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  • br Materials and methods br Results br Discussion

    2024-05-22


    Materials and methods
    Results
    Discussion The transcriptional activity of PGC-1α is regulated by a number of stimuli, exemplifying the range of settings in which mitochondrial biogenesis is induced. The mechanisms governing this regulation have been extensively studied and have been determined to vary between tissues and different settings [5]. AMPK, a member of the metabolite-sensing protein kinase family, is activated in response to alterations in cellular SCH 58261 receptor levels [32]. Activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, while switching off anabolic pathways that consume ATP [38]. AMPK also induces mitochondrial biogenesis via the activation of PGC-1α. Specifically, AMPK regulates PGC-1α directly through serine phosphorylation, as well as indirectly via the activation of Sirt1, which leads to the deacetylation of PGC-1α [5]. This coordinated signaling cascade, whereby the phosphorylation of PGC-1α by AMPK is required for the subsequent Sirt1-mediated deacetylation, demonstrates the complex and specific nature by which PGC-1α is regulated by AMPK [29]. Here, we found that increasing cardiac H2S levels through the dietary supplementation of SG-1002 led to the activation of AMPK and Sirt1 resulting in the phosphorylation and deacetylation of PGC-1α. More importantly, we found that SG-1002 failed to alter PGC-1α, induce PGC-1α target genes, and induce mitochondrial biogenesis in the hearts of AMPKα2 deficient mice – indicating that H2S induces mitochondrial biogenesis via AMPK. Our data also provides some insights into how H2S regulates AMPK. The activation of AMPK is mediated through different mechanisms involving the allosteric regulation of AMPK subunits through changes in adenosine metabolites, activation by LKB1, and changes in the activity of PP2A [32]. Here, we found that H2S did not change the levels of adenosine metabolites nor alter the phosphorylation of LKB1. Rather, our evidence indicates that H2S affects AMPK by decreasing the activity of the serine/threonine protein phosphatase, PP2A. Recently, H2S was shown to inhibit the activity of PTP1B via sulfhydration [35]. Sulfhydration or persulfidation is a post-translational modification by which H2S alters cysteine residues in proteins through the formation of a persulfide (-SSH) bond [34]. Studies indicate that protein sulfhydration is a major event by which H2S elicits cellular signaling. For instance, the antiapoptotic actions of NFkB are dependent on H2S sulfhydrating its p65 subunit [23]. Also, H2S induces endothelial cell and smooth muscle cell hyperpolarization and vasorelaxation by sulfhydrating ATP-sensitive potassium channels [39]. Here, we found that all three PP2A subunits displayed enhanced sulfhydration in the hearts of mice supplemented with SG-1002. Since this modification was accompanied by a decrease in activity, it can be suggested that like for PTP1B, sulfhydration of PP2A imparts inactivation. Further studies are warranted to elucidate the specific cysteine residues that are modified on each subunit and to determine how each affects the activity of PP2A. As noted, H2S is a known regulator of cellular bioenergetics via its actions on mitochondrial function. For instance, H2S acts as a stimulator of mitochondrial bioenergetics through its ability to donate electrons to the mitochondrial electron transport chain [12], [40]. This action serves a physiological role in the maintenance of mitochondrial electron transport, as well as complementing and balancing the bioenergetic role of Krebs cycle-derived electron donors [12]. In contrast, H2S is a potent and reversible inhibitor of mitochondrial function via its regulation of cytochrome c oxidase (complex IV of the mitochondrial electron transport chain) [41]. Paradoxically, this action contributes to the cardioprotective effects of exogenous H2S, as inhibition of mitochondrial respiration during the early stages of reperfusion injury limits the generation of reactive oxygen species, which ultimately preserves mitochondrial function [18], [19], [20]. In addition, H2S targets several cellular pathways that influence mitochondrial function [42]. PGC-1α not only regulates mitochondrial biogenesis, but also regulates energy expenditure in the heart. Specifically, PGC-1α is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation and ATP synthesis [26]. Consistent with our findings regarding the induction of PGC-1α signaling, we observed that augmenting cardiac H2S levels increased the maximal capacity for mitochondrial fatty acid β-oxidation and ATP synthesis, whereas lower H2S levels had the opposite effect.