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SC COBRE in Oxidants, Redox Balance and Stress Signaling

Marcelo Vargas, Ph.D.

Marcelo Vargas, Ph.d.
Assistant Professor
Cell and Molecular Pharmacology and Experimental Therapeutics

Ph.D., Universidad de la República-Uruguay, 2006

Mictochondrial antioxidant status and mitochondrial protein lysine acetylation in the central nervous system

Numerous lines of evidence suggest that mitochondria have a central role in aging and age-related neurodegenerative diseases. However, a major obstacle for the development of new therapies is our inadequate knowledge of basic mitochondrial biology of neurons and glial cells and its contribution to neurodegenerative conditions. Although reversible Nε-lysine acetylation as a mean of regulating protein function is well characterized for other cellular compartments, lysine acetylation of mitochondrial proteins has only recently been described. Reversible acetylation of lysine residues is regulated by the opposing activities of protein acetyltransferases and deacetylases. However no acetyltransferases have been described in the mitochondrial compartment and it has been proposed that acetyl-CoA exist at a high-enough concentration to allow for non-enzymatic acetylation of lysine residues in the mitochondria. On the other hand, Sirtuin 3 has been shown to specifically remove acetyl groups from different mitochondrial acetylated proteins. Sirtuins are NAD+-dependent deacetylases that share homology to the yeast silent information regulator (Sir)2 protein. Of the seven mammalian sirtuins (SirT1-7), three (SirT3, 4 and 5) are found in the mitochondria. Their enzymatic activity is regulated by the ratio of NAD+ to NADH. In line with this model, many metabolic proteins, such as tricarboxylic acid cycle enzymes, fatty acid oxidation enzymes and subunits of the OXPHOS complexes display differential acetylation in response to metabolic stress. In addition, SirT3 has been recently shown to control the levels of mitochondrial reactive oxygen species (ROS) by multiple mechanisms. This proposal intends to investigate how changes in mitochondrial antioxidant status affect protein lysine acetylation in the mitochondria of astrocytes and neurons. To investigate the correlation between mitochondrial antioxidant status and mitochondrial protein lysine acetylation in the central nervous system we are using knockout mice for the glutamate-cysteine ligase modifier subunit (GCLM) and mice that overexpress a catalase targeted to the mitochondria (MCAT). These models allow us to compare changes in the acetylated lysine subproteome in response to decreased antioxidant defenses [GCLM(-/-)] or increased mitochondrial peroxide detoxification (MCAT). The acetylation data generated will drive experimental efforts toward the functional characterization of lysine-acetylated proteins as well as the identification of potential targets for therapeutic intervention and early detection of mitochondrial dysfunction in neurodegenerative diseases.