{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:19:29Z","timestamp":1791980369233,"version":"4.4.0"},"reference-count":101,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,8]],"date-time":"2023-04-08T00:00:00Z","timestamp":1680912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG55549"],"award-info":[{"award-number":["RF1AG55549"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS107265"],"award-info":[{"award-number":["R01NS107265"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1AG062135"],"award-info":[{"award-number":["RO1AG062135"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG59093"],"award-info":[{"award-number":["AG59093"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG072898"],"award-info":[{"award-number":["AG072898"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG3\/UH3NS 113776"],"award-info":[{"award-number":["UG3\/UH3NS 113776"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1200908"],"award-info":[{"award-number":["1200908"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["21141247"],"award-info":[{"award-number":["21141247"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["RF1AG55549"],"award-info":[{"award-number":["RF1AG55549"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["R01NS107265"],"award-info":[{"award-number":["R01NS107265"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["RO1AG062135"],"award-info":[{"award-number":["RO1AG062135"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["AG59093"],"award-info":[{"award-number":["AG59093"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["AG072898"],"award-info":[{"award-number":["AG072898"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["UG3\/UH3NS 113776"],"award-info":[{"award-number":["UG3\/UH3NS 113776"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["1200908"],"award-info":[{"award-number":["1200908"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["21141247"],"award-info":[{"award-number":["21141247"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["RF1AG55549"],"award-info":[{"award-number":["RF1AG55549"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["R01NS107265"],"award-info":[{"award-number":["R01NS107265"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["RO1AG062135"],"award-info":[{"award-number":["RO1AG062135"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["AG59093"],"award-info":[{"award-number":["AG59093"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["AG072898"],"award-info":[{"award-number":["AG072898"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["UG3\/UH3NS 113776"],"award-info":[{"award-number":["UG3\/UH3NS 113776"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["1200908"],"award-info":[{"award-number":["1200908"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002848","name":"ANID scholarship","doi-asserted-by":"publisher","award":["21141247"],"award-info":[{"award-number":["21141247"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s 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, A\u03b2 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 A\u03b2 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.<\/jats:p>","DOI":"10.3390\/cells12081111","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T03:15:57Z","timestamp":1681096557000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP\/PS1 Mice"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5501-6582","authenticated-orcid":false,"given":"Jessica","family":"Panes","sequence":"first","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Physiology, Universidad de Concepcion, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6068-6222","authenticated-orcid":false,"given":"Thi Kim Oanh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9441-9579","authenticated-orcid":false,"given":"Huanyao","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trace A.","family":"Christensen","sequence":"additional","affiliation":[{"name":"Microscopy and Cell Analysis Core Facility, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Stojakovic","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Trushin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Salisbury","sequence":"additional","affiliation":[{"name":"Microscopy and Cell Analysis Core Facility, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Fuentealba","sequence":"additional","affiliation":[{"name":"Department of Physiology, Universidad de Concepcion, Concepci\u00f3n 4030000, Chile"},{"name":"Centro de Investigaciones Avanzadas en Biomedicina (CIAB-UdeC), Universidad de Concepci\u00f3n, Concepci\u00f3n 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Trushina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA"},{"name":"Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/s41593-020-0599-5","article-title":"The multiplex model of the genetics of Alzheimer\u2019s disease","volume":"23","author":"Sims","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5781","DOI":"10.1038\/s41467-020-19622-y","article-title":"Molecular estimation of neurodegeneration pseudotime in older brains","volume":"11","author":"Mukherjee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1016\/j.drudis.2021.04.025","article-title":"Mitochondrial dysfunction: A potential target for Alzheimer\u2019s disease intervention and treatment","volume":"26","author":"Ke","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1474-4422(18)30028-0","article-title":"Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer\u2019s disease: A longitudinal study","volume":"17","author":"Gordon","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s00259-008-1039-z","article-title":"FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer\u2019s