APOE expression and secretion are modulated by mitochondrial dysfunction
- Emory University, United States
- Middlebury College, United States
- University of Missouri, United States
- Johns Hopkins University, United States
- University of Miami, United States
Abstract
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.
Data availability
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Deutsch et al., 2020) partner repository with dataset identifiers: PXD038974 and PXD017501.RNAseq data were deposited in GEO with accession GSE201889
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APOE Expression and Secretion are Modulated by Copper-Dependent and -Independent Mitochondrial DysfunctionNCBI Gene Expression Omnibus, GSE201889.
Article and author information
Author details
Steven Michael Claypool
Funding
National Institute on Aging (1RF1AG060285)
- Victor Faundez
ARCS Foundation Award
- Alicia R Lane
Alzheimer's Disease Research Center, Emory University (P30AG066511)
- Victor Faundez
National Institute on Aging (U01AG061357)
- Nicholas T Seyfried
National Institute of Neurological Disorders and Stroke (F31AG067623)
- Meghan E Wynne
National Institute of Neurological Disorders and Stroke (5T32NS007480)
- Meghan E Wynne
National Institute of Neurological Disorders and Stroke (R01NS11430)
- Srikant Rangaraju
National Institute on Aging (RF1AG071587)
- Srikant Rangaraju
National Institute on Aging (F32AG064862)
- Sruti Rayaprolu
National Institute of Neurological Disorders and Stroke (1F31NS127419)
- Alicia R Lane
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Agnieszka Chacinska, IMol Polish Academy of Sciences, Poland
Version history
- Preprint posted: May 11, 2022 (view preprint)
- Received: December 23, 2022
- Accepted: May 11, 2023
- Accepted Manuscript published: May 12, 2023 (version 1)
- Version of Record published: May 31, 2023 (version 2)
Copyright
© 2023, Wynne et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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APOE expression and secretion are modulated by mitochondrial dysfunction
eLife 12:e85779.
https://doi.org/10.7554/eLife.85779
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