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.
Highlights
Mitochondria are dynamic organelles that are primarily recognized as the “powerhouse” of the cell, where the energy stored in nutrients is converted to ATP molecules through the oxidative phosphorylation (OXPHOS)
The role of mitochondria in cell death is linked to apoptosis, where mitochondrial outer membrane permeabilization (MOMP) originates a signaling cascade leading to cell death (Bock and Tait, 2020)
MOMP is initiated by the formation of macropores in the outer mitochondrial membrane (OMM) (Szabo and Zoratti, 2014), allowing the release of soluble proteins from the Mitochondrial Channels in Cell Death mitochondrial intermembrane space (IMS) in a process regulated by the B cell lymphoma 2 (BCL-2) protein family
Summary
Mitochondria are dynamic organelles that are primarily recognized as the “powerhouse” of the cell, where the energy stored in nutrients is converted to ATP molecules through the oxidative phosphorylation (OXPHOS). MCU opening is modulated by Pyk2: α1-AR signaling leads to translocation of activated Pyk2 from the cytosol to the mitochondrial matrix; this event accelerates mitochondrial Ca2+ uptake increasing mitochondrial ROS production and promoting PTP opening and apoptotic signaling.
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