The Role of Mitochondrial Dynamics and Mitophagy in Carcinogenesis, Metastasis and Therapy

Abstract

Mitochondria are key cellular organelles and play vital roles in energy metabolism, apoptosis regulation and cellular homeostasis. Mitochondrial dynamics refers to the varying balance between mitochondrial fission and mitochondrial fusion that plays an important part in maintaining mitochondrial homeostasis and quality. Mitochondrial malfunction is involved in aging, metabolic disease, neurodegenerative disorders, and cancers. Mitophagy, a selective autophagy of mitochondria, can efficiently degrade, remove and recycle the malfunctioning or damaged mitochondria, and is crucial for quality control. In past decades, numerous studies have identified a series of factors that regulate mitophagy and are also involved in carcinogenesis, cancer cell migration and death. Therefore, it has become critically important to analyze signal pathways that regulate mitophagy to identify potential therapeutic targets. Here, we review recent progresses in mitochondrial dynamics, the mechanisms of mitophagy regulation, and the implications for understanding carcinogenesis, metastasis, treatment, and drug resistance.

Keywords: carcinogenesis; mitochondria; mitochondrial dynamics; mitophagy; therapy.

FIGURE 1

Mechanism of mitophagy regulation in mammals. (a) In the PINK/PARKIN pathway, upon mitochondrial impairment or loss of mitochondrial potential, PINK1 can phosphorylate various target proteins, such as ubiquitin. Then, PINK1 recruits Parkin, and Parkin can amplify the signal through ubiquitination of miyochondrial surface receptor proteins. Receptor proteins can recognize the ubiquitinated proteins, which promotes mitochondria to form autophagosomes and eventually degrade them. (b) In the FUNDC1/BNIP3/NIX pathway, LC3 can be recognized by receptor proteins of mitochondria to promote the complementation of phagophores, thus targeting the mitochondrion for mitophagy. Mitochondrial outer membrane proteins FUNDC1, BNIP3 or NIX bind to LC3-II through their cytoplasmic LIR motifs to promote selective clearance of mitochondria. Δψ_m, mitochondrial potential; ROS, reactive oxygen species; IR, ischemia/reperfusion; Toxins, poisons produced naturally by organisms.

FIGURE 2

The roles of mitophagy in cancer. Mitophagy occurs in many types of cell. Mitophagic levels are usually enhanced or inhibited in cancer cells, which is different from normal cells. Mitophagy is associated with the occurrence and metastasis of cancers. In certain periods of tumorigenesis, limited mitophagy promotes the development of the tumor, while in established tumors, mitophagy can help the survival of tumor cells. Mitophagy also plays an important role in cancer metastasis. By making mitophagy as the target, inducers or inhibitors of mitophagy can have an anticancer effect through regulating the level of mitophagy. Damaged mitochondria in cancer cells are rapidly cleared through mitophagy which mediates the drug resistance of cancer cells.