Exogenous H2S Promoted USP8 Sulfhydration to Regulate Mitophagy in the Hearts of db/db Mice

Abstract

Hydrogen sulfide (H2S), an important gasotransmitter, regulates cardiovascular functions. Mitochondrial damage induced by the overproduction of reactive oxygen species (ROS) results in myocardial injury with a diabetic state. The purpose of this study was to investigate the effects of exogenous H2S on mitophagy formation in diabetic cardiomyopathy. In this study, we found that exogenous H2S could improve cardiac functions, reduce mitochondrial fragments and ROS levels, enhance mitochondrial respiration chain activities and inhibit mitochondrial apoptosis in the hearts of db/db mice. Our results showed that exogenous H2S facilitated parkin translocation into mitochondria and promoted mitophagy formation in the hearts of db/db mice. Our studies further revealed that the ubiquitination level of cytosolic parkin was increased and the expression of USP8, a deubiquitinating enzyme, was decreased in db/db cardiac tissues. S-sulfhydration is a novel posttranslational modification of specific cysteine residues on target proteins by H2S. Our results showed that the S-sulfhydration level of USP8 was obviously decreased in vivo and in vitro under hyperglycemia and hyperlipidemia, however, exogenous H2S could reverse this effect and promote USP8/parkin interaction. Dithiothreitol, a reducing agent that reverses sulfhydration-mediated covalent modification, increased the ubiquitylation level of parkin, abolished the effects of exogenous H2S on USP8 deubiquitylation and suppressed the interaction of USP8 with parkin in neonatal rat cardiomyocytes treated with high glucose, oleate and palmitate. Our findings suggested that H2S promoted mitophagy formation by increasing S-sulfhydration of USP8, which enhanced deubiquitination of parkin through the recruitment of parkin in mitochondria.

Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms

“…In contrast to DCM in T1DM, cardiac lipotoxicity is a key pathologic mechanism in DCM in T2DM. Some previous studies have shown that cardiac autophagy and mitophagy is inhibited in high-fat diet (HFD)-fed mice (Sciarretta et al, 2012;Guo et al, 2013;Mu et al, 2020;Sun et al, 2020;Yu et al, 2021), but others have shown the opposite. Mellor et al (2011) and Tang et al (2015) found that cardiac autophagy and mitophagy are activated in the hearts of mice and rats with T2DM, respectively, which they stated would be harmful.…”

“…In the hearts of mice with T1DM, Xu et al (2013) found that the expression of parkin and PINK1 was lower, which implies that mitophagy is impaired in diabetes. Hydrogen sulfide promotes mitophagy in the diabetic heart by increasing the S-sulfhydration of USP8, which increases the deubiquitination of parkin ( Sun et al, 2020 ). Sirt3 overexpression activates mitophagy to reduce myocardial apoptosis in vitro .…”

Hydrogen Sulfide, an Endogenous Stimulator of Mitochondrial Function in Cancer Cells

“…H 2 S has been shown to regulate all significant aspects of mitochondrial dynamics: mitochondrial fusion, mitochondrial fission, mitochondrial macroautophagy/mitophagy, and mitochondrial biogenesis) [ 87 , 94 , 95 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. The majority of the published studies indicate that H 2 S (especially in lower concentrations) tends to stabilize and preserve mitochondria, and, in many cases, can also stimulate mitochondrial biogenesis.…”

“…In the diabetic heart, ubiquitin specific peptidase 8 (USP8) has been implicated: H 2 S was found to increase the association of parkin with USP8. In turn, USP8 (a deubiquitination enzyme) was shown to promote the association of parkin to damaged mitochondria to augment mitophagy [ 145 ]. In another study focusing on cardiac myocytes, H 2 S-stimulated mitochondrial biogenesis was shown to involve AMP-activated protein kinase (AMPK) activation and subsequent induction of PGC1α signaling [ 87 ].…”

Hydrogen Sulfide and Endoplasmic Reticulum Stress: A Potential Therapeutic Target for Central Nervous System Degeneration Diseases

“…and sulfhydration of parkin diminishes, while the persulfidation of parkin protein promotes the activity of ubiquitin E3 ligase, thereby mediating cell protection. H 2 S may upregulate the expression of deubiquitinating enzymes USP8 to antagonize the degradation of Parkin protein (Sun et al, 2020). This implies that H 2 S donors may be potentially therapeutic (Vandiver et al, 2013).…”