Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration

Abstract Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimer’s disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Major revisions made throughout manuscript, including revised Figures and additional data.