2. Academic Validation
  3. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis

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

  • Nat Commun. 2023 Dec 11;14(1):8187. doi: 10.1038/s41467-023-43889-6.
Qiang Zhu 1,  Matthew E Combs 1,  Juan Liu 2,  Xue Bai 1,  Wenbo B Wang 3,  Laura E Herring 4,  Jiandong Liu 1 5,  Jason W Locasale 2,  Dawn E Bowles 6,  Ryan T Gross 6,  Michelle Mendiola Pla 6,  Christopher P Mack 1 5,  Joan M Taylor 7 8
Affiliations

Affiliations

  • 1 Department of Pathology, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 2 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
  • 3 Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 4 UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 5 McAllister Heart Institute University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 6 Division of Surgical Sciences, Duke University Medical Center, Durham, NC, 27710, USA.
  • 7 Department of Pathology, University of North Carolina, Chapel Hill, NC, 27599, USA. joan_m_taylor@med.unc.edu.
  • 8 McAllister Heart Institute University of North Carolina, Chapel Hill, NC, 27599, USA. joan_m_taylor@med.unc.edu.
PMID: 38081847 DOI: 10.1038/s41467-023-43889-6
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.

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