d Nature Publishing Group UK, 2023 |g 43(2024), 12 vom: 22. Apr., Seite 2337-2367 |w (DE-627)266022529 |w (DE-600)1467419-1 |x 1460-2075 |7 nnns |
773 | 1 | 8 | |g volume:43 |g year:2024 |g number:12 |g day:22 |g month:04 |g pages:2337-2367 |
856 | 4 | 0 | |u https://dx.doi.org/10.1038/s44318-024-00101-9 |m X:SPRINGER |x Resolving-System |z kostenfrei |3 Volltext |
912 | |a SYSFLAG_0 | ||
912 | |a GBV_SPRINGER | ||
912 | |a GBV_ILN_20 | ||
912 | |a GBV_ILN_22 | ||
912 | |a GBV_ILN_23 | ||
912 | |a GBV_ILN_24 | ||
912 | |a GBV_ILN_31 | ||
912 | |a GBV_ILN_32 | ||
912 | |a GBV_ILN_39 | ||
912 | |a GBV_ILN_40 | ||
912 | |a GBV_ILN_62 | ||
912 | |a GBV_ILN_63 | ||
912 | |a GBV_ILN_65 | ||
912 | |a GBV_ILN_69 | ||
912 | |a GBV_ILN_70 | ||
912 | |a GBV_ILN_73 | ||
912 | |a GBV_ILN_74 | ||
912 | |a GBV_ILN_90 | ||
912 | |a GBV_ILN_95 | ||
912 | |a GBV_ILN_100 | ||
912 | |a GBV_ILN_101 | ||
912 | |a GBV_ILN_105 | ||
912 | |a GBV_ILN_110 | ||
912 | |a GBV_ILN_120 | ||
912 | |a GBV_ILN_138 | ||
912 | |a GBV_ILN_150 | ||
912 | |a GBV_ILN_151 | ||
912 | |a GBV_ILN_161 | ||
912 | |a GBV_ILN_165 | ||
912 | |a GBV_ILN_168 | ||
912 | |a GBV_ILN_170 | ||
912 | |a GBV_ILN_187 | ||
912 | |a GBV_ILN_211 | ||
912 | |a GBV_ILN_213 | ||
912 | |a GBV_ILN_230 | ||
912 | |a GBV_ILN_252 | ||
912 | |a GBV_ILN_266 | ||
912 | |a GBV_ILN_285 | ||
912 | |a GBV_ILN_293 | ||
912 | |a GBV_ILN_602 | ||
912 | |a GBV_ILN_702 | ||
912 | |a GBV_ILN_2005 | ||
912 | |a GBV_ILN_2010 | ||
912 | |a GBV_ILN_2014 | ||
912 | |a GBV_ILN_2021 | ||
912 | |a GBV_ILN_2037 | ||
912 | |a GBV_ILN_2059 | ||
912 | |a GBV_ILN_2064 | ||
912 | |a GBV_ILN_2108 | ||
912 | |a GBV_ILN_2113 | ||
912 | |a GBV_ILN_2118 | ||
912 | |a GBV_ILN_2119 | ||
912 | |a GBV_ILN_2122 | ||
912 | |a GBV_ILN_2143 | ||
912 | |a GBV_ILN_2152 | ||
912 | |a GBV_ILN_2153 | ||
912 | |a GBV_ILN_2336 | ||
912 | |a GBV_ILN_2472 | ||
912 | |a GBV_ILN_4035 | ||
912 | |a GBV_ILN_4125 | ||
912 | |a GBV_ILN_4246 | ||
912 | |a GBV_ILN_4307 | ||
912 | |a GBV_ILN_4323 | ||
951 | |a AR | ||
952 | |d 43 |j 2024 |e 12 |b 22 |c 04 |h 2337-2367 |
author_variant |
w y wy c x cx s s ss q z qz j w jw z w zw c h m chm h w hw y y yy t w tw l s ls s z sz c h ch s x sx y p w ypw |
---|---|
matchkey_str |
article:14602075:2024----::ul1etitplmsciyainonacmtcodilignss |
hierarchy_sort_str |
2024 |
publishDate |
2024 |
allfields |
10.1038/s44318-024-00101-9 doi (DE-627)SPR05627646X (SPR)s44318-024-00101-9-e DE-627 ger DE-627 rakwb eng Yan, Weiwei verfasserin (orcid)0009-0007-8744-3275 aut SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 Xie, Chengmei verfasserin aut Sun, Sijun verfasserin aut Zheng, Quan verfasserin (orcid)0000-0002-4512-9233 aut Wang, Jingyi verfasserin aut Wang, Zihao verfasserin (orcid)0009-0007-5065-8897 aut Man, Cheuk-Him verfasserin aut Wang, Haiyan verfasserin aut Yang, Yunfan verfasserin (orcid)0000-0002-5266-7208 aut Wang, Tianshi verfasserin (orcid)0000-0001-8676-0737 aut Shi, Leilei verfasserin aut Zhang, Shengjie verfasserin (orcid)0000-0003-4158-9010 aut Huang, Chen verfasserin (orcid)0009-0003-5547-5951 aut Xu, Shuangnian verfasserin (orcid)0000-0002-4041-9039 aut Wang, Yi-Ping verfasserin (orcid)0000-0002-3130-0386 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 12 vom: 22. Apr., Seite 2337-2367 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 https://dx.doi.org/10.1038/s44318-024-00101-9 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 AR 43 2024 12 22 04 2337-2367 |
spelling |
10.1038/s44318-024-00101-9 doi (DE-627)SPR05627646X (SPR)s44318-024-00101-9-e DE-627 ger DE-627 rakwb eng Yan, Weiwei verfasserin (orcid)0009-0007-8744-3275 aut SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 Xie, Chengmei verfasserin aut Sun, Sijun verfasserin aut Zheng, Quan verfasserin (orcid)0000-0002-4512-9233 aut Wang, Jingyi verfasserin aut Wang, Zihao verfasserin (orcid)0009-0007-5065-8897 aut Man, Cheuk-Him verfasserin aut Wang, Haiyan verfasserin aut Yang, Yunfan verfasserin (orcid)0000-0002-5266-7208 aut Wang, Tianshi verfasserin (orcid)0000-0001-8676-0737 aut Shi, Leilei verfasserin aut Zhang, Shengjie verfasserin (orcid)0000-0003-4158-9010 aut Huang, Chen verfasserin (orcid)0009-0003-5547-5951 aut Xu, Shuangnian verfasserin (orcid)0000-0002-4041-9039 aut Wang, Yi-Ping verfasserin (orcid)0000-0002-3130-0386 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 12 vom: 22. Apr., Seite 2337-2367 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 https://dx.doi.org/10.1038/s44318-024-00101-9 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 AR 43 2024 12 22 04 2337-2367 |
