Background & Aims: Systemic metabolic dysfunction promotes degenerative diseases in many organs, including liver and kidney. The liver is a master regulator of systemic metal ion homeostasis. Hepatic copper deficiency is increasingly observed in metabolic dysfunction associated steatotic liver disease (MASLD) and is associated with greater disease severity and poor outcomes. However, mechanisms linking copper dysregulation to MASLD and its co-morbidities remain poorly defined. We investigated whether impaired mitochondrial copper homeostasis contributes to MASLD-related pathobiology and represents a modifiable therapeutic axis. Methods & Results: Using dietary mouse models of MASLD and in vitro systems, we found that dietary copper deficiency induces lipotoxicity and suppresses mitochondrial metabolic programs. MASLD livers exhibited marked depletion of copper, impaired cytochrome c oxidase integrity, and bioenergetic failure. Targeted restoration of mitochondrial copper with the copper ionophore elesclomol normalized copper-handling programs, improved mitochondrial function, and suppressed ferroptotic stress, hepatocyte senescence, and fibroinflammatory remodeling. Mechanistically, reduced expression of the mitochondrial copper transporter SLC25A3 and MT-CO1 disrupted the SLC25A3/SCO1/MT-CO1/CTR1 axis, limited copper uptake and destabilized copper-iron balance, promoting maladaptive cell fate changes. Across multiple human cohorts and mouse models, copper-iron imbalance tracks with MASLD progression, clinical outcomes, and multiple extrahepatic comorbidities; restoring copper homeostasis in mice with MASLD attenuates both liver and kidney inflammation and fibrosis. Conclusions: Mitochondrial copper deficiency is a mechanistically actionable driver of MASLD that promotes bioenergetic failure, ferroptosis, senescence and fibroinflammatory damage in the liver and other organs. Targeting copper-centered mitochondrial regulation represents a novel biomarker and therapeutic strategy for MASLD and its systemic complications.
Ren, N., Wang, L., Dutta, R., Umbaugh, D., Zhang, Q., Oh, S. H., Ko, D. C., Song, M., Diehl, A. M., DU, K.
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