Placental mitochondrial calcium uniporter modulates offspring susceptibility to obesity in a sex-dependent manner

Mitochondria regulate bioenergetics, metabolism, and calcium storage, but their role in the placenta and how they may shape offspring metabolic health remains unclear despite associations with pregnancy complications. We examined this relationship by using a murine model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO). We found that female placental trophoblasts exhibited higher respiration rates than males at baseline. MCU deletion impaired mitochondrial function specifically in female placentas, accompanied by changes in metabolomic profiles of amino acid and lipid catabolism. Transcriptome analysis indicated reduced placental cellular growth, which was supported by smaller placentas and reduced embryonic body weights in PI-MCUKO. These deficits normalized postnatally, with body weight and glucose metabolism remaining comparable to the controls under normal chow diet. Notably, under a metabolic challenge of high-fat-diet feeding, Pl-MCUKO females showed reduced weight gain, improved glucose and insulin tolerance, smaller fat depots and increased ambulatory activity, compared to controls. These results provide direct evidence linking placental mitochondrial function to offspring metabolic health.