Hyperhomocysteinemia abrogates fasting-induced cardioprotection against ischemia/reperfusion by limiting bioavailability of hydrogen sulfide anions

Abstract

Two-day fasting of mice ameliorates ischemia/reperfusion injury in Langendorff hearts. H2S-producing enzymes, CBS and CTH, are essential in fasting-induced cardioprotection. Administration of a H2S donor (NaHS) confers cardioprotection against IR injury. NaHS effects are absent in Cth (-/-), Cbs (-/-), and dietary hyperhomocysteinemic mice. Homocysteine captures cardioprotective HS(-) to form homocysteine persulfide.

Differential adaptive responses to 1‐ or 2‐day fasting in various mouse tissues revealed by quantitative PCR analysis

“…Such antioxidant responses may underlie cytoprotective effects conferred by fasting [1,3] . Indeed we observed that 2-day fasting of mice provides marked cardioprotection against ischemia/reperfusion injury [29] and thus, fasting-induced cytoprotection could be expected also in thymic and renal injuries. Furthermore, xCT , an aspartate/glutamate/cystine transporter gene, was induced upon fasting in thymus ( Fig.…”

Persulfide synthases that are functionally coupled with translation mediate sulfur respiration in mammalian cells

“…However, how H 2 S was supplied endogenously in mitochondria remained unclear. Our various studies suggest that CSE, CBS and 3-mercapopyruvate sulfur transferase are not primary H 2 S sources in mitochondria in different mammalian cell lines and in vivo in mice (Nishida et al, 2012;Morikawa et al, 2012;Ono, et al, 2014;Shirozu et al, 2014;Nakano et al, 2015;Yadav et al, 2016). In fact, our recent study was the first to confirm that HS À (or H 2 S) was formed indirectly from CARS2 via CysSSH generation in the mitochondrial environment .…”

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

“…5e and Supplementary Fig. 18 ) 7 , 20 – 24 . In this context, our study is the first to verify that HS − (or H 2 S) is indirectly formed from CARS2 via CysSSH generation in the mitochondrial environment (Figs.…”

“…Until now, endogenous persulfides were thought to be formed as a result of H 2 S/HS − oxidation via post-translational processes, and serve as protein cysteine thiol-bound intermediates of detoxification enzymes 3 , 7 , 21 , and as metal ligands for iron and zinc complexes 11 – 15 . While CSE and CBS can catalyze CysSSH biosynthesis by using cystine as a substrate 3 , 4 , 6 – 10 , 18 – 21 , several cells and tissues without CSE/CBS expression and CBS/CSE KO mice reportedly synthesized appreciable amounts of persulfides 3 , 20 , 22 – 24 , but the source of the persulfides (polysulfides) or the sulfane sulfur reservoir has remained elusive. We here demonstrate that CARSs catalyze CysS–(S) n –H formation from cysteine and co-translational protein polysulfidation.…”

“…Two H 2 S-generating enzymes involved in sulfur-containing amino acid metabolism—cystathionine γ-lyase (cystathionase, CSE) and cystathionine β-synthase (CBS)—can catalyze CysSSH biosynthesis using cystine (CysSSCys) as a substrate 3 , 4 , 6 – 10 , 18 – 21 . However, the observed K m is high, and both cells and mice lacking CSE and/or CBS still display appreciable levels of CysSSH 20 – 24 , which suggests the possibility that alternative processes may be responsible for endogenous persulfide production. Thus, it appears that other biosynthetic routes of CysSSH formation exist that have yet to be identified.…”