Miro2 sulfhydration by CBS/H2S 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 (H₂S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H₂S levels were lower in PE patients' plasma; H₂S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H₂S donor, 1 µM) promoted CBS/H₂S 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/H₂S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2^C185/C504) were highly sulfhydrated by H₂S. Knockdown Miro2 or double mutation of Miro2^C185/^C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H₂S. The present study showed that human cytotrophoblast receives low dose H₂S regulation; CBS/H₂S sustained mitochondria functions via Miro2^C185/C504 sulfhydration to enhance cytotrophoblast mobility. These findings established a new regulatory pathway for cytotrophoblast functions, and provided new targets for IUGR and PE.