Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improve...
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Autor*in:	Jessica Panes [verfasserIn] Thi Kim Oanh Nguyen [verfasserIn] Huanyao Gao [verfasserIn] Trace A. Christensen [verfasserIn] Andrea Stojakovic [verfasserIn] Sergey Trushin [verfasserIn] Jeffrey L. Salisbury [verfasserIn] Jorge Fuentealba [verfasserIn] Eugenia Trushina [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics

Übergeordnetes Werk:	In: Cells - MDPI AG, 2012, 12(2023), 8, p 1111
Übergeordnetes Werk:	volume:12 ; year:2023 ; number:8, p 1111

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cells12081111

Katalog-ID:	DOAJ089885589

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allfields	10.3390/cells12081111 doi (DE-627)DOAJ089885589 (DE-599)DOAJ2f0ee5c85b0d48ab8791c7aedf5023f2 DE-627 ger DE-627 rakwb eng QH573-671 Jessica Panes verfasserin aut Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD. Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics Cytology Thi Kim Oanh Nguyen verfasserin aut Huanyao Gao verfasserin aut Trace A. Christensen verfasserin aut Andrea Stojakovic verfasserin aut Sergey Trushin verfasserin aut Jeffrey L. Salisbury verfasserin aut Jorge Fuentealba verfasserin aut Eugenia Trushina verfasserin aut In Cells MDPI AG, 2012 12(2023), 8, p 1111 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:12 year:2023 number:8, p 1111 https://doi.org/10.3390/cells12081111 kostenfrei https://doaj.org/article/2f0ee5c85b0d48ab8791c7aedf5023f2 kostenfrei https://www.mdpi.com/2073-4409/12/8/1111 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023 8, p 1111
spelling	10.3390/cells12081111 doi (DE-627)DOAJ089885589 (DE-599)DOAJ2f0ee5c85b0d48ab8791c7aedf5023f2 DE-627 ger DE-627 rakwb eng QH573-671 Jessica Panes verfasserin aut Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD. Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics Cytology Thi Kim Oanh Nguyen verfasserin aut Huanyao Gao verfasserin aut Trace A. Christensen verfasserin aut Andrea Stojakovic verfasserin aut Sergey Trushin verfasserin aut Jeffrey L. Salisbury verfasserin aut Jorge Fuentealba verfasserin aut Eugenia Trushina verfasserin aut In Cells MDPI AG, 2012 12(2023), 8, p 1111 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:12 year:2023 number:8, p 1111 https://doi.org/10.3390/cells12081111 kostenfrei https://doaj.org/article/2f0ee5c85b0d48ab8791c7aedf5023f2 kostenfrei https://www.mdpi.com/2073-4409/12/8/1111 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023 8, p 1111
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allfieldsSound	10.3390/cells12081111 doi (DE-627)DOAJ089885589 (DE-599)DOAJ2f0ee5c85b0d48ab8791c7aedf5023f2 DE-627 ger DE-627 rakwb eng QH573-671 Jessica Panes verfasserin aut Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD. Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics Cytology Thi Kim Oanh Nguyen verfasserin aut Huanyao Gao verfasserin aut Trace A. Christensen verfasserin aut Andrea Stojakovic verfasserin aut Sergey Trushin verfasserin aut Jeffrey L. Salisbury verfasserin aut Jorge Fuentealba verfasserin aut Eugenia Trushina verfasserin aut In Cells MDPI AG, 2012 12(2023), 8, p 1111 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:12 year:2023 number:8, p 1111 https://doi.org/10.3390/cells12081111 kostenfrei https://doaj.org/article/2f0ee5c85b0d48ab8791c7aedf5023f2 kostenfrei https://www.mdpi.com/2073-4409/12/8/1111 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2023 8, p 1111
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topic_facet	Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics Cytology
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callnumber-first	Q - Science
author	Jessica Panes
spellingShingle	Jessica Panes misc QH573-671 misc Alzheimer’s disease (AD) misc mitochondria misc endoplasmic reticulum (ER) misc serial block-face scanning electron microscopy (SBFSEM) misc three-dimensional electron microscopy (3DEM) misc small molecule mitochondria targeted therapeutics misc Cytology Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice
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topic_title	QH573-671 Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice Alzheimer’s disease (AD) mitochondria endoplasmic reticulum (ER) serial block-face scanning electron microscopy (SBFSEM) three-dimensional electron microscopy (3DEM) small molecule mitochondria targeted therapeutics
topic	misc QH573-671 misc Alzheimer’s disease (AD) misc mitochondria misc endoplasmic reticulum (ER) misc serial block-face scanning electron microscopy (SBFSEM) misc three-dimensional electron microscopy (3DEM) misc small molecule mitochondria targeted therapeutics misc Cytology
topic_unstemmed	misc QH573-671 misc Alzheimer’s disease (AD) misc mitochondria misc endoplasmic reticulum (ER) misc serial block-face scanning electron microscopy (SBFSEM) misc three-dimensional electron microscopy (3DEM) misc small molecule mitochondria targeted therapeutics misc Cytology
topic_browse	misc QH573-671 misc Alzheimer’s disease (AD) misc mitochondria misc endoplasmic reticulum (ER) misc serial block-face scanning electron microscopy (SBFSEM) misc three-dimensional electron microscopy (3DEM) misc small molecule mitochondria targeted therapeutics misc Cytology
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title	Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice
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title_full	Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice
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author_browse	Jessica Panes Thi Kim Oanh Nguyen Huanyao Gao Trace A. Christensen Andrea Stojakovic Sergey Trushin Jeffrey L. Salisbury Jorge Fuentealba Eugenia Trushina
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title_sort	partial inhibition of complex i restores mitochondrial morphology and mitochondria-er communication in hippocampus of app/ps1 mice
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title_auth	Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice
abstract	Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.
abstractGer	Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.
abstract_unstemmed	Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.
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title_short	Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice
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Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. 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Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

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