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Cited by 89Mitochondrial Function and PathologyCardiac Ischemia and ReperfusionCell death mechanisms and regulation

RhoA regulates Drp1 mediated mitochondrial fission through ROCK to protect cardiomyocytes

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Brand, Cameron S., Tan, Valerie P., Brown, Joan Heller, Miyamoto, Shigeki·2018·Cellular Signalling
DOI 10.1016/j.cellsig.2018.06.012PMC PMC6361616
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Abstract

Cardiac ischemia/reperfusion, loss of blood flow and its subsequent restoration, causes damage to the heart. Oxidative stress from ischemia/reperfusion leads to dysfunction and death of cardiomyocytes, increasing the risk of progression to heart failure. Alterations in mitochondrial dynamics, in particular mitochondrial fission, have been suggested to play a role in cardioprotection from oxidative stress. We tested the hypothesis that activation of RhoA regulates mitochondrial fission in cardiomyocytes. Our studies show that expression of constitutively active RhoA in cardiomyocytes increases phosphorylation of Dynamin-related protein 1 (Drp1) at serine-616, and leads to localization of Drp1 at mitochondria. Both responses are blocked by inhibition of Rho-associated Protein Kinase (ROCK). Endogenous RhoA activation by the GPCR agonist sphingosine-1-phosphate (S1P) also increases Drp1 phosphorylation and its mitochondrial translocation in a RhoA and ROCK dependent manner. Consistent with the role of mitochondrial Drp1 in fission, RhoA activation in cardiomyocytes leads to formation of smaller mitochondria and this is attenuated by inhibition of ROCK, by siRNA knockdown of Drp1 or by expression of a phosphorylation-deficient Drp1 S616A mutant. In addition, activation of RhoA prevents cell death in cardiomyocytes challenged by oxidative stress and this protection is blocked by siRNA knockdown of Drp1 or by Drp1 S616A expression. Taken together our findings demonstrate that RhoA activation can regulate Drp1 to induce mitochondrial fission and subsequent cellular protection, implicating regulation of fission as a novel mechanism contributing to RhoA-mediated cardioprotection.

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  • ROCK can directly phosphorylate Drp1 to increase the fission activity of Drp1 in cardiomyocytes and podocytes.

    “It seems that ROCK can directly phosphorylate Drp1 to increase the fission activity of Drp1 in cardiomyocytes and podocytes [133,134], while in dopaminergic neurons, a ROCK-mediated dephosphorylation of Drp1 was reported to induce mitochondrial fission [132].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [134]

    The Results section reports that ROCK inhibition prevented RhoA-induced Drp1 phosphorylation at serine-616 in cardiomyocytes, and that a non-phosphorylatable Drp1 mutant prevented RhoA-induced mitochondrial fission. But the Discussion proposes, rather than demonstrates, that ROCK directly phosphorylates Drp1. This paper studies cardiomyocytes; it mentions podocyte findings from another study, so it does not itself establish the claim in podocytes. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Brand, C. S., Tan, V. P., Brown, J. H., & Miyamoto, S.
Affiliations
University of California San Diego (US)
Corresponding author
  • Brown, Joan Heller
  • Miyamoto, Shigeki
ORCID
Venue
Cellular Signalling
Publisher
Elsevier BV
Published
2018-10
Volume
50
Pages
48-57
ISSN
0898-6568 (ISSN-L)
DOI
10.1016/j.cellsig.2018.06.012
PMC
PMC6361616
OpenAlex
W2809961376
Cited by
89
References
6
Citations by year
2026: 9 · 2025: 17 · 2024: 13 · 2023: 9 · 2022: 13 · 2021: 4 · 2020: 12 · 2019: 7 · 2018: 5
FWCI
2.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular Signalling (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institutes of Health (T32HL007444, F32HL140851, R37HL028143, R56HL097037)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
RhoA, Drp1, mitochondrial fission, rocks, cardiomyocytes, cardioprotection, cardiac ischemia-reperfusion, oxidative stress, sphingosine-1-phosphate, G protein-coupled receptor signaling, mitochondrial dynamics, cell death
MeSH terms
Animals, Lysophospholipids, Mitochondria, Heart, Phosphorylation, Sphingosine, Signal Transduction, Cell Death, Rats, Sprague-Dawley, Oxidative Stress, rho GTP-Binding Proteins, rhoA GTP-Binding Protein, Myocytes, Cardiac, Dynamins, Rats, rho-Associated Kinases, Mitochondrial Dynamics

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