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Antioxid Redox Signal. 2017 Dec 20;27(18):1447-1459. doi: 10.1089/ars.2016.6855. Epub 2017 Jul 7.

The Keap1-Nrf2 Stress Response Pathway Promotes Mitochondrial Hyperfusion Through Degradation of the Mitochondrial Fission Protein Drp1.

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1 Department of Biochemistry and Molecular Biology, University of Calgary , Calgary, Canada .
2 Department of Neuroscience, University of Calgary , Calgary, Canada .
3 Department of Atherosclerosis, Genetics and Cell Biology, University of Ottawa Heart Institute , Ottawa, Canada .
4 Department of Cellular and Molecular Medicine, University of Ottawa , Ottawa, Canada .
5 Children's Hospital of Eastern Ontario Research Institute , Ottawa, Canada .
6 Department of Biochemistry, Sunnybrook Research Institute , Toronto, Canada .
7 Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute , Ottawa, Canada .
8 Department of Neurology and Neurosurgery, Montreal Neurological Institute , Montreal, Canada .
9 Department of Medical Genetics, University of Calgary , Calgary, Canada .



Mitochondrial function is coupled to metabolic and survival pathways through both direct signaling cascades and dynamic changes in mitochondrial morphology. For example, a hyperfused mitochondrial reticulum is activated upon cellular stress and is protective against cell death. As part of a genome-wide small inhibitory ribonucleic acid screen, we identified the central redox regulator, Keap1, as a novel regulator of mitochondrial morphology. Here, we aimed to determine the mechanism through which redox signaling and Keap1 mediate changes in mitochondrial morphology.


We found that the Nrf2 transcription factor is required for mitochondrial hyperfusion induced by knockdown of Keap1. Nrf2, which is negatively regulated by Keap1, mediates the cell's response to stress by controlling the expression of several hundred genes, including proteasome expression. We next showed that increased proteasome activity, a result of increased Nrf2 activity, is responsible for the degradation of the mitochondrial fission protein Drp1, which occurs in an ubiquitin-independent manner.


Our study described a novel pathway by which Nrf2 activation, known to occur in response to increased oxidative stress, decreases mitochondrial fission and contributes to a hyperfused mitochondrial network.


This study has identified the Keap1-Nrf2 nexus and modulation of proteasomal activity as novel avenues to inhibit mitochondrial fission. These findings are important, because inhibiting mitochondrial fission is a promising therapeutic approach to restore the balance between fission and fusion, which is attractive for an increasing number of disorders linked to mitochondrial dysfunction. Antioxid. Redox Signal. 27, 1447-1459.


Drp1; Keap1/Nrf2; mitochondria; mitochondrial fission; proteasome

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