Abstract
SummaryIschemia/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.
Highlights
Ischemia/reperfusion (I/R) injury is a fundamental obstacle in liver resection and transplantation surgery
We recently reported that sirtuin 1 (SIRT1) interacts with mitofusin 2 (MFN2), a mitochondrial outer membrane protein and that this interaction is required for SIRT1-dependent cytoprotection against prolonged ischemia (Biel et al, 2016)
Individual overexpression of SIRT1 or MFN2 alone did not prevent the loss of MFN2 or SIRT1, respectively. These results suggest that both SIRT1 and MFN2 are needed for survival after I/R in old hepatocytes
Summary
Ischemia/reperfusion (I/R) injury is a fundamental obstacle in liver resection and transplantation surgery. SIRT1 overexpression reversed pathological events through its interaction with and subsequent deacetylation of MFN2 This mitochondrial outer membrane protein has diverse functions such as mitochondrial fusion (Chen et al, 2003), tethering between mitochondria and endoplasmic reticulum (ER) (de Brito & Scorrano, 2008; Naon et al, 2016), metabolic regulation (Bach et al, 2003; Sebastian et al, 2012), and the endocytic/secretory pathway (Daniele et al, 2014; Zhao et al, 2012). It is currently unknown how SIRT1 and MFN2 are affected by I/R in old hepatocytes. We provide mechanistic insights into how extramitochondrial SIRT1 deacetylates mitochondrial MFN2
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