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Cited by 476Mitochondrial Function and PathologyAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells

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Wang, Wenjian, Wang, Yin, Long, Jianyin, Wang, Jinrong, Haudek, Sandra B., Overbeek, Paul, Chang, Benny H.J., Schumacker, Paul T. +1 more·2012·Cell Metabolism
DOI 10.1016/j.cmet.2012.01.009PMC PMC3278719
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Abstract

Several lines of evidence suggest that mitochondrial dysfunction plays a critical role in the pathogenesis of microvascular complications of diabetes, including diabetic nephropathy. However, the signaling pathways by which hyperglycemia leads to mitochondrial dysfunction are not fully understood. Here we examined the role of Rho-associated coiled coil-containing protein kinase 1 (ROCK1) on mitochondrial dynamics by generating two diabetic mouse models with targeted deletions of ROCK1 and an inducible podocyte-specific knockin mouse expressing a constitutively active (cA) mutant of ROCK1. Our findings suggest that ROCK1 mediates hyperglycemia-induced mitochondrial fission by promoting dynamin-related protein-1 (Drp1) recruitment to the mitochondria. Deletion of ROCK1 in diabetic mice prevented mitochondrial fission, whereas podocyte-specific cA-ROCK1 mice exhibited increased mitochondrial fission. Importantly, we found that ROCK1 triggers mitochondrial fission by phosphorylating Drp1 at serine 600 residue. These findings provide insights into the unexpected role of ROCK1 in a signaling cascade that regulates mitochondrial dynamics.

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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 [133]

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Cited by

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Authors
Wang, W., Wang, Y., Long, J., Wang, J., Haudek, S. B., Overbeek, P., Chang, B. H. J., Schumacker, P. T., & Danesh, F. R.
Affiliations
  • Baylor College of Medicine (US)
  • Northwestern University (US)
Corresponding author
Danesh, Farhad R.
ORCID
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2012-02
Volume
15
Issue
2
Pages
186-200
ISSN
1550-4131 (ISSN-L)
DOI
10.1016/j.cmet.2012.01.009
PMC
PMC3278719
OpenAlex
W2020871623
Cited by
476
References
3
Citations by year
2026: 23 · 2025: 30 · 2024: 27 · 2023: 45 · 2022: 36 · 2021: 35 · 2020: 49 · 2019: 36 · 2018: 36 · 2017: 34 · 2016: 32 · 2015: 22 · 2014: 34 · 2013: 29 · 2012: 6
FWCI
10.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL035440)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078900, R01DK091310, R01 RO1DK091310)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mitochondrial fission, hyperglycemia, ROCK1, podocytes, endothelial cells, Drp1, mitochondrial dynamics, diabetic nephropathy, diabetic microvascular complications
MeSH terms
Amino Acid Sequence, Analysis of Variance, Animals, Diabetes Mellitus, Experimental, Enzyme Activation, Flow Cytometry, Hyperglycemia, Mice, Transgenic, Molecular Sequence Data, Phosphorylation, Mutagenesis, Sequence Alignment, Gene Deletion, DNA Primers, Models, Animal, Mitochondrial Diseases, Dynamins, RNA, Small Interfering, Endothelial Cells, Podocytes, Glomerular Basement Membrane, Mice, rho-Associated Kinases, Gene Knock-In Techniques

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