1. Miro2 sulfhydration by CBS/H 2 S promotes human trophoblast invasion and migration via regulating mitochondria dynamics.
- Author
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Feng H, Sun Z, Han B, Xia H, Chen L, Tian C, Yan S, Shi Y, Yin J, Song W, Gong P, Wang S, and Li Y
- Subjects
- Humans, Female, Pregnancy, Morpholines pharmacology, Mitochondrial Proteins metabolism, Mitochondrial Proteins genetics, Signal Transduction, Adult, Trophoblasts metabolism, Trophoblasts pathology, Hydrogen Sulfide metabolism, Hydrogen Sulfide pharmacology, Cell Movement, Cystathionine beta-Synthase metabolism, Cystathionine beta-Synthase genetics, Mitochondrial Dynamics, Mitochondria metabolism, rho GTP-Binding Proteins metabolism, rho GTP-Binding Proteins genetics, Pre-Eclampsia metabolism, Pre-Eclampsia pathology, Pre-Eclampsia genetics, Organothiophosphorus Compounds pharmacology
- Abstract
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 H2 S levels were lower in PE patients' plasma; H2 S synthetic enzyme cystathionine β-synthetase (CBS) was reduced in PE extravillious invasive trophoblasts. GYY4137 (H2 S donor, 1 µM) promoted CBS/H2 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/H2 S signal. Disturbance of mitochondria dynamics inhibited cell invasion and migration. The 185 and 504 cysteines of Mitochondrial Rho GTPase 2 (Miro2C185/C504 ) were highly sulfhydrated by H2 S. Knockdown Miro2 or double mutation of Miro2C185 /C504 to serine fragmented mitochondria, and inhibited cell invasion and migration which can't be rescued by H2 S. The present study showed that human cytotrophoblast receives low dose H2 S regulation; CBS/H2 S sustained mitochondria functions via Miro2C185/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).)- Published
- 2024
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