A PGAM5–KEAP1–Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking
Open accessAbstract
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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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”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [104]
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Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass
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Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer
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NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells
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Nrf-2 as a therapeutic target in acute kidney injury
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Functional role of PGAM5 multimeric assemblies and their polymerization into filaments
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Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia
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Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases
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Carbamate compounds induced toxic effects by affecting Nrf2 signaling pathways
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Aflatoxin B1 induces ROS‐dependent mitophagy by modulating the PINK1/Parkin pathway in HepG2 cells
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Loss of KEAP1 Causes an Accumulation of Nondegradative Organelles
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Sulforaphane acutely activates multiple starvation response pathways
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p62: Intersection of Antioxidant Defense and Autophagy Pathways
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A Comparative Study of the Toxic Effects of t‐BHP on AC16 and H9c2 Cardiomyocytes
Liu, Z. G., Du, Q., Zhao, J., Yang, R., Yan, Z., Liu, C., & Zhao, Y. (2025) · Journal of Applied Toxicology · doi:10.1002/jat.4970 · Cited by 1 · see citing works
Cumambrin B Alleviates Sepsis-Associated Acute Lung Injury by Activating the Nrf2/HO-1 Pathway
Que, Y., Ruan, D., Xu, M.-X., Nie, Y.-L., Huang, G.-Z., Zhao, H., & Yang, Y.-Z. (2026) · Biomedicines · doi:10.3390/biomedicines14030729 · Cited by 1 · see citing works
Jarocka-Karpowicz, I., Gęgotek, A., Žarković, N., Maruška, A., & Skrzydlewska, E. (2026) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl47793 · Cited by 1 · see citing works
Circadian rhythms, NRF2 signalling and redox homeostasis: A holy grail for a healthy life course?
Sutton, E., & Pekovic‐Vaughan, V. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.05.318 · Cited by 1 · see citing works
Митохондриальные нарушения при болезни Альцгеймера
Sukhorukov, V. S., Mudzhiri, N. M., Voronkova, A. S., Baranich, T. I., Glinkina, V. V., & Illarioshkin, S. N. (2021) · Biochemistry (Moscow) · doi:10.31857/s0320972521060051
Shukla, K., Zhang, Z., Plafker, K. S., Matsuzaki, S., Salinas-Salinas, C., Thomason, Y. M., Houmam, S., Barber, D., Faakye, A., Humphries, K. M., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.20.700642
Self-citationYao, R., Rivera, I., Maldonado, J., Best-Popescu, C., Xu, H., Sarkaria, J. N., Wang, J.-X., Lu, Y., Selting, K. A., Harley, B. A. C., et al. (2026) · Clinical and Translational Radiation Oncology · doi:10.1016/j.ctro.2026.101204
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BindingDB (2025) · UC San Diego · doi:10.7270/q29028gr
- 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
- Publisher
- The Company of Biologists
- Published
- 2017-10-15
- Volume
- 130
- Issue
- 20
- Pages
- 3467-3480
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC5665445
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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