Miro2 sulfhydration by CBS/H 2 S 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 (H ₂ S) enhanced CTB migration without knowing the mechanism(s) and the pathophysiological significance. By studying human samples and cell line, we found that H ₂ S levels were lower in PE patients' plasma; H ₂ S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H ₂ S donor, 1 µM) promoted CBS/H ₂ S 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/H ₂ S 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 H ₂ S. 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 H ₂ S. The present study showed that human cytotrophoblast receives low dose H ₂ S regulation; CBS/H ₂ S 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.
(© 2024. The Author(s).)