Mitochondrial permeability transition in redox homeostasis and ferroptosis

Mitochondria are major sources of intracellular reactive oxygen species (ROS), and act as central signaling hubs in maintaining homeostasis of cellular oxidative states. Mitochondrial permeability transition (MPT) is coordinately mediated by mitochondrial outer membrane permeabilization (MOMP) and opening of the permeability transition pore (PTP). MPT is highly sensitive to ROS, and serves as a critical checkpoint in redox balances and cell death. This review will summarize the regulatory systems of mitochondrial and intracellular redox homeostasis, as well as the recent advances in understanding of MPT regulatory mechanisms. Furthermore, this review highlights the functional roles of MPT in redox homeostasis and ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death. The PTP is a critical molecular switch, which can convert from a defender against mitochondrial redox stress and cell death processes, including specifically iron-dependent, lipid peroxidation-driven cell death, known as ferroptosis, into a ROS amplifier and cell death promoter depending on its open states. MOMP causes the uncoupling of the mitochondrial respiratory chain, and increases ROS production, leading to oxidative stress. The most recent work suggests that the interplay between mitochondrial carrier homolog 2 and F-ATP synthase coordinates MOMP and the PTP opening to mediate the occurrence of MPT. This review provides insights on molecular switches that regulate MPT, determining redox state and cell death.