Cited by 736Mitochondrial Function and PathologyCell death mechanisms and regulationAutophagy in Disease and Therapy

Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models

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Brooks, Craig, Wei, Qingqing, Cho, Sung-Gyu, Dong, Zheng·2009·Journal of Clinical Investigation

Abstract

The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.

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  • Mitochondrial fission occurs in kidneys and heart after acute ischemia/reperfusion injury in mice.

    “For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
  • Prevention of mitochondrial fission is beneficial in kidneys and heart after acute ischemia/reperfusion injury in mice.

    “For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
  • Silencing of Drp1 expression is not associated with reduced translocation of the pro-apoptotic protein Bax to mitochondria, suggesting that Drp1 functions downstream of Bax during apoptosis.

    “Moreover, these studies revealed that silencing of Drp1 expression was not associated with reduced translocation of the pro-apoptotic protein Bax to mitochondria, suggesting that Drp1 functions downstream of Bax during apoptosis.”
  • Overexpression of the dominant-negative mutant Drp1K38A induces mitochondrial fusion and confers resistance to apoptosis by preventing a loss of Δψm and inhibiting cytochrome c release.

    “The role of mitochondrial dynamics in regulating apoptosis is mainly based on the finding that overexpression of the dominant-negative mutant Drp1K38A induces mitochondrial fusion and confers resistance to apoptosis by preventing a loss of Δψm and inhibiting cytochrome c release (Breckenridge et al., 2003; Brooks et al., 2009; Frank et al., 2001; Karbowski et al., 2002).”

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Authors
Brooks, C., Wei, Q., Cho, S.-G., & Dong, Z.
Affiliations
Charlie Norwood VA Medical Center (US)
Corresponding author
Dong, Zheng
Venue
Journal of Clinical Investigation
Published
2009-05-01
Volume
119
Issue
5
Pages
1275-1285
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2155978870
Cited by
735
References
58
Citations by year
2026: 24 · 2025: 31 · 2024: 51 · 2023: 34 · 2022: 59 · 2021: 49 · 2020: 64 · 2019: 59 · 2018: 43 · 2017: 54 · 2016: 42 · 2015: 40 · 2014: 45 · 2013: 36 · 2012: 41
FWCI
13.84
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • Brigham and Women's Hospital
  • Silence Therapeutics
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial dynamics, mitochondrial fragmentation, acute kidney injury, apoptosis, mitochondrial outer membrane permeabilization, cytochrome c release, Drp1, Mdivi-1, renal ischemia-reperfusion, cisplatin nephrotoxicity, Bcl-2, caspase activation, ATP depletion
MeSH terms
Adenosine Triphosphate, Animals, Cell Line, Cells, Cultured, Cisplatin, Enzyme Inhibitors, Kidney Tubular Necrosis, Acute, Kidney Tubules, Proximal, Male, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mitochondria, Reperfusion Injury, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Sodium Azide, GTP Phosphohydrolases, Imaging, Three-Dimensional, Dynamins, RNA, Small Interfering, Cytochromes c, Mice, Rats, Caspase Inhibitors

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