Autophagy is an evolutionarily degradative process that eliminates unnecessary intracellular materials through lysosomal proteolysis. In addition to bulk and non-selective degradation, selective autophagy can specifically sequestrate damaged organelles and unfolded proteins through cargo receptors and deliver them into autophagic vacuoles for decomposition. Mitophagy is a kind of selective autophagy that degrades deformed mitochondria and promotes the regeneration of mitochondria. Defects in autophagy and mitophagy in the liver have been demonstrated to promote the development of liverassociated diseases, suggesting that the precise regulation of hepatic autophagy and mitophagy is critical to maintaining liver physiology. However, there remains unclear how intracellular metabolism, such as glycolysis regulates hepatic autophagy and mitophagy.

Our current studies show that lactate treatment in liver cells induces the entire autophagy throughout autolysosome maturation and increases autophagic flux. In addition, we find that the lactate-activated autophagy specifically engulfs mitochondria and delivers them to autolysosomes, suggesting that lactate may play a role in regulating mitophagy and mitochondrial turnover. However, less is known about how lactate and related metabolism function in controlling mitophagy. Thus, this research proposal aims to decipher the molecular process of lactate-induced hepatic mitophagy and unveil the underlying molecular mechanism. To this end, three specific aims are proposed as follows,
Aim I: To study how lactate induces hepatic mitophagy
Aim II: To uncover the molecular mechanism underlying how lactate activates hepatic mitophagy
Aim III: To delineate the physiological role(s) of lactate-related metabolism in the regulation of hepatic mitophagy

The accomplishment of this research proposal will promote us to understand how mitophagy is regulated by lactate and may provide compelling information on the physiological significance of lactate-activated mitophagy in the pathogenesis of liver diseases.