MOTS-c attenuates placental vascular endothelial cell apoptosis in intrahepatic cholestasis of pregnancy by inhibiting K33-linked deubiquitination of BACH1.

Pregnant mice with ICP induced by cholic acid were given MOTS-c, and the paper reports that treatment promoted placental angiogenesis and reduced apoptosis of placental vascular endothelial cells. In parallel, human umbilical vein endothelial cells (HUVECs) exposed to taurocholic acid were treated with MOTS-c in vitro, where it reduced oxidative stress and apoptosis. Mechanistically, the authors report that MOTS-c binds the D560 residue of BACH1, displacing the deubiquitinase USP7 and promoting K33-linked polyubiquitination and proteasomal degradation of BACH1, which relieves repression of SLC25A51 and supports mitochondrial NAD+ import and biogenesis. In vivo, MOTS-c treatment in the ICP mice was associated with higher birth weight, placental efficiency, and neonatal survival. Clinical samples from ICP patients showed lower MOTS-c protein in maternal serum and placental tissue than controls.

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