The Mitochondrial-Autophagy Axis in MASLD: Mechanisms, Crosstalk, and Therapeutic Targets

This review seeks to integrate contemporary evidence regarding mitochondrial dysfunction and autophagic regulation in metabolic dysfunction associated steatotic liver disease (MASLD), elucidating mechanistic pathways, indigenous determinants, and emerging therapeutic targets.

A thorough search was performed in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar. Research publications on mitochondrial activity, oxidative phosphorylation, fatty acid oxidation, mitophagy, lipophagy, and associated autophagic pathways in MASLD or MASH were incorporated.

This review integrates findings that show mitochondrial dysfunction is a key mediator of MASLD progression. Mitochondrial dysfunction due to fatty acid oxidation, electron transport chain uncoupling, increased reactive oxygen species, and was found to be associated with steatosis, inflammation, and fibrosis. Simultaneous inhibition of autophagy, including lipophagy and mitophagy, contributes to lipid accumulation and persistence of dysfunctional mitochondria. Novel mediators of MASLD progression include gut dysbiosis, ferroptosis, and mitoDAMP signaling.

In summary, the results indicate that mitochondrial dysfunction and autophagy dysregulation are interdependent mediators of MASLD pathogenesis. Their interaction mediates metabolic overload to oxidative stress, inflammation, and fibrotic remodeling. The understanding of these mechanisms provides a common platform for MASLD progression and suggests mitochondrial quality control, autophagy modulation, and associated metabolic pathways as promising targets for future MASLD therapeutic and preventive strategies.