A PGAM5-KEAP1-Nrf2 complex is required for stress-induced mitochondrial retrograde trafficking.
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.
["O'Mealey|Gary B|GB|", 'Plafker|Kendra S|KS|http://orcid.org/0000-0001-8015-6168', 'Berry|William L|WL|http://orcid.org/0000-0002-1661-5443', 'Janknecht|Ralf|R|', 'Chan|Jefferson Y|JY|http://orcid.org/0000-0003-4139-4379', 'Plafker|Scott M|SM|http://orcid.org/0000-0003-1998-8904']
D000818:Animals D001692:Biological Transport D005260:Female D057809:HEK293 Cells D006801:Humans D000072019:Kelch-Like ECH-Associated Protein 1 D053078:Membrane Potential, Mitochondrial D008810:Mice, Inbred C57BL D008870:Microtubules D008928:Mitochondria D063154:Mitochondrial Dynamics D024101:Mitochondrial Proteins D051267:NF-E2-Related Factor 2 D018384:Oxidative Stress D010749:Phosphoprotein Phosphatases D000072417:Protein Domains D059748:Proteolysis D020741:rho GTP-Binding Proteins
Nrf2 Mitochondria Proteasome Miro2 Ubiquitin Clustering