TY - JOUR T1 - APOE Expression and Secretion are Modulated by Copper-Dependent and -Independent Mitochondrial Dysfunction JF - bioRxiv DO - 10.1101/2022.05.11.491499 SP - 2022.05.11.491499 AU - Meghan E. Wynne AU - Oluwaseun Ogunbona AU - Alicia R. Lane AU - Avanti Gokhale AU - Stephanie Zlatic AU - Chongchong Xu AU - Zhexing Wen AU - Duc Duong AU - Anna Ivanova AU - Eric A. Orlund AU - Nicholas T. Seyfried AU - Amanda Crocker AU - Vinit Shanbhag AU - Michael Petris AU - Nanami Senoo AU - Selvaraju Kandasamy AU - Steven M. Claypool AU - Aliza P. Wingo AU - Thomas S. Wingo AU - Allan Levey AU - Erica Werner AU - Victor Faundez Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/11/2022.05.11.491499.abstract N2 - Mitochondria are dynamic organelles that 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 inner mitochondrial membrane caused upregulation of the Alzheimer’s disease risk factor apolipoprotein E (APOE) and other secretome components. This upregulation of secretory proteins was of a similar extent as modifications to the mitochondrial annotated proteome. Gene editing of SLC25A family inner mitochondrial membrane transporters, as well as genetic and pharmacological disruption of copper-dependent and independent steps of electron transport chain assembly and function, caused upregulation of APOE transcript, protein, and secretion, up to 16-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC- derived human astrocytes as part of an inflammatory gene expression program. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.Competing Interest StatementThe authors have declared no competing interest. ER -