Disrupted Mitochondrial Copper Homeostasis Promotes Ferroptotic Stress, Senescence and MASLD Progression

Area of Science:

• Hepatology
• Mitochondrial Biology
• Metabolic Diseases

Background:

• Systemic metabolic dysfunction can lead to degenerative diseases affecting organs like the liver and kidney.
• The liver plays a crucial role in maintaining systemic metal ion homeostasis.
• Copper deficiency is increasingly noted in metabolic dysfunction-associated steatotic liver disease (MASLD), correlating with disease severity.

Purpose of the Study:

• To investigate if impaired mitochondrial copper homeostasis contributes to MASLD pathobiology.
• To explore mitochondrial copper regulation as a potential therapeutic target for MASLD.

Main Methods:

• Utilized dietary mouse models of MASLD and in vitro systems.
• Analyzed copper levels, mitochondrial function, and cellular stress markers.
• Investigated the role of the SLC25A3-SCO1-MT-CO1-CTR1 axis in copper transport.

Main Results:

• Dietary copper deficiency in MASLD models induced lipotoxicity and suppressed mitochondrial metabolism.
• MASLD livers showed copper depletion, impaired cytochrome c oxidase, and bioenergetic failure.
• Restoring mitochondrial copper normalized function, reduced ferroptosis and senescence, and attenuated liver and kidney fibrosis.

Conclusions:

• Mitochondrial copper deficiency is a key driver of MASLD, causing bioenergetic failure and tissue damage.
• Targeting mitochondrial copper regulation presents a novel therapeutic approach for MASLD and associated systemic complications.