GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

Qiang Zhu, Matthew E. Combs, Juan Liu, Xue Bai, Wenbo B. Wang, Laura E. Herring, Jiandong Liu, Jason W. Locasale, Dawn E. Bowles, Ryan T. Gross, Michelle Mendiola Pla, Christopher P. Mack and Joan M. Taylor ()
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Qiang Zhu: University of North Carolina
Matthew E. Combs: University of North Carolina
Juan Liu: Duke University School of Medicine
Xue Bai: University of North Carolina
Wenbo B. Wang: University of North Carolina
Laura E. Herring: University of North Carolina
Jiandong Liu: University of North Carolina
Jason W. Locasale: Duke University School of Medicine
Dawn E. Bowles: Duke University Medical Center
Ryan T. Gross: Duke University Medical Center
Michelle Mendiola Pla: Duke University Medical Center
Christopher P. Mack: University of North Carolina
Joan M. Taylor: University of North Carolina

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The serine/threonine kinase, PINK1, and the E3 ubiquitin ligase, Parkin, are known to facilitate LC3-dependent autophagosomal encasement and lysosomal clearance of dysfunctional mitochondria, and defects in this process contribute to a variety of cardiometabolic and neurological diseases. Although recent evidence indicates that dynamic actin remodeling plays an important role in PINK1/Parkin-mediated mitochondrial autophagy (mitophagy), the underlying signaling mechanisms remain unknown. Here, we identify the RhoGAP GRAF1 (Arhgap26) as a PINK1 substrate that regulates mitophagy. GRAF1 promotes the release of damaged mitochondria from F-actin anchors, regulates mitochondrial-associated Arp2/3-mediated actin remodeling and facilitates Parkin-LC3 interactions to enhance mitochondria capture by autophagosomes. Graf1 phosphorylation on PINK1-dependent sites is dysregulated in human heart failure, and cardiomyocyte-restricted Graf1 depletion in mice blunts mitochondrial clearance and attenuates compensatory metabolic adaptations to stress. Overall, we identify GRAF1 as an enzyme that coordinates cytoskeletal and metabolic remodeling to promote cardioprotection.

Date: 2023
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DOI: 10.1038/s41467-023-43889-6

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