Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway

Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammation in pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a bi-organellar protein responsible for mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro. MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation.