The Biological Clock-Mitochondria Axis in the Liver: From Molecular Mechanisms to Metabolic Disease

The liver ranks among the peripheral organs exhibiting the most robust circadian rhythmicity, with glucose homeostasis, lipid metabolism, and bile acid turnover governed by tightly phased diurnal oscillations. Mitochondria execute these programs, their output coordinated with the hepatocyte circadian state. The mitochondrial network undergoes dynamic remodeling across the 24 h cycle, encompassing oscillatory changes in bioenergetics, fusion-fission balance, and quality control. This interplay is bidirectional: core clock components drive rhythmic remodeling via cyclin-dependent kinase 1/mitogen-activated protein kinase (CDK1/MAPK)-dependent phosphorylation of dynamin-related protein 1 (DRP1) and the NAD⁺-SIRT1/SIRT3 axis, while retrograde signals modulate clock amplitude and entrainment. Circadian disruption is associated with mitochondrial dysfunction implicated in MASLD onset and progression to MASH and HCC, though this evidence remains largely correlative and derives predominantly from rodent models. This review integrates clock-mitochondria coupling with metabolic liver disease. Restoring this coupling has been proposed as a candidate chronotherapeutic strategy, supported by preliminary rhythmicity data in primary human hepatocytes and a hepatocellular carcinoma cell line, though causal validation in healthy human liver is lacking. Time-restricted feeding, NAD⁺ precursors, PPAR agonists, and ACC inhibitors converge on clock-regulated pathways and may benefit from circadian-informed timing, though this remains unverified.