disease","volume":"36","author":"Mosconi","year":"2009","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.mcn.2019.06.009","article-title":"Mitochondrial dynamics and transport in Alzheimer\u2019s disease","volume":"98","author":"Flannery","year":"2019","journal-title":"Mol. Cell Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1007\/s40473-019-00179-0","article-title":"Mitochondrial Dysfunction in Alzheimer\u2019s Disease and Progress in Mitochondria-Targeted Therapeutics","volume":"6","author":"Flannery","year":"2019","journal-title":"Curr. Behav. Neurosci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41593-021-00999-y","article-title":"Large-scale deep multi-layer analysis of Alzheimer\u2019s disease brain reveals strong proteomic disease-related changes not observed at the RNA level","volume":"25","author":"Johnson","year":"2022","journal-title":"Nat. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.3233\/JAD-215139","article-title":"Synaptic Mitochondria: An Early Target of Amyloid-beta and Tau in Alzheimer\u2019s Disease","volume":"84","author":"Torres","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113321","DOI":"10.1016\/j.expneurol.2020.113321","article-title":"Mitochondria in Alzheimer\u2019s disease and their potential role in Alzheimer\u2019s proteostasis","volume":"330","author":"Weidling","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.3233\/JAD-170585","article-title":"Mitochondria and Mitochondrial Cascades in Alzheimer\u2019s Disease","volume":"62","author":"Swerdlow","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-020-00376-6","article-title":"Mitochondria dysfunction in the pathogenesis of Alzheimer\u2019s disease: Recent advances","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1089\/ars.2011.4149","article-title":"Mitochondria and cell bioenergetics: Increasingly recognized components and a possible etiologic cause of Alzheimer\u2019s disease","volume":"16","author":"Swerdlow","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"591","DOI":"10.3233\/JAD-221177","article-title":"Mitochondria Profoundly Influence Apolipoprotein E Biology","volume":"92","author":"Gabrielli","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3233\/JAD-200286","article-title":"Mitochondrial DNA Manipulations Affect Tau Oligomerization","volume":"77","author":"Weidling","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102651","DOI":"10.1016\/j.conb.2022.102651","article-title":"Amyloid precursor protein and mitochondria","volume":"78","author":"Strope","year":"2023","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cmet.2015.05.013","article-title":"Evolution of Mitochondria as Signaling Organelles","volume":"22","author":"Chandel","year":"2015","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4578809","DOI":"10.1155\/2021\/4578809","article-title":"Structure and Function of Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Role in Cardiovascular Diseases","volume":"2021","author":"Luan","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1083\/jcb.2.4.73","article-title":"Close topographical relationship between mitochondria and ergastoplasm of liver cells in a definite phase of cellular activity","volume":"2","author":"Bernhard","year":"1956","journal-title":"J. Biophys. Biochem. Cytol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102343","DOI":"10.1016\/j.ceca.2020.102343","article-title":"Mitochondria Associated Membranes (MAMs): Architecture and physiopathological role","volume":"94","author":"Barazzuol","year":"2021","journal-title":"Cell Calcium"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1038\/emboj.2012.202","article-title":"Upregulated function of mitochondria-associated ER membranes in Alzheimer disease","volume":"31","author":"Tambini","year":"2012","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"158489","DOI":"10.1016\/j.bbalip.2019.06.015","article-title":"The role of ceramide in regulating endoplasmic reticulum function","volume":"1865","author":"Zelnik","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"537","DOI":"10.3233\/JAD-2011-111202","article-title":"Increased ceramide in brains with Alzheimer\u2019s and other neurodegenerative diseases","volume":"29","author":"Filippov","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Custodia, A., Romaus-Sanjurjo, D., Aramburu-Nunez, M., Alvarez-Rafael, D., Vazquez-Vazquez, L., Camino-Castineiras, J., Leira, Y., Pias-Peleteiro, J.M., Aldrey, J.M., and Sobrino, T. (2022). Ceramide\/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer\u2019s Disease and Other Neurodegenerative Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158082"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.brainresrev.2010.11.004","article-title":"Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases","volume":"67","author":"Reddy","year":"2011","journal-title":"Brain Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"900","DOI":"10.4103\/1673-5374.184477","article-title":"A shape shifting organelle: Unusual mitochondrial phenotype determined with three-dimensional electron microscopy reconstruction","volume":"11","author":"Trushina","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Trushina, E., Nemutlu, E., Zhang, S., Christensen, T., Camp, J., Mesa, J., Siddiqui, A., Tamura, Y., Sesaki, H., and Wengenack, T.M. (2012). Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer\u2019s Disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032737"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"18725","DOI":"10.1038\/srep18725","article-title":"Altered brain energetics induces mitochondrial fission arrest in Alzheimer\u2019s Disease","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.neurobiolaging.2016.12.001","article-title":"Ultrastructural evidence for impaired mitochondrial fission in the aged rhesus monkey dorsolateral prefrontal cortex","volume":"51","author":"Morozov","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"jcs221028","DOI":"10.1242\/jcs.221028","article-title":"Elongated mitochondrial constrictions and fission in muscle fatigue","volume":"131","author":"Lavorato","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5517","DOI":"10.1093\/cercor\/bhaa134","article-title":"Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema","volume":"30","author":"Kirov","year":"2020","journal-title":"Cereb. Cortex"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nature12985","article-title":"Mitochondrial form and function","volume":"505","author":"Friedman","year":"2014","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ebiom.2015.03.009","article-title":"Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer\u2019s Disease","volume":"2","author":"Zhang","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s42003-020-01584-y","article-title":"Partial inhibition of mitochondrial complex I ameliorates Alzheimer\u2019s disease pathology and cognition in APP\/PS1 female mice","volume":"4","author":"Stojakovic","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.ebiom.2019.03.062","article-title":"Corrigendum to \u201cModulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer\u2019s disease\u201d [EBioMedicine 2 (2015) 294-305]","volume":"42","author":"Zhang","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gao, H., Tripathi, U., Trushin, S., Okromelidze, L., Pichurin, N.P., Wei, L., Zhuang, Y., Wang, L., and Trushina, E. (Mitochondrion, 2021). A Genome-Wide Association Study in Human Lymphoblastoid Cells Supports Safety of Mitochondrial Complex I Inhibitor, Mitochondrion, in press.","DOI":"10.1016\/j.mito.2021.02.005"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3233\/JAD-201015","article-title":"Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice","volume":"79","author":"Stojakovic","year":"2021","journal-title":"J. Alzheimers Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/s41586-021-04059-0","article-title":"Disruption of mitochondrial complex I induces progressive parkinsonism","volume":"599","author":"Zampese","year":"2021","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41583-023-00676-y","article-title":"Mitochondrial complex I deficiency and Parkinson disease","volume":"24","year":"2023","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_40","first-page":"45","article-title":"Mitochondria and Parkinson\u2019s Disease: Clinical, Molecular, and Translational Aspects","volume":"11","author":"Borsche","year":"2021","journal-title":"J. Park. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2617","DOI":"10.1016\/j.neurobiolaging.2015.05.008","article-title":"Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo","volume":"36","author":"Kim","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14D","DOI":"10.1016\/j.amjcard.2008.02.003","article-title":"Why have antioxidants failed in clinical trials?","volume":"101","author":"Steinhubl","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"326rv323","DOI":"10.1126\/scitranslmed.aac7410","article-title":"Novel targets for mitochondrial medicine","volume":"8","author":"Wang","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.apsb.2021.11.003","article-title":"Mitochondrial complex I as a therapeutic target for Alzheimer\u2019s disease","volume":"12","author":"Trushina","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1056\/NEJMra1905136","article-title":"Effects of Intermittent Fasting on Health, Aging, and Disease","volume":"381","author":"Mattson","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1039\/C9FO02611H","article-title":"The effects of caloric restriction and its mimetics in Alzheimer\u2019s disease through autophagy pathways","volume":"11","author":"Yang","year":"2020","journal-title":"Food Funct."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.aax3768","article-title":"Mitocellular communication: Shaping health and disease","volume":"366","author":"Mottis","year":"2019","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fnins.2020.00131","article-title":"Relationship Between Exercise and Alzheimer\u2019s Disease: A Narrative Literature Review","volume":"14","author":"Meng","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nm0198-097","article-title":"Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes","volume":"4","author":"Holcomb","year":"1998","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Hinton, A., Katti, P., Christensen, T.A., Mungai, M., Shao, J., Zhang, L., Trushin, S., Alghanem, A., Jaspersen, A., and Geroux, R.E. (2021). A comprehensive approach to artifact-free sample preparation and the assessment of mitochondrial morphology in tissue and cultured cells. bioRxiv.","DOI":"10.1101\/2021.06.27.450055"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Deerinck, T.J., Bushong, E.A., Ellisman, M., and Thor, A. (2022). Preparation of Biological Tissues for Serial Block Face Scanning Electron Microscopy (SBEM) v2. protocols.io, University of California.","DOI":"10.17504\/protocols.io.36wgq7je5vk5\/v2"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/j.1365-2818.2005.01466.x","article-title":"Reconstruct: A free editor for serial section microscopy","volume":"218","author":"Fiala","year":"2005","journal-title":"J. Microsc."