High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated with Mitochondrial Abnormalities

Abstract

Aim: Sirtuins are NAD+-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3-/-) mice.Materials and Methods: Isolated and Langendorff-mode perfused hearts of WT and SIRT3-/- mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA).Results: Analysis of mitochondrial sirtuins demonstrated that SIRT3 deficiency upregulated SIRT4 with no effect on SIRT5 expression. Hearts of SIRT3-/- mice exhibited significantly less recovery of cardiac function at the end of IR compared to WT mice. Intact (non-perfused) SIRT3-/- hearts exhibited an increased rate of Ca2+-induced swelling in mitochondria as an indicator of mPTP opening. However, there was no difference in mPTP opening and cyclophilin D acetylation between WT and SIRT3-/- hearts subjected to IR injury. Ca2+-stimulated H2O2 production was significantly higher in SIRT3-/- mitochondria that was prevented by SfA. Superoxide dismutase activity was lower in SIRT3-/- heart mitochondria subjected to IR which correlated with an increase in protein carbonylation. However, mitochondrial DNA integrity was not affected in SIRT3-/- hearts after IR.Conclusion: SIRT3 deficiency exacerbates cardiac dysfunction during post-ischemic recovery, and increases mPTP opening and ROS generation without oxidative damage to mitochondrial proteins and DNA.

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

“…The significant role of SIRT3 activity in ROS detoxification was shown in studies with oxygen and glucose deprivation‐induced neuronal damage (Dai et al, ), oxidative stress in type I diabetic model (Liu et al, ), heart ischemia‐induced damage (Parodi‐Rullan, Chapa‐Dubocq, Rullan, Jang, & Javadov, ), intracerebral hemorrhage in diabetic animals (Zheng et al, ), or protective mechanisms in adaptive responses of neurons to physiological challenges and resistance to degeneration (Cheng et al, ). Our data show that SIRT3KO mice exhibit increased ROS levels when compared to WT animals with no change after NMN administration.…”

Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials

“…Cardiomyocyte‐specific SIRT3 expression has been shown to protect the heart against pathological hypertrophy through activation of FoxO3‐dependent antioxidant genes (Sundaresan et al ., ). Meanwhile, its deficiency resulted in increased vulnerability to I/R due to inhibition of MnSOD (Porter et al ., ) and opening of the mitochondrial permeability transition pore (mPTP) (Parodi‐Rullán et al ., ).…”

Regulation of Sirtuin‐Mediated Protein Deacetylation by Cardioprotective Phytochemicals

“…As demonstrated in previous studies, sirt3 −/− mice develop cardiac hypertrophy, fibrosis, and mitochondrial dysfunction in an age-dependent manner [ 31 ]. In addition, sirt3 −/− mice are more sensitive to damage induced by I/R injury [ 32 – 35 ] and microvascular dysfunction [ 34 ]. In contrast, overexpression of Sirt3 in mice hearts provides protection against cardiac hypertrophy and fibrosis [ 36 , 37 ].…”