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

The following data sets were generated

Article and author information

Author details

  1. Meghan E Wynne

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Oluwaseun Ogunbona

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alicia R Lane

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6404-7559
  4. Avanti Gokhale

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephanie A Zlatic

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Chongchong Xu

    Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Zhexing Wen

    Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Duc M Duong

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sruti Rayaprolu

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Anna Ivanova

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6221-6240
  11. Eric A Ortlund

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Eric B Dammer

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Nicholas T Seyfried

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Blaine R Roberts

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Amanda Crocker

    Program in Neuroscience, Middlebury College, Middlebury, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Vinit Shanbhag

    Department of Biochemistry, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Michael Petris

    Department of Biochemistry, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Nanami Senoo

    Department of Physiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Selvaraju Kandasamy

    Department of Physiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Steven Michael Claypool

    Department of Physiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5316-1623
  21. Antoni Barrientos

    Department of Neurology, University of Miami, Miami, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9018-3231
  22. Aliza Wingo

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Thomas S Wingo

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7679-6282
  24. Srikant Rangaraju

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Allan I Levey

    Department of Neurology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3153-502X
  26. Erica Werner

    Department of Cell Biology, Emory University, Atlanta, United States
    For correspondence
    ewerner@emory.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8183-1601
  27. Victor Faundez

    Department of Cell Biology, Emory University, Atlanta, United States
    For correspondence
    vfaunde@emory.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2114-5271

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.

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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  1. Meghan E Wynne
  2. Oluwaseun Ogunbona
  3. Alicia R Lane
  4. Avanti Gokhale
  5. Stephanie A Zlatic
  6. Chongchong Xu
  7. Zhexing Wen
  8. Duc M Duong
  9. Sruti Rayaprolu
  10. Anna Ivanova
  11. Eric A Ortlund
  12. Eric B Dammer
  13. Nicholas T Seyfried
  14. Blaine R Roberts
  15. Amanda Crocker
  16. Vinit Shanbhag
  17. Michael Petris
  18. Nanami Senoo
  19. Selvaraju Kandasamy
  20. Steven Michael Claypool
  21. Antoni Barrientos
  22. Aliza Wingo
  23. Thomas S Wingo
  24. Srikant Rangaraju
  25. Allan I Levey
  26. Erica Werner
  27. Victor Faundez
(2023)
APOE expression and secretion are modulated by mitochondrial dysfunction
eLife 12:e85779.
https://doi.org/10.7554/eLife.85779

Share this article

https://doi.org/10.7554/eLife.85779

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