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Garza-Lopez, E., Vue, Z., Katti, P., Neikirk, K., Biete, M., Lam, J., Beasley, H.K., Marshall, A.G., Rodman, T.A., and Christensen, T.A. (2021). Protocols for Generating Surfaces and Measuring 3D Organelle Morphology Using Amira. Cells, 11.","DOI":"10.3390\/cells11010065"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/nprot.2009.151","article-title":"Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells","volume":"4","author":"Wieckowski","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s13205-022-03123-4","article-title":"Hippocampus and its involvement in Alzheimer\u2019s disease: A review","volume":"12","author":"Rao","year":"2022","journal-title":"3 Biotech"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"109509","DOI":"10.1016\/j.celrep.2021.109509","article-title":"3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus","volume":"36","author":"Faitg","year":"2021","journal-title":"Cell Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3233\/JAD-132543","article-title":"Amyloid-beta peptides are generated in mitochondria-associated endoplasmic reticulum membranes","volume":"43","author":"Schreiner","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41419-017-0215-0","article-title":"A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease","volume":"9","author":"Bonilla","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1042\/CS20200844","article-title":"Mitochondria-associated membranes (MAMs): A potential therapeutic target for treating Alzheimer\u2019s disease","volume":"135","author":"Yu","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1091\/mbc.e09-09-0818","article-title":"Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function","volume":"21","author":"Kong","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4081","DOI":"10.1111\/febs.15700","article-title":"NUPR1 interacts with eIF2alpha and is required for resolution of the ER stress response in pancreatic tissue","volume":"288","author":"Borrello","year":"2021","journal-title":"FEBS J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41467-021-20904-2","article-title":"NUPR1 is a critical repressor of ferroptosis","volume":"12","author":"Liu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Yang, L., and Nao, J. (2022). Ferroptosis: A potential therapeutic target for Alzheimer\u2019s disease. Rev. Neurosci., online.","DOI":"10.1515\/revneuro-2022-0121"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"15953","DOI":"10.1021\/bi002189x","article-title":"Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state","volume":"39","author":"Poon","year":"2000","journal-title":"Biochemistry"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2789","DOI":"10.1046\/j.1432-1033.2002.02957.x","article-title":"Suppression of apolipoprotein C-II amyloid formation by the extracellular chaperone, clusterin","volume":"269","author":"Hatters","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1158\/1541-7786.MCR-09-0277","article-title":"Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells","volume":"8","author":"Zoubeidi","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/ncb1291","article-title":"Clusterin inhibits apoptosis by interacting with activated Bax","volume":"7","author":"Zhang","year":"2005","journal-title":"Nat. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1038\/onc.2012.212","article-title":"GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer","volume":"32","author":"Li","year":"2013","journal-title":"Oncogene"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4407","DOI":"10.1021\/bi401621d","article-title":"ATP allosterically activates the human 5-lipoxygenase molecular mechanism of arachidonic acid and 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid","volume":"53","author":"Smyrniotis","year":"2014","journal-title":"Biochemistry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1172\/JCI42545","article-title":"Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation","volume":"121","author":"Oh","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.immuni.2015.02.013","article-title":"Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals","volume":"42","author":"Lee","year":"2015","journal-title":"Immunity"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4284","DOI":"10.4049\/jimmunol.1200704","article-title":"The unique cytoplasmic domain of human FcgammaRIIIA regulates receptor-mediated function","volume":"189","author":"Li","year":"2012","journal-title":"J. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1016\/j.febslet.2006.09.007","article-title":"WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum","volume":"580","author":"Takei","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/s41419-022-04522-4","article-title":"Glucose-regulated protein 78 modulates cell growth, epithelial-mesenchymal transition, and oxidative stress in the hyperplastic prostate","volume":"13","author":"Fu","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1074\/jbc.M708169200","article-title":"Thioredoxin-interacting protein (Txnip) is a critical regulator of hepatic glucose production","volume":"283","author":"Chutkow","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1097\/CM9.0000000000001091","article-title":"Critical hubs of renal ischemia-reperfusion injury: Endoplasmic reticulum-mitochondria tethering complexes","volume":"133","author":"Zhao","year":"2020","journal-title":"Chin. Med. J."