allfields_unstemmed |
10.1038/s44318-024-00101-9 doi (DE-627)SPR05627646X (SPR)s44318-024-00101-9-e DE-627 ger DE-627 rakwb eng Yan, Weiwei verfasserin (orcid)0009-0007-8744-3275 aut SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 Xie, Chengmei verfasserin aut Sun, Sijun verfasserin aut Zheng, Quan verfasserin (orcid)0000-0002-4512-9233 aut Wang, Jingyi verfasserin aut Wang, Zihao verfasserin (orcid)0009-0007-5065-8897 aut Man, Cheuk-Him verfasserin aut Wang, Haiyan verfasserin aut Yang, Yunfan verfasserin (orcid)0000-0002-5266-7208 aut Wang, Tianshi verfasserin (orcid)0000-0001-8676-0737 aut Shi, Leilei verfasserin aut Zhang, Shengjie verfasserin (orcid)0000-0003-4158-9010 aut Huang, Chen verfasserin (orcid)0009-0003-5547-5951 aut Xu, Shuangnian verfasserin (orcid)0000-0002-4041-9039 aut Wang, Yi-Ping verfasserin (orcid)0000-0002-3130-0386 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 12 vom: 22. Apr., Seite 2337-2367 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 https://dx.doi.org/10.1038/s44318-024-00101-9 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 AR 43 2024 12 22 04 2337-2367 |
allfieldsGer |
10.1038/s44318-024-00101-9 doi (DE-627)SPR05627646X (SPR)s44318-024-00101-9-e DE-627 ger DE-627 rakwb eng Yan, Weiwei verfasserin (orcid)0009-0007-8744-3275 aut SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 Xie, Chengmei verfasserin aut Sun, Sijun verfasserin aut Zheng, Quan verfasserin (orcid)0000-0002-4512-9233 aut Wang, Jingyi verfasserin aut Wang, Zihao verfasserin (orcid)0009-0007-5065-8897 aut Man, Cheuk-Him verfasserin aut Wang, Haiyan verfasserin aut Yang, Yunfan verfasserin (orcid)0000-0002-5266-7208 aut Wang, Tianshi verfasserin (orcid)0000-0001-8676-0737 aut Shi, Leilei verfasserin aut Zhang, Shengjie verfasserin (orcid)0000-0003-4158-9010 aut Huang, Chen verfasserin (orcid)0009-0003-5547-5951 aut Xu, Shuangnian verfasserin (orcid)0000-0002-4041-9039 aut Wang, Yi-Ping verfasserin (orcid)0000-0002-3130-0386 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 12 vom: 22. Apr., Seite 2337-2367 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 https://dx.doi.org/10.1038/s44318-024-00101-9 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 AR 43 2024 12 22 04 2337-2367 |
allfieldsSound |
10.1038/s44318-024-00101-9 doi (DE-627)SPR05627646X (SPR)s44318-024-00101-9-e DE-627 ger DE-627 rakwb eng Yan, Weiwei verfasserin (orcid)0009-0007-8744-3275 aut SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 Xie, Chengmei verfasserin aut Sun, Sijun verfasserin aut Zheng, Quan verfasserin (orcid)0000-0002-4512-9233 aut Wang, Jingyi verfasserin aut Wang, Zihao verfasserin (orcid)0009-0007-5065-8897 aut Man, Cheuk-Him verfasserin aut Wang, Haiyan verfasserin aut Yang, Yunfan verfasserin (orcid)0000-0002-5266-7208 aut Wang, Tianshi verfasserin (orcid)0000-0001-8676-0737 aut Shi, Leilei verfasserin aut Zhang, Shengjie verfasserin (orcid)0000-0003-4158-9010 aut Huang, Chen verfasserin (orcid)0009-0003-5547-5951 aut Xu, Shuangnian verfasserin (orcid)0000-0002-4041-9039 aut Wang, Yi-Ping verfasserin (orcid)0000-0002-3130-0386 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2024), 12 vom: 22. Apr., Seite 2337-2367 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 https://dx.doi.org/10.1038/s44318-024-00101-9 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 AR 43 2024 12 22 04 2337-2367 |
language |
English |
source |
Enthalten in The EMBO Journal 43(2024), 12 vom: 22. Apr., Seite 2337-2367 volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 |
sourceStr |
Enthalten in The EMBO Journal 43(2024), 12 vom: 22. Apr., Seite 2337-2367 volume:43 year:2024 number:12 day:22 month:04 pages:2337-2367 |
format_phy_str_mv |
Article |
institution |
findex.gbv.de |
topic_facet |
FMS-like Tyrosine Kinase 3 Lysine Succinylation Mitochondrial Biogenesis Mitochondrial RNA Polymerase Succinate-CoA Ligase |
isfreeaccess_bool |
true |
container_title |
The EMBO Journal |
authorswithroles_txt_mv |
