Sex-specific mitochondrial dysregulation and metformin response in Wilson disease

Authors: MEDICI, VALENTINA - University Of California, Davis; SHIBATA, NOREENE - University Of California, Davis; VORKAPICH, ALDO - University Of California, Davis; DANG, JENNIFER - University Of California, Davis; MULLAH, RIDA - University Of California, Davis; TORK, ATENA - University Of California, Davis; SNODGRASS, ISABEL - University Of California, Davis; Kim, Dohee; Newman, John; GREENBLATT, ZOE - University Of California, Davis; TRAN, HUY-ANN - University Of California, Davis; LI, IELEEN - University Of California, Davis; SIERRA, KEREN - University Of California, Davis; GONG, QIXUAN - University Of California, Davis; GIULIVI, CECELIA - University Of California, Davis

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/16/2026
Publication Date: 6/27/2026
Citation: Medici, V., Shibata, N., Vorkapich, A., Dang, J., Mullah, R., Tork, A., Snodgrass, I.F., Kim, D., Newman, J.W., Greenblatt, Z.L., Tran, H., Li, I., Sierra, K., Gong, Q., Giulivi, C. 2026. Sex-specific mitochondrial dysregulation and metformin response in Wilson disease. Scientific Reports. https://doi.org/10.1038/s41598-026-58720-7.
DOI: https://doi.org/10.1038/s41598-026-58720-7

Interpretive Summary: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to opper accumulation in the liver, mitochondrial injury, and systemic metabolic dysfunction. Metformin is a common antihyperglycemic drug with metal-binding properties. We tested whether metformin modifies mitochondrial abnormalities in the liver of a mouse model of WD, stratified by sex. Adult male and female Atp7b'/' mice were treated with metformin in water (500 mg/kg/day) or water alone for 2 weeks. Liver mitochondria were evaluated for changes in structure, respiratory chain enzyme activities, reactive oxygen production, and accumulation of copper and iron. Whole liver changes in metals, glucocorticoids and bile acids were also assessed. Female Atp7b'/'mice showed greater mitochondrial injury and higher levels of copper/iron than males. In females, metformin improved mitochondrial structure and function, while producing favorable changes in glucocorticoid and bile acid profiles. In contrast, metformin produced limited improvement in mitochondrial function or stress-related endpoints in males. These findings establish sex as a critical determinant of therapeutic response in WD and support sex-informed evaluation of mitochondrial-targeted therapies in larger cohorts and clinical studies.

Technical Abstract: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to hepatic copper accumulation, mitochondrial injury, and systemic metabolic dysfunction. Metformin is a common antihyperglycemic drug with mitochondrial and metal-binding properties. We tested whether metformin modifies hepatic mitochondrial abnormalities in a mouse model of WD, stratified by sex. Adult male and female Atp7b'/' mice were treated with metformin in water (500 mg/kg/day) or water alone for 2 weeks. Liver mitochondria were evaluated by TEM and quantitative morphometry, respiratory chain enzyme activities, ROS production, hepatic and mitochondrial copper/iron quantification, and targeted glucocorticoid and bile acid profiling. At baseline, female Atp7b'/' mice exhibited greater mitochondrial ultrastructural injury, reduced fusion-associated morphology, and higher hepatic and mitochondrial copper/iron levels compared with males. Metformin resulted in higher circulating exposure in females and was associated with improved mitochondrial structure, increased fusion-associated features, enhanced respiratory complex activity, reduced oxidative stress, and favorable modulation of glucocorticoid and bile acid profiles. In contrast, metformin produced limited improvement in mitochondrial function or stressrelated endpoints in males. These findings establish sex as a critical determinant of therapeutic response in WD and support sex-informed evaluation of mitochondrial-targeted adjunctive therapies, warranting validation in larger cohorts and clinical studies.