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In this study, we identified an interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein phosphatase. We confirmed their endogenous interaction in mouse brain tissue and determined that APP and PGAM5 are both present at mitochondria-ER contact sites (MERCS) and. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane and regulates mitochondrial respiration and stress responses. We found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Accordingly, mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain (ETC) function. Together, these findings suggest that APP supports mitochondrial respiration by binding to PGAM5 and modulating Keap1-Nrf2 signaling.<\/jats:p>","DOI":"10.64898\/2026.01.20.700642","type":"posted-content","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:00:11Z","timestamp":1769000411000},"source":"Crossref","is-referenced-by-count":0,"title":["Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration"],"prefix":"10.64898","author":[{"given":"Kriti","family":"Shukla","sequence":"first","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73072, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kendra S.","family":"Plafker","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casandra","family":"Salinas-Salinas","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvonne","family":"Thomason","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samah","family":"Houmam","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"},{"name":"Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dylan","family":"Barber","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Neuroscience Program, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Faakye","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth M.","family":"Humphries","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott M.","family":"Plafker","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather C.","family":"Rice","sequence":"additional","affiliation":[{"name":"Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA"},{"name":"Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK, 73072, USA"},{"name":"Department of Biochemistry & Physiology, University of Oklahoma Health Center, Oklahoma City, OK, 73104, USA"},{"name":"Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026031602450482000_2026.01.20.700642v2.1","doi-asserted-by":"crossref","unstructured":"Serrano-Pozo, A. , Frosch, M. 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