Recently, in an effort to understand the signaling pathways controlling nebula/DSCR1, we discovered that nebula interacts with the adenine nucleotide translocator (ANT), a mitochondrial protein, and affects mitochondrial function. ? ANT is involved in the exchange of ADP/ATP and is the most abundant protein in the inner mitochondrial membrane. During aerobic respiration, electrons are passed through complexes I-IV of the electron transport chain to generate a proton gradient across the mitochondrial inner membrane. The movement of protons back to the mitochondrial matrix through complex V (ATP synthase) provides the energy to condense ADP and Pi to make ATP. Matrix ATP is then exported to the cytosol by ANT to provide the energy necessary for normal cellular function. In exchange, ADP is transported from the cytosol back into the mitochondrial matrix by ANT to allow further generation of ATP. Thus, ANT regulates the adenine nucleotide concentrations in the cytoplasm and within mitochondria, and is vital in coupling ATP synthesis to cellular energy demand. In addition to its translocase activity, ANT is an important component of the mitochondrial permeability transition pore (MPTP) and participates in mitochondrial-mediated apoptosis.? ANT exists in multiple isoforms in a number of species and shows tissue-specific gene expression. The ANT-1 isoform (ANT1) in humans and mice is expressed in skeletal muscle, heart, eye, and brain. In humans, ANT1 mutation is associated with autosomal dominant progressive external opthalmoplegia (adPEO), an adult-onset mitochondrial disorder characterized by reduced activities of the respiratory-chain enzymes and multiple deletions of the mitochondrial genome. To delineate the role of ANT1 in mitochondrial diseases, ANT1 knockout mice were generated by Gram et al26, and these mice have ragged red muscle fibers with marked proliferation of mitochondria, exercise intolerance, and respiratory defects. ANT1 knockout mice also showed increased production of toxic mitochondrial reactive oxygen species (ROS) and increased mtDNA rearrangement. These findings directly demonstrate that a deficit in ATP/ADP transport can dramatically affect mitochondrial activity and number of mitochondria, and generate oxidative damage.
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