Yan, Weiwei @@aut@@ Xie, Chengmei @@aut@@ Sun, Sijun @@aut@@ Zheng, Quan @@aut@@ Wang, Jingyi @@aut@@ Wang, Zihao @@aut@@ Man, Cheuk-Him @@aut@@ Wang, Haiyan @@aut@@ Yang, Yunfan @@aut@@ Wang, Tianshi @@aut@@ Shi, Leilei @@aut@@ Zhang, Shengjie @@aut@@ Huang, Chen @@aut@@ Xu, Shuangnian @@aut@@ Wang, Yi-Ping @@aut@@ |
publishDateDaySort_date |
2024-04-22T00:00:00Z |
hierarchy_top_id |
266022529 |
id |
SPR05627646X |
language_de |
englisch |
fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR05627646X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240618064810.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240618s2024 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/s44318-024-00101-9</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR05627646X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s44318-024-00101-9-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Yan, Weiwei</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0007-8744-3275</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2024</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2024</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">FMS-like Tyrosine Kinase 3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Lysine Succinylation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mitochondrial Biogenesis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mitochondrial RNA Polymerase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Succinate-CoA Ligase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Xie, Chengmei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sun, Sijun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zheng, Quan</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-4512-9233</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Jingyi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Zihao</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0007-5065-8897</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Man, Cheuk-Him</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Haiyan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yang, Yunfan</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5266-7208</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Tianshi</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-8676-0737</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Shi, Leilei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhang, Shengjie</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-4158-9010</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huang, Chen</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0003-5547-5951</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Xu, Shuangnian</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-4041-9039</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Yi-Ping</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-3130-0386</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">43(2024), 12 vom: 22. Apr., Seite 2337-2367</subfield><subfield code="w">(DE-627)266022529</subfield><subfield code="w">(DE-600)1467419-1</subfield><subfield code="x">1460-2075</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:43</subfield><subfield code="g">year:2024</subfield><subfield code="g">number:12</subfield><subfield code="g">day:22</subfield><subfield code="g">month:04</subfield><subfield code="g">pages:2337-2367</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1038/s44318-024-00101-9</subfield><subfield code="m">X:SPRINGER</subfield><subfield code="x">Resolving-System</subfield><subfield code="z">kostenfrei</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_0</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_32</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_90</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_100</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_138</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_150</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_165</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_168</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_187</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_211</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_252</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_266</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_702</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2113</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2119</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2472</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">43</subfield><subfield code="j">2024</subfield><subfield code="e">12</subfield><subfield code="b">22</subfield><subfield code="c">04</subfield><subfield code="h">2337-2367</subfield></datafield></record></collection>
