Abstract
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 Statement
The authors have declared no competing interest.