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  • br Competing interests br Acknowledgments This

    2024-04-01


    Competing interests
    Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2014R1A4A1071040).
    Introduction Mitochondria occupy an important position as mediators of cellular homeostasis due to their role in the regulation of fuel utilization, calcium storage, intracellular signaling, and cell death [1], [2]. As such, impairments in mitochondrial function lead to the development of various disorders, such as neurodegenerative disease, cancer, aging, diabetes, and heart failure [1]. The heart is particularly susceptible to impairments in mitochondrial function given its limited regenerative capacity and persistent Melphalan requirements [2]. As a result, the mitochondrial quality control system, consisting of mitophagy, fission and fusion, and biogenesis, is critically important in maintaining the fidelity of the heart under physiological and pathological conditions [1], [2], [3]. The mitochondrial biogenic response in the heart is tightly regulated by a complex network orchestrating both nuclear and mitochondrial genome transcription and replication [3]. This system coordinates both genomes during cardiac development and in response to physiological stimuli when there are changes in substrate availability and energetic demands [3]. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial biogenesis and energy expenditure [4], [5]. Cardiac PGC-1α is induced at birth when the heart undergoes a dramatic shift in fuel preference from relying on glucose and lactate during the fetal period to the use of fatty acids (FA) after birth [6]. PGC-1α regulates the activity of a number of transcription factors, including, peroxisome proliferator-activated receptor-α (PPARα), estrogen receptor–related α (ERRα) and nuclear respiratory factor 1 (NRF1) [5]. By regulating the transcriptional activities of these proteins, PGC-1α modulates genes involved in mitochondrial biogenesis and metabolic pathways. Mitochondrial content is significantly reduced in the failing hearts of both rodents and humans [7], [8]. Furthermore, downregulation of PGC-1α signaling has also been observed in the setting of experimental heart failure [9]. As such, understanding the mechanisms by which PGC-1α signaling is regulated in the heart could lead to the development of therapies aimed at inducing mitochondrial biogenesis and augmenting energy production in the setting of increased contractile demand [8]. Hydrogen sulfide (H2S) is a critically important physiological gaseous signaling molecule that regulates a multitude of biological processes, including angiogenesis, proliferation, redox balance, inflammation, and cell death [10]. It is produced enzymatically in all mammalian species via the actions of cysteine metabolic enzymes: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfutransferase (3MST) [10], [11]. Although all three enzymes are expressed in the cardiovascular system, prevailing data indicates that CSE plays the foremost role in cardiovascular physiology [10]. Numerous proteins and pathways have been identified as cellular targets of H2S. However, a common cellular target for many studies aimed at understanding the biology and therapeutic potential of H2S has been the mitochondria. H2S has a dual affect on mitochondrial bioenergetics with low concentrations serving as electron donors to the electron transport chain and higher concentrations serving as inhibitors of cytochrome c oxidase [12]. H2S also influences the levels/activation of a number of proteins related to mitochondrial biogenesis (PGC1α [13], [14]; AMP-activated protein kinase (AMPK) [15], [16]; endothelial nitric oxide synthase (eNOS) [11], [17], [18]) and there is evidence that mitochondrial content is higher in brains [13] and hearts [19] treated with exogenous H2S. While these studies provided evidence for elevated mitochondrial levels in response to H2S treatment, it was not clear if the observed increase was due to a direct effect of H2S or was simply an indirect consequence of H2S altering injury. Therefore, the main goal of the current study was to address this issue by determining if H2S levels directly influence cardiac mitochondrial content under non-stressed conditions. Additionally, we sought to gain insights into the mechanisms by which H2S induces mitochondrial biogenesis in the setting of myocardial ischemia-reperfusion.