No abstract

Mitochondria play a key role in the growth and development of the placenta, an organ essential for pregnancy in eutherian mammals. Mitochondrial dysfunction has been associated with pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals at a cellular and mechanistic level are unknown. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) is a bi-organellar protein responsible for optimal mitochondrial function to achieve energy and redox homeostasis. In addition, MNRR1 also is required for optimal induction of cellular stress-responsive signaling pathways such as the mitochondrial unfolded protein response (UPRmt). Here, in a lipopolysaccharide-induced model of placental inflammation, we show that MNRR1 levels are reduced in placental tissues and cell lines. Reduction in MNRR1 is associated with mitochondrial dysfunction and enhanced oxidative stress along with activation of pro-inflammatory signaling. Mechanistically, we uncover a non-conventional pathway independent of Toll-like receptor 4 (TLR4) that results in a specific ATM kinase-dependent threonine phosphorylation and activation of a mitochondrial protease, YME1L1, degrading MNRR1. Furthermore, enhancing MNRR1 levels in placental cells either genetically or with specific activators abrogates the bioenergetic defect and induces an anti-inflammatory phenotype, suggesting that MNRR1 is upstream of the mitochondrial dysfunction observed in our model. Reduction in MNRR1 levels is a generalized phenomenon observed in cells under an inflammatory stimulus. We therefore propose MNRR1 as a novel anti-inflammatory therapeutic target in pathologies associated with placental inflammation.