Research Assistant Professor
Postdoctoral Studies: University of South Alabama
Ph.D. - Institute of Cell Biology and Genetic Engineering, Ukrainian Academy of Sciences, Kiev, Ukraine
Mitochondrial Dysfunction and Diabetes
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance primarily in skeletal muscle. The mechanisms responsible for the reduced sensitivity of muscle to insulin still remain unclear, but there is a strong correlation between insulin resistance and the presence of increased lipid levels in skeletal muscle in T2DM. Oxidative stress which results from an increased content of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) has been implicated in mitochondrial dysfunction in skeletal muscle in T2DM. There is evidence that muscular free fatty acids (FFA) accumulation might be responsible for mitochondrial dysfunction. ROS and RNS directly oxidize and damage DNA, proteins, and lipids and play a direct key role in the pathogenesis of T2DM. Skeletal muscle is particularly vulnerable to oxidative stress because they are postmitotic cells and thus are capable of accumulating oxidative damage over time and also because they consume a large amount of oxygen for their action, which can result in increased level of ROS/RNS production.
Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Apart from producing energy, mitochondria also are a major source of ROS. The focus of our research is FFA-induced mitochondrial DNA (mtDNA) damage. We recently identified that chronic damage to mtDNA, produced by the continuous exposure to FFA, is a critical contributor to skeletal muscle atrophy likely through the induction of apoptosis. We are now working on the developing experimental approaches to target DNA repair enzymes to mitochondria of skeletal muscle cells in an effort to more precisely define the role of mtDNA damage in the pathogenesis of skeletal muscle diabetes complications. Our studies have potential therapeutic benefit for the treatment of some of the secondary complications resulting from T2DM.
Rachek L. I., Thornley N. P. Grishko V.I., LeDoux S. P., Wilson G. L. Protection of INS-1 Cells From Free Fatty Acid-Induced Apoptosis by Targeting hOGG1 to Mitochondria.Diabetes 55(4):1022-8 (2006).
Rachek L. I., Grishko V.I., LeDoux S. P., Wilson G. L. Role of NO-induced mtDNA damage in mitochondrial dysfunction and apoptosis. Free Radic. Biol. Med. 5:754-762 (2006).
Grishko V.I., Rachek L. I., Spitz D.R., Wilson G. L., LeDoux S. P. Contribution of mitochondrial DNA repair to cell resistance from oxidative stress. J. Biol. Chem. 280:8901-8905 (2005).
Grishko V.I., Rachek L. I., LeDoux S. P., Wilson G. L. Involvement of mtDNA damage in free fatty acid- induced apoptosis. Free Radic. Biol. Med. 38:755-762 (2005).
Rachek L. I., Grishko V.I.., Alexeyev M.F., Pastukh V.V., LeDoux S. P.,Wilson G. L. Endonuclease III and Endonuclease VIII conditionally targeted into mitochondria increase mitochondrial DNA repair and cell survival. Nucl Acids Res., 32:3240-3247 (2004).
Rachek L. I., Grishko V.I., Musiyenko S.I., Kelley M.R., LeDoux S.P., Wilson G.L. Conditional Targetiting of the DNA Repair Enzyme hOGG1 into Mitochondria. J. Biol. Chem. 277: 44932-44937 (2002).
Rachek L. I., Hines A.P., Tucker A. M., Winkler H. H, Wood D.O. Transformation of Riickettsia prowazekii to Erythromycin Resistance encoded by the Escherichia coli ereB gene. J. Bacteriol 182: 3289-3291 (2000).
Rachek L. I., Tucker A. M., Winkler H. H, Wood D.O. Transformation of Rickettsia prowazekii to rifampin resistance. J. Bacteriol.180: 2118-2124 (1998).
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