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Bogar, F., Fulop, L., and Penke, B. (2022). Novel Therapeutic Target for Prevention of Neurodegenerative Diseases: Modulation of Neuroinflammation with Sig-1R Ligands. Biomolecules, 12.","DOI":"10.3390\/biom12030363"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"105104","DOI":"10.1016\/j.neuint.2021.105104","article-title":"ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer\u2019s disease","volume":"148","author":"Ismael","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1038\/tp.2012.45","article-title":"Genome-wide association study of Alzheimer\u2019s disease","volume":"2","author":"Kamboh","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cmet.2020.04.001","article-title":"Benefits of Metformin in Attenuating the Hallmarks of Aging","volume":"32","author":"Kulkarni","year":"2020","journal-title":"Cell Metab."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.celrep.2019.09.070","article-title":"Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK","volume":"29","author":"Wang","year":"2019","journal-title":"Cell Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fendo.2018.00400","article-title":"The Therapeutic Potential of Metformin in Neurodegenerative Diseases","volume":"9","author":"Rotermund","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.nbd.2017.06.009","article-title":"Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant alpha-synuclein rat model of parkinsonism","volume":"106","author":"Gleave","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cmet.2015.10.013","article-title":"Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges","volume":"23","author":"Cheng","year":"2016","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/s41580-020-0210-7","article-title":"The cell biology of mitochondrial membrane dynamics","volume":"21","author":"Giacomello","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1523\/JNEUROSCI.1510-16.2016","article-title":"Reversible Disruption of Neuronal Mitochondria by Ischemic and Traumatic Injury Revealed by Quantitative Two-Photon Imaging in the Neocortex of Anesthetized Mice","volume":"37","author":"Kislin","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1038\/s42003-021-02840-5","article-title":"Cellular senescence links mitochondria-ER contacts and aging","volume":"4","author":"Ziegler","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cels.2016.01.014","article-title":"Longitudinal RNA-Seq Analysis of Vertebrate Aging Identifies Mitochondrial Complex I as a Small-Molecule-Sensitive Modifier of Lifespan","volume":"2","author":"Baumgart","year":"2016","journal-title":"Cell Syst."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Madrigal-Perez, L.A., and Ramos-Gomez, M. (2016). Resveratrol Inhibition of Cellular Respiration: New Paradigm for an Old Mechanism. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030368"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"480","DOI":"10.14336\/AD.2020.0702","article-title":"Metformin: A Potential Candidate for Targeting Aging Mechanisms","volume":"12","author":"Hu","year":"2021","journal-title":"Aging Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1007\/s11357-012-9489-4","article-title":"Dietary resveratrol prevents Alzheimer\u2019s markers and increases life span in SAMP8","volume":"35","author":"Porquet","year":"2013","journal-title":"Age"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"946678","DOI":"10.3389\/fcell.2022.946678","article-title":"The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells","volume":"10","author":"Liabeuf","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41419-022-05153-5","article-title":"ER stress and UPR in Alzheimer\u2019s disease: Mechanisms, pathogenesis, treatments","volume":"13","author":"Ajoolabady","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9100","DOI":"10.1074\/jbc.M109.060061","article-title":"AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism","volume":"285","author":"Vingtdeux","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.isci.2018.10.006","article-title":"AMP-Activated Protein Kinase Is Essential for the Maintenance of Energy Levels during Synaptic Activation","volume":"9","author":"Marinangeli","year":"2018","journal-title":"iScience"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1096\/fj.10-167361","article-title":"Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation","volume":"25","author":"Vingtdeux","year":"2011","journal-title":"FASEB J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ijdevneu.2019.01.007","article-title":"Involvement of AMP-activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain","volume":"77","author":"Saito","year":"2019","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1126\/scisignal.aav3249","article-title":"AMPK directly activates mTORC2 to promote cell survival during acute energetic stress","volume":"12","author":"Kazyken","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1080\/15548627.2020.1749490","article-title":"The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses","volume":"17","author":"Hu","year":"2021","journal-title":"Autophagy"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"9895121","DOI":"10.1155\/2020\/9895121","article-title":"The Bewildering Effect of AMPK Activators in Alzheimer\u2019s Disease: Review of the Current Evidence","volume":"2020","author":"Assefa","year":"2020","journal-title":"Biomed. Res. Int."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1111\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:12:29Z","timestamp":1760123549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/8\/1111"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,8]]},"references-count":101,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["cells12081111"],"URL":"https:\/\/doi.org\/10.3390\/cells12081111","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,8]]}}}