Perspectives of Molecular Therapy-Targeted Mitochondrial Fission in Hepatocellular Carcinoma

Abstract

Current advances of molecular-targeting therapies for hepatocellular carcinoma (HCC) have improved the overall survival significantly, whereas the results still remain unsatisfied. Recently, much attention has been focused on organelles, such as the mitochondria, to reveal novel strategies to control the cancers. The mitochondria are vital organelles which supply energy and maintain metabolism in most of the eukaryotic cells. They not only execute critical bioenergetic and biosynthetic functions but also regulate ROS homeostasis and apoptosis. Existing in a dynamic equilibrium state, mitochondria constantly undergo the fission and fusion processes in normal situation. Increasing evidences have showed that mitochondrial fission is highly related to the diseases and cancers. Distinctive works have proved the significant effects of mitochondrial fission on HCC behaviors and the crosstalks with other molecular pathways. Here, we provide an overview of the mitochondrial fission and the link with HCC, emphasizing on the underlying molecular pathways and several novel materials that modulate HCC behaviors.

Figure 1

Mechanism of mitochondrial fission. (a) Drp1 are recruited to the surface of the mitochondria from cytosol by Fis1, MFF, MiD49, and MiD51. (b) Drp1 assembles into higher-order structures, forming rings and spirals around mitochondria. (c) The spiral structures sever the mitochondria through GTP hydrolysis.

Figure 2

The mechanisms of Ca²⁺ positive feedback loop in HCC. Increasing mitochondrial fission activates the STIM1-mediated SOCE pathway and upregulates the level of Ca²⁺ influx, thus activating the CAMKK/AMPK and CaMKII/ERK/FAK pathways and promoting autophagy and migration of HCC. Influx of Ca²⁺ into cytosol upregulates Drp1 and Fis1 transcription factors NFATC2 and c-Myc, facilitating mitochondrial fission and forming a Ca²⁺ positive feedback loop. BAPTA-AM serves the function of HCC blocking the positive feedback loop by chelating cytosolic Ca²⁺.