|
author |
Yan, Weiwei |
spellingShingle |
Yan, Weiwei misc FMS-like Tyrosine Kinase 3 misc Lysine Succinylation misc Mitochondrial Biogenesis misc Mitochondrial RNA Polymerase misc Succinate-CoA Ligase SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
authorStr |
Yan, Weiwei |
ppnlink_with_tag_str_mv |
@@773@@(DE-627)266022529 |
format |
electronic Article |
delete_txt_mv |
keep |
author_role |
aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut |
collection |
springer |
remote_str |
true |
illustrated |
Not Illustrated |
issn |
1460-2075 |
topic_title |
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression FMS-like Tyrosine Kinase 3 (dpeaa)DE-He213 Lysine Succinylation (dpeaa)DE-He213 Mitochondrial Biogenesis (dpeaa)DE-He213 Mitochondrial RNA Polymerase (dpeaa)DE-He213 Succinate-CoA Ligase (dpeaa)DE-He213 |
topic |
misc FMS-like Tyrosine Kinase 3 misc Lysine Succinylation misc Mitochondrial Biogenesis misc Mitochondrial RNA Polymerase misc Succinate-CoA Ligase |
topic_unstemmed |
misc FMS-like Tyrosine Kinase 3 misc Lysine Succinylation misc Mitochondrial Biogenesis misc Mitochondrial RNA Polymerase misc Succinate-CoA Ligase |
topic_browse |
misc FMS-like Tyrosine Kinase 3 misc Lysine Succinylation misc Mitochondrial Biogenesis misc Mitochondrial RNA Polymerase misc Succinate-CoA Ligase |
format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
format_main_str_mv |
Text Zeitschrift/Artikel |
carriertype_str_mv |
cr |
hierarchy_parent_title |
The EMBO Journal |
hierarchy_parent_id |
266022529 |
hierarchy_top_title |
The EMBO Journal |
isfreeaccess_txt |
true |
familylinks_str_mv |
(DE-627)266022529 (DE-600)1467419-1 |
title |
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
ctrlnum |
(DE-627)SPR05627646X (SPR)s44318-024-00101-9-e |
title_full |
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
author_sort |
Yan, Weiwei |
journal |
The EMBO Journal |
journalStr |
The EMBO Journal |
lang_code |
eng |
isOA_bool |
true |
recordtype |
marc |
publishDateSort |
2024 |
contenttype_str_mv |
txt |
container_start_page |
2337 |
author_browse |
Yan, Weiwei Xie, Chengmei Sun, Sijun Zheng, Quan Wang, Jingyi Wang, Zihao Man, Cheuk-Him Wang, Haiyan Yang, Yunfan Wang, Tianshi Shi, Leilei Zhang, Shengjie Huang, Chen Xu, Shuangnian Wang, Yi-Ping |
container_volume |
43 |
format_se |
Elektronische Aufsätze |
author-letter |
Yan, Weiwei |
doi_str_mv |
10.1038/s44318-024-00101-9 |
normlink |
(ORCID)0009-0007-8744-3275 (ORCID)0000-0002-4512-9233 (ORCID)0009-0007-5065-8897 (ORCID)0000-0002-5266-7208 (ORCID)0000-0001-8676-0737 (ORCID)0000-0003-4158-9010 (ORCID)0009-0003-5547-5951 (ORCID)0000-0002-4041-9039 (ORCID)0000-0002-3130-0386 |
normlink_prefix_str_mv |
(orcid)0009-0007-8744-3275 (orcid)0000-0002-4512-9233 (orcid)0009-0007-5065-8897 (orcid)0000-0002-5266-7208 (orcid)0000-0001-8676-0737 (orcid)0000-0003-4158-9010 (orcid)0009-0003-5547-5951 (orcid)0000-0002-4041-9039 (orcid)0000-0002-3130-0386 |
author2-role |
verfasserin |
title_sort |
suclg1 restricts polrmt succinylation to enhance mitochondrial biogenesis and leukemia progression |
title_auth |
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
abstract |
Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. © The Author(s) 2024 |
abstractGer |
Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. © The Author(s) 2024 |
abstract_unstemmed |
Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development. Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models. Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer. © The Author(s) 2024 |
collection_details |
SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2005 GBV_ILN_2010 GBV_ILN_2014 GBV_ILN_2021 GBV_ILN_2037 GBV_ILN_2059 GBV_ILN_2064 GBV_ILN_2108 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2336 GBV_ILN_2472 GBV_ILN_4035 GBV_ILN_4125 GBV_ILN_4246 GBV_ILN_4307 GBV_ILN_4323 |
container_issue |
12 |
title_short |
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression |
