Autophagy maintains cellular homeostasis by targeting the intracellular components to lysosomes for degradation. Not only for bulk and non-selective degradation, but autophagy can also selectively engulf damaged organelles through cargo receptors, so-called ‶organellophagy″ and degrade them by lysosomal hydrolases. Mitophagy is a specific organellophagy that eliminates defective mitochondria to promote mitochondrial turnover. Recently, mitophagy has been shown to maintain liver physiology, and dysfunctional mitophagy may participate in the pathogenesis of liver diseases. However, whether and how hepatic mitophagy is regulated by external stimuli, such as bacterial toxins, remains largely unknown. LPS is the Gram-negative bacteria-derived endotoxin that constitutes the bacteria's cell envelope and induces the host's immunoinflammatory responses. Recently, LPS has been demonstrated to alter mitochondrial biogenesis, which may contribute to the development of several human diseases, including liver diseases. Our current studies show that LPS treatment in liver cells activates autophagy throughout autolysosome maturation and enhances autophagic flux. In addition, we find that the LPS-induced autophagic vacuoles may sequestrate mitochondria in liver cells. Moreover, LPS treatment in liver cells leads to mitochondrial fission and loss of mitochondrial integrity. These results suggest that LPS may activate hepatic mitophagy to promote the turnover of mitochondria. So far, little is known about how LPS regulates mitophagy in the liver, and its physiological significance is also unclear. Thus, this research proposal aims to delineate the molecular mechanism underlying LPS-induced hepatic mitophagy and its potential role(s) in liver physiology and liver diseases. To this end, three specific aims are proposed as follows, Aim I: To investigate how LPS activates hepatic mitophagy Aim II: To study the molecular mechanism underlying how LPS induces hepatic mitophagy Aim III: To uncover the physiological significance of LPS-triggered hepatic mitophagy The accomplishment of this research proposal will help us to understand how hepatic mitophagy is activated by LPS and may provide compelling information on the physiological significance of LPS-activated mitophagy in regulating liver physiology and liver diseases.