Adenine nucleotide translocator 1 deficiency increases resistance of mouse brain and neurons to excitotoxic insults

Abstract

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.

Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3

“…However, studies by Kokoszka and colleagues, who have used mice in which ANT is not expressed, indicate that the PTP still forms (Kokoszka et al, 2004). However, the same group has demonstrated that even though ANT-1 might not be a component of the PTP per se, it can control susceptibility to MPT induction (Lee et al, 2009). So, even though the composition of the PTP is unclear, the current data demonstrate that an increase in the acetylation and activity of cyclophilin-D can enhance the interaction of cyclophilin-D with a protein of the mitochondrial inner membrane that modulates sensitivity to PTP opening.…”

Adenine nucleotide translocase: a component of the phylogenetically conserved cell death machinery

“…56 Recently, ant1 À/À neurons have been ascribed with a near-to-complete resistance to glutamate-, kainate-and etoposide-induced cytotoxicity. 57 Although the phenotype of whole-body ant2 À/À animals remains to be characterized, ant4 À/À mice exhibit a significant reduction in testicular size (yet do not manifest any other obvious abnormality). 47 In the mouse liver, tissue-specific double knockout of ant1 and ant2 failed to yield a major cell death phenotype, 58 presumably due to a 'rescuing' effect ensured by additional ANT isoforms (or perhaps by other members of the MCP family).…”

“…Still, hepatocytes deficient for both ANT1 and ANT2 were more resistant to Ca 2 þ -induced PT than their ANT-proficient counterparts, 58 as did mitochondria isolated from ANT1-deficient neurons. 57 As ANT deficiency only elevated the amount of Ca 2 þ required to trigger PT, yet did not confer an absolute protection, 58 it has been a matter of (a perhaps semantic) debate whether ANT is a bona fide component or just a 'modulator' of the molecular machinery that permeabilizes mitochondria. It is conceivable that multiple proteins from the MCP family (e.g.…”

Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer

“…Heterologous overexpression of ANT1 in cardiomyocytes also significantly induces apoptosis with multiple consequences, such as a decrease in NF-kB activity, a down-regulation of Akt activation and Bcl-xL protein levels, a depolarization of the mitochondrial membrane potential and the upregulation of Bax expression (Baines and Molkentin, 2009). Supporting a pro-apoptotic role of ANT1 in vivo, ANT1 deficiency increases the resistance of mouse brain and neurons to excitotoxic stress (Lee et al, 2009). In addition, ANT1 transfection in breast adenocarcinoma cells (MDA-MB-231 cells) in a nude mice model proved to induce apoptosis, to inactivate NF-kB, to increase Bax expression and finally to stimulate tumor regression, validating the hypothesis that ANT1 could be a potent therapeutic target for the treatment of cancer (Jang et al, 2008a).…”