Hydrogen sulfide sustains mitochondria functions via targeting mitochondria fission regulator 1 like protein to restore human cytotrophoblast invasion and migration

Hydrogen sulfide (H2S) is bioactive in mammals. Reduced H2S was observe in pregnancy complications, pre-eclampsia (PE). Our previous data demonstrated that low dose of H2S enhanced cytotrophoblast (CTB) invasion and migration via mitochondria dynamics without knowing the mechanisms. This study was designed to explore the functional regulation of CTB by mitochondrial fission regulator 1 like (MTFR1L) and the mechanisms. By studying human placenta samples and HTR-8/SVneo cell line, MTFR1L was found expressed in CTB. While MTFR1L expression was lower in PE placenta and CTB comparing with Normal pregnancy. Knockdown of MTFR1L decreased CTB invasion and migration, as well as the ATP production, while increased the mitochondria fragmentation, ROS production and mitochondria membrane potential indicating MTFR1L was key regulator of mitochondria. The posttranslational modulation analysis showed enhanced persulfidation of MTFR1L on cystine 222 and 230 by H2S. Mutations of MTFR1LC222/C230 suppressed ATP production, CTB invasion, migration, and increased mitochondria fragmentation, ROS production and mitochondria membrane potential. The present study showed the functional MTFR1L received endogenous CBS/H2S regulation. MTFR1LC222/230 persulfidation by H2S maintained mitochondria morphology and functions thus restored CTB invasion and migration. These findings established a new regulatory pathway for CTB invasion and migration, and provided new targets for PE treatment.Hydrogen sulfide (H2S) is bioactive in mammals. Reduced H2S was observe in pregnancy complications, pre-eclampsia (PE). Our previous data demonstrated that low dose of H2S enhanced cytotrophoblast (CTB) invasion and migration via mitochondria dynamics without knowing the mechanisms. This study was designed to explore the functional regulation of CTB by mitochondrial fission regulator 1 like (MTFR1L) and the mechanisms. By studying human placenta samples and HTR-8/SVneo cell line, MTFR1L was found expressed in CTB. While MTFR1L expression was lower in PE placenta and CTB comparing with Normal pregnancy. Knockdown of MTFR1L decreased CTB invasion and migration, as well as the ATP production, while increased the mitochondria fragmentation, ROS production and mitochondria membrane potential indicating MTFR1L was key regulator of mitochondria. The posttranslational modulation analysis showed enhanced persulfidation of MTFR1L on cystine 222 and 230 by H2S. Mutations of MTFR1LC222/C230 suppressed ATP production