Fig. 6

Possible mechanism of AMLN diet and exercise on mitochondrial homeostasis during MASLD development. Under normal circumstances, the liver is ruddy in color and the mitochondria function properly. However, alterations were found in PERK-eIF2α-ATF4 signaling pathway, mitochondrial UPR gene expression, and mitokine secretion at different stages of MASLD pathogenesis development. (A) Early stage of MASLD development: a 14-week AMLN diet induced hepatic steatosis and ER stress. This mild mitochondrial stress initiated a diverse set of retrograde stress responses, including mitonuclear communication, UPRmt, and FGF21 secretion, which contribute to maintaining mitochondrial function, enabling mitochondrial self-healing, and alleviating liver damage. (B) Late stage of MASLD development: an 18-week AMLN diet aggravated the accumulation of hepatic lipids. Severe lipid deposition led to disconnect communication between mitochondria and nuclear, impaired UPRmt through overactivating the eIF2α/ATF4 pathway, then resulted in mitochondria losing their self-repair ability. Moreover, exercise intervention significantly improved the imbalanced mitochondrial homeostasis due to chronic AMLN diet, which plays a pivotal role in reversing the progression of MASLD. Red arrows: increase effect; Black arrows: decreased effect.