Miro2 sulfhydration by CBS/HS promotes human trophoblast invasion and migration via regulating mitochondria dynamics.

Insufficient cytotrophoblast (CTB) migration and invasion into the maternal myometrium leads to pregnancy related complications like Intra-uterus Growth Restriction (IUGR), and pre-eclampsia (PE). We previously found that hydrogen sulfide (HS) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that HS levels were lower in PE patients' plasma; HS synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (HS donor, 1 µM) promoted CBS/HS translocation onto mitochondria, preserved mitochondria functions, enhanced cell invasion and migration. CBS knockdown hindered the above functions which were rescued by GYY4137, indicating the vital roles of CBS/HS signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2) were highly sulfhydrated by HS. Knockdown Miro2 or double mutation of Miro2/ to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by HS. The present study showed that human cytotrophoblast receives low dose HS regulation; CBS/HS sustained mitochondria functions via Miro2 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.