Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers

Sung Kook Chun, Sooyeon Lee, Joseph Flores-Toro, U. Rebecca Y., Ming Jim Yang, Kristina L. Go, Thomas G. Biel, Catherine E. Miney, Schiley Pierre Louis, Brian K. Law, Mary E. Law, Elizabeth M. Thomas, Kevin E. Behrns, Christiaan Leeuwenburgh, Jae Sung Kim

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Ischemia/reperfusion (I/R) injury is a causative factor contributing to morbidity and mortality during liver resection and transplantation. Livers from elderly patients have a poorer recovery from these surgeries, indicating reduced reparative capacity with aging. Mechanisms underlying this age-mediated hypersensitivity to I/R injury remain poorly understood. Here, we investigated how sirtuin 1 (SIRT1) and mitofusin 2 (MFN2) are affected by I/R in aged livers. Young (3 months) and old (23–26 months) male C57/BL6 mice were subjected to hepatic I/R in vivo. Primary hepatocytes isolated from each age group were also exposed to simulated in vitro I/R. Biochemical, genetic, and imaging analyses were performed to assess cell death, autophagy flux, mitophagy, and mitochondrial function. Compared to young mice, old livers showed accelerated liver injury following mild I/R. Reperfusion of old hepatocytes also showed necrosis, accompanied with defective autophagy, onset of the mitochondrial permeability transition, and mitochondrial dysfunction. Biochemical analysis indicated a near-complete loss of both SIRT1 and MFN2 after I/R in old hepatocytes, which did not occur in young cells. Overexpression of either SIRT1 or MFN2 alone in old hepatocytes failed to mitigate I/R injury, while co-overexpression of both proteins promoted autophagy and prevented mitochondrial dysfunction and cell death after reperfusion. Genetic approaches with deletion and point mutants revealed that SIRT1 deacetylated K655 and K662 residues in the C-terminus of MFN2, leading to autophagy activation. The SIRT1-MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/R injury in aged livers.

Original languageEnglish (US)
Article numbere12761
JournalAging cell
Volume17
Issue number4
DOIs
StatePublished - Aug 2018
Externally publishedYes

Keywords

  • aging
  • autophagy
  • hepatocytes
  • liver
  • mitochondria
  • mitophagy

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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