Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Huan Yang, Caroline Sibilla, Raymond Liu, Jina Yun, Bruce A. Hay, Craig Blackstone, David C. Chan, Robert J. Harvey and Ming Guo ()
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Huan Yang: UCLA David Geffen School of Medicine
Caroline Sibilla: National Institute of Neurological Disorders and Stroke
Raymond Liu: California Institute of Technology
Jina Yun: UCLA David Geffen School of Medicine
Bruce A. Hay: California Institute of Technology
Craig Blackstone: National Institute of Neurological Disorders and Stroke
David C. Chan: California Institute of Technology
Robert J. Harvey: University of the Sunshine Coast
Ming Guo: UCLA David Geffen School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1.

Date: 2022
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DOI: 10.1038/s41467-022-29071-4

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