GSE201889
APOE Expression and Secretion are Modulated by Copper-Dependent and -Independent Mitochondrial Dysfunction
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. We report RNAseq profiles of human cell lines with CRISPR mediated mutagenesis of SLC25A1 and SLC5A4. Overall design: Comparative gene expression profiling of  Wild type or gene-edited HAP1 cells (SLC25A1 and SLC25A4).