A Dual Function for the Mitochondrial ATP Synthase

Besides their central role in ATP synthesis and oxidative metabolism of nutrients, mitochondria contribute to intracellular Ca homeostasis and generation of reactive oxygen species (ROS) and are determinant for both cell survival and cell death. Important for any cell type, these functions are crucial for cardiac myocytes. Mitochondrial processes are highly compartmentalized because of the existence of 2 limiting membranes and to the selective localization of proteins, nucleotides, and coenzymes in the intermembrane and matrix spaces. The outer mitochondrial membrane (OMM) is the interface between mitochondria and other cellular components and represents a physical barrier preventing the release of mitochondrial proteins involved in apoptosis, such as cytochrome c. OMM proteins are involved in apoptosis, intracellular signaling, tethering to the endoplasmic reticulum/sarcoplasmic reticulum, autophagy, and mitophagy. OMM permeability to metabolites and small peptides (<5 kDa) is regulated by the voltage-dependent anion channel and other transporters including the translocator protein of 18 kDa. The inner mitochondrial membrane (IMM), whose permeability to solutes is controlled by highly specific transporters and tightly regulated channels, is the site of coupling between substrate oxidation and ATP synthesis in the process of oxidative phosphorylation. Mitochondria operate a sequence of energy conversion processes through which the exergonic flow of electrons along the respiratory complexes supports the endergonic pumping of protons from the matrix to the intermembrane space. The resulting proton motive force (∆p) drives the rotation of the Fo sector of ATP synthase leading to the synthesis of ATP in the F 1 sector. The 2 components of ∆p, namely ∆ψ m and ∆pH, are also used for the uptake of ADP and inorganic phosphate (Pi), respectively, and for the release of ATP into the cytosol in exchange for ADP. In addition, ∆p Review