Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults.
The mitochondrial adenine nucleotide translocators (Ant) are bi-functional proteins that transport ADP and ATP across the mitochondrial inner membrane, and regulate the mitochondrial permeability transition pore (mtPTP) which initiates apoptosis. The mouse has three Ant isoforms: Ant1 expressed in heart, muscle, and brain; Ant2 expressed in all tissues but muscle; and Ant4 expressed primarily in testis. Ant1-deficient mice manifest muscle and heart but not brain pathology. Brain Ant1 is induced by stress, while Ant2 is not. Ant1-deficient mice are resistant to death induced by systemic exposure to the brain excitotoxin, kainic acid (KA), and their hippocampal and cortical neurons are significantly more resistant to neuronal death induced by glutamate, KA, and etoposide. The mitochondrial membrane potential of Ant1-deficient brain mitochondria is increased and the mtPTP is more resistance to Ca(++) induced permeability transition. Hence, Ant1-deficiency may protect the brain from excitotoxicity by desensitizing the mtPTP and by blocking the pro-apoptotic induction of Ant1 by stress.
Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940, USA.
Jaewon
J
Lee
Samuel E
SE
Schriner
Douglas C
DC
Wallace
D033741:Adenine Nucleotide Translocator 1 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D004351:Drug Resistance; D015870:Gene Expression; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity*
D033741:Adenine Nucleotide Translocator 1; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009498:Neurotoxins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007608:Kainic Acid