APOE expression and secretion are modulated by mitochondrial dysfunction
Meghan E Wynne,
Oluwaseun Ogunbona,
Alicia R Lane,
Avanti Gokhale,
Stephanie A Zlatic,
Chongchong Xu,
Zhexing Wen,
Duc M Duong,
Sruti Rayaprolu,
Anna Ivanova,
Eric A Ortlund,
Eric B Dammer,
Nicholas T Seyfried,
Blaine R Roberts,
Amanda Crocker,
Vinit Shanbhag,
Michael Petris,
Nanami Senoo,
Selvaraju Kandasamy,
Steven Michael Claypool,
Antoni Barrientos,
Aliza Wingo,
Thomas S Wingo,
Srikant Rangaraju,
Allan I Levey,
Erica Werner,
Victor Faundez
Affiliations
Meghan E Wynne
Department of Cell Biology, Emory University, Atlanta, United States
Oluwaseun Ogunbona
Department of Cell Biology, Emory University, Atlanta, United States; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, United States
Department of Cell Biology, Emory University, Atlanta, United States
Avanti Gokhale
Department of Cell Biology, Emory University, Atlanta, United States
Stephanie A Zlatic
Department of Cell Biology, Emory University, Atlanta, United States
Chongchong Xu
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, United States
Zhexing Wen
Department of Cell Biology, Emory University, Atlanta, United States; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, United States; Department of Neurology and Human Genetics, Emory University, Atlanta, United States
Duc M Duong
Department of Biochemistry, Emory University, Atlanta, United States
Sruti Rayaprolu
Department of Neurology and Human Genetics, Emory University, Atlanta, United States
Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.
