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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/12/8/1111 |
| _version_ | 1797605979470168064 |
|---|---|
| author | Jessica Panes Thi Kim Oanh Nguyen Huanyao Gao Trace A. Christensen Andrea Stojakovic Sergey Trushin Jeffrey L. Salisbury Jorge Fuentealba Eugenia Trushina |
| author_facet | Jessica Panes Thi Kim Oanh Nguyen Huanyao Gao Trace A. Christensen Andrea Stojakovic Sergey Trushin Jeffrey L. Salisbury Jorge Fuentealba Eugenia Trushina |
| author_sort | Jessica Panes |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T05:08:49Z |
| format | Article |
| id | doaj.art-2f0ee5c85b0d48ab8791c7aedf5023f2 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T05:08:49Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-2f0ee5c85b0d48ab8791c7aedf5023f22023-11-17T18:42:41ZengMDPI AGCells2073-44092023-04-01128111110.3390/cells12081111Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 MiceJessica Panes0Thi Kim Oanh Nguyen1Huanyao Gao2Trace A. Christensen3Andrea Stojakovic4Sergey Trushin5Jeffrey L. Salisbury6Jorge Fuentealba7Eugenia Trushina8Department of Neurology, Mayo Clinic, Rochester, MN 55905, USADepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USADepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USAMicroscopy and Cell Analysis Core Facility, Mayo Clinic, Rochester, MN 55905, USADepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USADepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USAMicroscopy and Cell Analysis Core Facility, Mayo Clinic, Rochester, MN 55905, USADepartment of Physiology, Universidad de Concepcion, Concepción 4030000, ChileDepartment of Neurology, Mayo Clinic, Rochester, MN 55905, USAAlzheimer’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.https://www.mdpi.com/2073-4409/12/8/1111Alzheimer’s disease (AD)mitochondriaendoplasmic reticulum (ER)serial block-face scanning electron microscopy (SBFSEM)three-dimensional electron microscopy (3DEM)small molecule mitochondria targeted therapeutics |
| spellingShingle | Jessica Panes Thi Kim Oanh Nguyen Huanyao Gao Trace A. Christensen Andrea Stojakovic Sergey Trushin Jeffrey L. Salisbury Jorge Fuentealba Eugenia Trushina Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice Cells 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 |
| title | Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice |
| title_full | Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice |
| title_fullStr | Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice |
| title_full_unstemmed | Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice |
| title_short | Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice |
| title_sort | partial inhibition of complex i restores mitochondrial morphology and mitochondria er communication in hippocampus of app ps1 mice |
| topic | 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 |
| url | https://www.mdpi.com/2073-4409/12/8/1111 |
| work_keys_str_mv | AT jessicapanes partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT thikimoanhnguyen partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT huanyaogao partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT traceachristensen partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT andreastojakovic partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT sergeytrushin partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT jeffreylsalisbury partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT jorgefuentealba partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice AT eugeniatrushina partialinhibitionofcomplexirestoresmitochondrialmorphologyandmitochondriaercommunicationinhippocampusofappps1mice |