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

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.

CircERCC2 ameliorated intervertebral disc degeneration by regulating mitophagy and apoptosis through miR-182-5p/SIRT1 axis

“…Our previous studies demonstrated that SIRT1 has a protective role in IVDD 31,32 . Furthermore, several studies revealed that SIRT1 plays a key role in mitophagy and apoptosis in a variety of aging-related diseases via SIRT1-Parkin-Mitohphagy pathway [33][34][35][36][37] . In present study, we showed that circERCC2 regulated the expression of SIRT1 by sponging miR-182-5p.…”

CD5L‑induced activation of autophagy is associated with hepatoprotection in ischemic reperfusion injury via the CD36/ATG7 axis

“…Autophagy serves an important role in supporting hepato-cellular viability following I/R injury (21). Promotion of autophagy prevents mitochondrial dysfunction and cell death following reperfusion (35). A recent study has demonstrated that increasing the level of autophagy decreases hepatic I/R injury (36).…”

Role and Mechanisms of Mitophagy in Liver Diseases

“…Interestingly, severe liver injury is observed in aged mice following hepatic IR exposure compared to young mice, indicating that an aged liver responds differently to the stress [170]. Although the basal autophagy level is comparable in young and aged mice, the aged mice fail to remove damaged mitochondria after hepatic IR, showing defective SIRT1/Mfn2 mediated-mitophagy in the liver, which contributes to increased susceptibility to IR injury [171]. In human hepatic biopsy specimens, Parkin expression is negatively correlated with donor age and the peak level for aspartate aminotransferase is within the first week after liver transplantation, suggesting that PINK1/Parkin-mediated mitophagy is likely to be a protective mechanism in IR-induced injury [172].…”