Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis

Sung Gyu Cho, Quansheng Du, Shuang Huang, Zheng Dong

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Recent studies revealed a striking morphological change of mitochondria during apoptosis. Mitochondria become fragmented and notably, the fragmentation contributes to mitochondrial outer membrane permeabilization and consequent release of apoptotic factors. In renal tubular cells, mitochondrial fragmentation involves the activation of Drp1, a key mitochondrial fission protein. However, it is unclear how Drp1 is regulated during tubular cell apoptosis. In this study, we examined Drp1 regulation during tubular cell apoptosis following ATP depletion. Rat kidney proximal tubular cells (RPTC) were subjected to azide treatment or severe hypoxia in glucose-free medium to induce ATP depletion. During ATP depletion, Drp1 was shown to be dephosphorylated at serine-637. Drp1 dephosphorylation could be suppressed by cyclosporine A and FK506, two calcineurin inhibitors. Importantly, cyclosporine A and FK506 could also prevent mitochondrial fragmentation, Bax accumulation, cytochrome c release, and apoptosis following ATP depletion in RPTC. The results suggest that calcineurin-mediated serine-637 dephosphorylation is involved in Drp1 activation during ATP depletion in renal tubular cells. Upon activation, Drp1 contributes to mitochondrial fragmentation and outer membrane permeabilization, resulting in the release of apoptogenic factors and apoptosis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume299
Issue number1
DOIs
StatePublished - Jul 1 2010

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Adenosine Triphosphate
Apoptosis
Wounds and Injuries
Kidney
Mitochondrial Membranes
Tacrolimus
Serine
Cyclosporine
Mitochondria
Mitochondrial Dynamics
Azides
Calcineurin
Mitochondrial Proteins
Cytochromes c
Glucose

Keywords

  • Bax
  • Calcineurin
  • Cyclosporine A
  • Cytochrome c
  • FK506
  • Mitochondrial dynamics

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Drp1 dephosphorylation in ATP depletion-induced mitochondrial injury and tubular cell apoptosis. / Cho, Sung Gyu; Du, Quansheng; Huang, Shuang; Dong, Zheng.

In: American Journal of Physiology - Renal Physiology, Vol. 299, No. 1, 01.07.2010.

Research output: Contribution to journalArticle

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