The Role of Mitochondrial Ion Channels in the Evolution of Anticancer Drug Resistance

Apoptosis, drug resistance, and cellular metabolism are all crucially regulated by mitochondria, especially through ion channels and translocases embedded in their membranes. The outer mitochondrial membrane (OMM) contains the voltage dependent anion channel (VDAC), which acts with proteins such as hexokinase II and BAX to regulate apoptosis and metabolic reprogramming in cancer while facilitating the flow of important metabolites and ions. Anti apoptotic proteins like Bcl2 and Mcl1 closely regulate the mitochondrial apoptosis induced channel (MAC), which is created by pro-apoptotic Bcl2 family members BAX and BAK and controls cytochrome c release when overexpressed, leading to drug resistance. Furthermore, the translocase of the outer membrane (TOM) complex, which regulates mitochondrial protein import, is frequently dysregulated in cancers. Numerous ion channels, such as potassium channels, the mitochondrial calcium uniporter (MCU), and the mitochondrial permeability transition pore (m-PTP), are found within the inner mitochondrial membrane (IMM) and regulate important functions like ATP synthesis, the control of reactive oxygen species (ROS), and apoptotic signaling. Cancer cells can avoid apoptosis, adapt to environmental stress, and become resistant to treatments like doxorubicin and cisplatin when these channels are dysregulated. Metabolic flexibility and antioxidant defense are improved by overexpressing or functionally modifying IMM potassium channels and calcium transporters. Additionally, drug resistance is facilitated by increased mitophagy and anti-apoptotic proteins that inhibit m-PTP opening. This review discusses the functions of mitochondrial ion channels.