Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway.

Abstract

Mitochondrial fusion is linked to heart and liver ischemia-reperfusion (IR) insult. Unfortunately, there is no report to elucidate the detailed influence of mitochondrial fusion in renal IR injury. This study principally investigated the mechanism by which mitochondrial fusion protected kidney against IR injury. Our results indicated that sirtuin 3 (Sirt3) was inhibited after renal IR injury in vivo and in vitro. Overexpression of Sirt3 improved kidney function, modulated oxidative injury, repressed inflammatory damage, and reduced tubular epithelial cell apoptosis. The molecular investigation found that Sirt3 overexpression attenuated IR-induced mitochondrial damage in renal tubular epithelial cells, as evidenced by decreased reactive oxygen species production, increased antioxidants sustained mitochondrial membrane potential, and inactivated mitochondria-initiated death signaling. In addition, our information also illuminated that Sirt3 maintained mitochondrial homeostasis against IR injury by enhancing optic atrophy 1 (OPA1)-triggered fusion of mitochondrion. Inhibition of OPA1-induced fusion repressed Sirt3 overexpression-induced kidney protection, leading to mitochondrial dysfunction. Further, our study illustrated that OPA1-induced fusion could be affected through ERK; inhibition of ERK abolished the regulatory impacts of Sirt3 on OPA1 expression and mitochondrial fusion, leading to mitochondrial damage and tubular epithelial cell apoptosis. Altogether, our results suggest that renal IR injury is closely associated with Sirt3 downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK-OPA1 cascade may represent new therapeutic modalities for renal IR injury.

• Authors: Qiang Wang, Junnan Xu, Xiaoli Li, Zhijia Liu, Yong Han, Xiaoguang Xu, Xiubin Li, Yuzhe Tang, Yubao Liu, Tao Yu, Xiang Li
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 12 Pg. 23495-23506 (12 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 31173361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Extracellular Signal-Regulated MAP Kinases
• Sirtuin 3
• GTP Phosphohydrolases
• Opa1 protein, mouse

Topics

• Acute Kidney Injury (enzymology, genetics, pathology)
• Animals
• Apoptosis
• Disease Models, Animal
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• GTP Phosphohydrolases (metabolism)
• Kidney (enzymology, pathology)
• LLC-PK1 Cells
• Mice, Transgenic
• Mitochondria (enzymology, pathology)
• Mitochondrial Dynamics
• Oxidative Stress
• Reperfusion Injury (enzymology, genetics, pathology)
• Signal Transduction
• Sirtuin 3 (genetics, metabolism)
• Swine