url |
https://dx.doi.org/10.1038/s44318-024-00101-9 |
remote_bool |
true |
author2 |
Xie, Chengmei Sun, Sijun Zheng, Quan Wang, Jingyi Wang, Zihao Man, Cheuk-Him Wang, Haiyan Yang, Yunfan Wang, Tianshi Shi, Leilei Zhang, Shengjie Huang, Chen Xu, Shuangnian Wang, Yi-Ping |
author2Str |
Xie, Chengmei Sun, Sijun Zheng, Quan Wang, Jingyi Wang, Zihao Man, Cheuk-Him Wang, Haiyan Yang, Yunfan Wang, Tianshi Shi, Leilei Zhang, Shengjie Huang, Chen Xu, Shuangnian Wang, Yi-Ping |
ppnlink |
266022529 |
mediatype_str_mv |
c |
isOA_txt |
true |
hochschulschrift_bool |
false |
doi_str |
10.1038/s44318-024-00101-9 |
up_date |
2024-07-03T21:20:31.074Z |
_version_ |
1803594373348196352 |
fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR05627646X</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240618064810.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240618s2024 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/s44318-024-00101-9</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR05627646X</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s44318-024-00101-9-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Yan, Weiwei</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0007-8744-3275</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2024</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2024</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Whether mitochondrial DNA function is affected by cellular metabolism remains poorly understood. Here, the Krebs cycle enzyme succinate-CoA ligase (SUCLG1) is shown to restrict succinylation of mitochondrial RNA polymerase (POLRMT) and thereby sustain mitochondrial transcription. This mechanism is relevant for mutant FLT3-driven leukemogenesis. SUCLG1 reduces succinyl-CoA levels to restrict POLRMT succinylation.K622 succinylation suppresses POLRMT activity.FLT3 mutations regulate SUCLG1 to activate POLRMT.Mutant FLT3 alters nuclear transcription to remodel mitochondrial biogenesis.Genetic depletion of POLRMT or SUCLG1 delays leukemia progression in mice and humanized models.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Krebs cycle succinate-CoA ligase targets mitochondrial RNA polymerase and mtDNA transcription supporting mutant FLT3-driven blood cancer.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">FMS-like Tyrosine Kinase 3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Lysine Succinylation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mitochondrial Biogenesis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Mitochondrial RNA Polymerase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Succinate-CoA Ligase</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Xie, Chengmei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sun, Sijun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zheng, Quan</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-4512-9233</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Jingyi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Zihao</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0007-5065-8897</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Man, Cheuk-Him</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Haiyan</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yang, Yunfan</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-5266-7208</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Tianshi</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-8676-0737</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Shi, Leilei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhang, Shengjie</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-4158-9010</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huang, Chen</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0009-0003-5547-5951</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Xu, Shuangnian</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-4041-9039</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wang, Yi-Ping</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-3130-0386</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">43(2024), 12 vom: 22. Apr., Seite 2337-2367</subfield><subfield code="w">(DE-627)266022529</subfield><subfield code="w">(DE-600)1467419-1</subfield><subfield