Cited by 99Mitochondrial Function and PathologyGenomics, phytochemicals, and oxidative stressAutophagy in Disease and Therapy

A PGAM5–KEAP1–Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking

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O'Mealey, Gary B., Plafker, Kendra S., Berry, William L., Janknecht, Ralf, Chan, Jefferson Y., Plafker, Scott M.·2017·Journal of Cell Science

Abstract

The Nrf2 transcription factor is a master regulator of the cellular anti-stress response. A population of the transcription factor associates with the mitochondria through a complex with KEAP1 and the mitochondrial outer membrane histidine phosphatase, PGAM5. To determine the function of this mitochondrial complex, we knocked down each component and assessed mitochondrial morphology and distribution. We discovered that depletion of Nrf2 or PGAM5, but not KEAP1, inhibits mitochondrial retrograde trafficking induced by proteasome inhibition. Mechanistically, this disrupted motility results from aberrant degradation of Miro2, a mitochondrial GTPase that links mitochondria to microtubules. Rescue experiments demonstrate that this Miro2 degradation involves the KEAP1–cullin-3 E3 ubiquitin ligase and the proteasome. These data are consistent with a model in which an intact complex of PGAM5–KEAP1–Nrf2 preserves mitochondrial motility by suppressing dominant-negative KEAP1 activity. These data further provide a mechanistic explanation for how age-dependent declines in Nrf2 expression impact mitochondrial motility and induce functional deficits commonly linked to neurodegeneration.

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Crossref · 10.1242/jcs.203216

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  • PGAM5 can recruit both Keap1 and Nrf2 to the outer mitochondrial membrane to form a ternary Keap1-PGAM5-Nrf2 complex, resulting in stress-induced Keap1-mediated ubiquitination and degradation of Miro2 rather than Nrf2.

    “Interestingly, PGAM5 can recruit both Keap1 and Nrf2 to the outer mitochondrial membrane by binding to one molecule of a Keap1 dimer while simultaneously binding Nrf2 to form a ternary Keap1-PGAM5-Nrf2 complex [102,103]. Interestingly, this results in the stress-induced Keap1-mediated ubiquitination and degradation of not Nrf2, but of mitochondrial Rho GTPase 2 (Miro2), a mitochondrial GTPase inv”

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Authors
O'Mealey, G. B., Plafker, K. S., Berry, W. L., Janknecht, R., Chan, J. Y., & Plafker, S. M.
Affiliations
  • Oklahoma Medical Research Foundation (US)
  • University of Oklahoma Health Sciences Center (US)
  • University of California, Irvine (US)
Venue
Journal of Cell Science
Published
2017-10-15
Volume
130
Issue
20
Pages
3467-3480
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
OpenAlex
W2745428357
Cited by
99
References
98
Citations by year
2026: 7 · 2025: 11 · 2024: 17 · 2023: 7 · 2022: 9 · 2021: 15 · 2020: 13 · 2019: 9 · 2018: 11
FWCI
3.69
Type
journal article
Language
en
Open access
Locations
  • Journal of Cell Science (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institutes of Health (R01GM092900)
  • Oklahoma Center for the Advancement of Science and Technology (HR16-068)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
PGAM5, Keap1, Nrf2, mitochondrial motility, Miro2, proteasome inhibition, mitochondrial morphology, neurodegeneration, aging
MeSH terms
Kelch-Like ECH-Associated Protein 1, Protein Domains, Animals, Biological Transport, Female, Humans, Mice, Inbred C57BL, Microtubules, Mitochondria, Phosphoprotein Phosphatases, Oxidative Stress, rho GTP-Binding Proteins, Mitochondrial Proteins, NF-E2-Related Factor 2, Membrane Potential, Mitochondrial, HEK293 Cells, Proteolysis, Mitochondrial Dynamics

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