Hydrogen sulfide promotes mitochondrial biogenesis through PPARγ activation in intra‐cerebral administration of homocysteine (1126.18)

Previously we have shown that homocysteine (Hcy) induced oxidative stress, mitophagy and cerebrovascular dysfunction in mouse brain, which was mitigated by H2S (hydrogen sulfide) treatment. Further, Hcy‐induced oxidative stress affecting mitochondrial biogenesis and the protective mechanism implies by H2S are still unclear. The regulation of mitochondrial biogenesis primarily occurs by the transcription factors peroxisome proliferator‐activated receptor gamma (PPARγ), PGC‐1α, nuclear respiratory factor 2 (NRF2), and controlled through signaling (AKT) pathways during stress. Therefore, we hypothesize that H2S can ameliorate Hcy‐induced oxidative stress affecting mitochondrial biogenesis through PPARγ activation and AKT signaling. To test this hypothesis we employed 8‐10 weeks old male wild type (WT) mice: 1) WT+aCSF, 2) WT+ Hcy (0.5µmol) intra‐cerebral (I.C., once prior to NaHS treatment), 3) WT+Hcy +NaHS (NaHS precursor of H2S, 30 µmol/kg, body weight; i.p. for 7 days after Hcy treatment), and 4) WT+NaHS alone. We observed that Hcy led to down regulation of PPARγ through AKT signaling. The results also suggest down regulation of NRF2 which is implicated in mitochondrial biogenesis failure and apoptosis (Caspase‐3 and Caspase‐9) through alternation of mitochondrial markers (Triose Phosphate, NOX, PHB1, HSP60, COX‐4, Cyt‐p450, DRP‐1, MFN‐2, ATP) and DNA damage. Interestingly, H2S ameliorates all these events and endorses mitochondrial biogenesis. These findings demonstrate that Hcy‐induced mitochondrial biogenesis in part by PPARγ activation, AKT and NRF2 involvements, which is potentially mitigated through H2S treatment. Grant Funding Source : HL107640