code="x">1460-2075</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:43</subfield><subfield code="g">year:2024</subfield><subfield code="g">number:12</subfield><subfield code="g">day:22</subfield><subfield code="g">month:04</subfield><subfield code="g">pages:2337-2367</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1038/s44318-024-00101-9</subfield><subfield code="m">X:SPRINGER</subfield><subfield code="x">Resolving-System</subfield><subfield code="z">kostenfrei</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_0</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_20</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_22</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_23</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_24</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_31</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_32</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_39</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_62</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_63</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_65</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_69</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_70</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_73</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_74</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_90</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_95</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_100</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_101</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_105</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_110</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_120</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_138</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_150</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_151</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_161</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_165</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_168</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_170</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_187</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_211</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_213</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_230</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_252</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_266</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_285</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_293</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_602</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_702</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2005</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2010</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2014</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2021</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2037</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2059</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2064</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2108</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2113</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2118</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2119</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2122</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2143</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2152</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2153</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2336</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_2472</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4035</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4125</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4246</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4307</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_4323</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">43</subfield><subfield code="j">2024</subfield><subfield code="e">12</subfield><subfield code="b">22</subfield><subfield code="c">04</subfield><subfield code="h">2337-2367</subfield></datafield></record></collection>
|
score |
7.3985167 |