Mitochondrial Ion Channels of the Inner Membrane and Their Regulation in Cell Death Signaling

Abstract

Mitochondria are bioenergetic organelles with a plethora of fundamental functions ranging from metabolism and ATP production to modulation of signaling events leading to cell survival or cell death. Ion channels located in the outer and inner mitochondrial membranes critically control mitochondrial function and, as a consequence, also cell fate. Opening or closure of mitochondrial ion channels allow the fine-tuning of mitochondrial membrane potential, ROS production, and function of the respiratory chain complexes. In this review, we critically discuss the intracellular regulatory factors that affect channel activity in the inner membrane of mitochondria and, indirectly, contribute to cell death. These factors include various ligands, kinases, second messengers, and lipids. Comprehension of mitochondrial ion channels regulation in cell death pathways might reveal new therapeutic targets in mitochondria-linked pathologies like cancer, ischemia, reperfusion injury, and neurological disorders.

Alternative Targets for Modulators of Mitochondrial Potassium Channels

“…Several potassium channels have been identified in the IMM, such as ATP-sensitive potassium channels (mitoK ATP ); small (mitoSK Ca ), intermediate (mitoIK Ca ), and large conductance (mitoBK Ca ) calcium activated potassium channels; sodium dependent potassium (mitoSlo2) channels; and voltage-dependent (mitoKv1.3 and mitoKv7.4) potassium channels [ 4 , 5 ].…”

MICS1 is the Ca2+/H+ antiporter of mammalian mitochondria

“…Intracellularly, mitochondria have been established as major sinks of Ca 2+ , an ion of comparatively low concentration to K + and Na + . The role of mitochondrial Ca 2+ buffering has been extensively studied (Giorgi et al, 2018;Pallafacchina et al, 2018), yet some of the players in maintaining this Ca 2+ balance have not been identified (De Stefani et al, 2016;Urbani et al, 2020). One of the missing pieces in this molecular puzzle is the Na + -independent Ca 2+ efflux pathway, a putative Ca 2+ /H + exchanger (CHE).…”

Diverse Functions of Tim50, a Component of the Mitochondrial Inner Membrane Protein Translocase

“…The mitochondrial outer membrane (MOM) is semipermeable due to the presence of multiple pores created by the most abundant mitochondrial protein, voltage-dependent anion channel (VDAC) that allows fluxes of small molecules and metabolites [2]. Whereas mitochondrial inner membrane (MIM) is impermeable even to ions and is folded inwards to form cristae [3]. MIM separates two aqueous compartments in the mitochondria, the innermost matrix and inter membrane space (IMS).…”