Mitochondrial Dysfunction in Wilson disease: A Systematic Review and Meta–Analysis Across Human and Animal Models

Raya Amin¹Valentina Medici²Erik Davis Fausak³Keren Sierra¹Ieleen Li¹Joshua Gong¹Cecilia Giulivi^1,4*

• ¹Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, United States
• ²Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, Sacramento, United States
• ³University Library, University of California, Davis, United States
• ⁴Medical Investigations of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, Sacramento, United States

Background & Aims: Wilson disease (WD) is a genetic disorder of copper metabolism caused by ATP7B mutations, leading to hepatic and systemic copper accumulation. While lysosomes are early storage sites, mitochondria appear highly vulnerable to copper toxicity. We performed a systematic review and meta–analysis to assess mitochondrial outcomes in WD patients and animal models. Methods: PubMed, Scopus, and SciFinder were searched through September 11, 2025, for studies reporting hepatic mitochondrial endpoints in WD (in patients and models using mice, rats, and dogs). Outcomes included mitochondrial copper, morphology, oxidative stress, mtDNA copy number, ATP production, and respiratory Complex activities. Random–effects meta–analyses were conducted. Results: Thirteen studies met the inclusion criteria. Mitochondrial copper was consistently elevated (SMD ± SE: 6.7 ± 0.9, P < 0.001), with ultrastructural abnormalities (4 ± 2, P = 0.012). Oxidative stress markers increased (2.9 ± 0.9, P = 0.001), while MnSOD and aconitase declined with disease progression. mtDNA copy number was reduced (-0.7 ± 0.3, P = 0.032). ATP synthesis (-1.5 ± 0.6, P = 0.023) and Complex activities (-1.0 ± 0.3, P = 0.001) were impaired, especially in older or symptomatic subjects. Citrate synthase activity increased (2.8 ± 0.9, P = 0.003), consistent with compensatory biogenesis. Several abnormalities appeared in presymptomatic or young animals. Conclusions: Across human and animal studies, hepatic mitochondria in WD exhibit copper accumulation, structural injury, impaired bioenergetics, oxidative stress, and mitochondrial genome loss. Mitochondrial dysfunction arises early and worsens with progression, highlighting it as a central pathogenic feature and therapeutic target.