biostudies-literatureSohn JHNIDDK NIH HHSNIGMS NIH HHS1356-1372.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC10528355biostudies-literatureUnknown35(8)Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrCell metabolismLiver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.PMC10528355R01 DK117655F32 GM136019K99 DK133502R01 DK089883P30 DK135043R01 DK081418Kantorovich NPuigserver PLatorre-Muro PSohn JHLiang JSharabi KGygi SPMutlu BBanks ASJedrychowski MBennett CFfalseLiver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestr2023-01-01T00:00:00Z2023 Aug2025-04-26T01:13:59.021Z2025-04-06T10:01:08.487ZS-EPMC105283553747375410.1016/j.cmet.2023.06.015