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Cited by 35Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

APOE expression and secretion are modulated by mitochondrial dysfunction

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Wynne, Meghan E, Ogunbona, Oluwaseun, Lane, Alicia R, Gokhale, Avanti, Zlatic, Stephanie A, Xu, Chongchong, Wen, Zhexing, Duong, Duc M +19 more·2023·eLife
DOI 10.7554/elife.85779PMC PMC10231934

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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.

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  • APOE affects mitochondrial structure and function, and mitochondrial dysfunction impacts APOE gene and protein expression and secretion.

    “not only has APOE been shown to affect mitochondrial structure and function, but also mitochondrial dysfunction has been shown to impact APOE gene and protein expression and secretion180.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [180]

    The Results report that mitochondrial perturbations increased APOE mRNA, cellular protein, and secreted protein; the Discussion likewise concludes that mitochondria regulate APOE expression and secretion. The Introduction says APOE4 is thought to cause mitochondrial dysfunction, but the passages do not establish the broader claim that APOE affects mitochondrial structure. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Wynne, M. E., Ogunbona, O., Lane, A. R., Gokhale, A., Zlatic, S. A., Xu, C., Wen, Z., Duong, D. M., Rayaprolu, S., Ivanova, A., Ortlund, E. A., Dammer, E. B., Seyfried, N. T., Roberts, B. R., Crocker, A., Shanbhag, V., Petris, M., Senoo, N., Kandasamy, S., Claypool, S. M., Barrientos, A., Wingo, A., Wingo, T. S., Rangaraju, S., Levey, A. I., Werner, E., & Faundez, V.
Affiliations
  • Emory University (US)
  • Middlebury College (US)
  • University of Missouri (US)
  • Johns Hopkins University (US)
  • University of Miami (US)
  • Department of Cell Biology, Emory University
Corresponding author
Werner, Erica
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2023-05-12
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.85779
PMC
PMC10231934
OpenAlex
W4376223985
Cited by
35
References
19
Citations by year
2026: 8 · 2025: 13 · 2024: 9 · 2023: 5
FWCI
3.11
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institute on Aging (1RF1AG060285, U01AG061357, RF1AG071587, F32AG064862)
  • Alzheimer's Disease Research Center, Emory University (P30AG066511)
  • National Institute of Neurological Disorders and Stroke (F31AG067623, 5T32NS007480, R01NS11430, 1F31NS127419)
  • ARCS Foundation
  • Emory University (Robert W Woodruff Fellowship)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
apolipoprotein E, mitochondrial dysfunction, electron transport chain, secretome, mitochondrial complex I, respiratory complex IV, astrocytes, neuroinflammation, 5xFAD mice, Alzheimer's disease risk, iPSC-derived astrocytes, paracrine signaling
MeSH terms
Animals, Apolipoproteins E, Astrocytes, Genotype, Humans, Mitochondria, Mice, Apolipoprotein E4

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