The purpose of these studies is to establish a better understanding of the energy metabolism of biological tissues. Towards this goal, the laboratory concentrates on the use of screening approaches in proteomics and post-translational modifications. The following major findings were made over the last year: 1) We have previously shown that protein phosphorylation in the mitochondria matrix is extensive. Using minimally disruptive blue native gel electrophoresis we have demonstrated that much of the kinase activity phosphorylating mitochondria oxidative phosphorylation complexes was identified to exist within the Complex itself. That is, when the different complexes were purified by blue native electrophoresis, the protein kinase activity within the complex was maintained. This implies that mitochondrial kinases are compartmentalized in the protein assemblies making up the oxidative phosphorylation complexes. Antibody screening suggested that typical cytosolic protein kinases (PKA, PKC etc) are not present in these complexes, suggesting that the complexes themselves have unique protein kinase activity. Further studies have revealed that these protein phosphorylations are acid sensitive suggesting they may represent early bacterial protein phosphorylation signaling pathways involving the autophosphorylation of aspartate and histidine. 2) A hypothesis has been developed that tissues with large swings in metabolic activity (i.e. heart and muscle) hold mitochondrial electron transport activity in reserve via post translational modifications while more constant activity tissues (i.e. liver) have most of their enzymatic activity active and available. We also propose that this relationship holds in animals of different sizes where the heart has very high (man, large animals) or low (mouse, rat, small animals) dynamic range due to their relative differences in basal activity. We have demonstrated that the activity of mitochondria Complex V and IV indeed follow this notion, being suppressed in heart and skeletal muscle of pigs while fully active in the porcine liver. In contrast, the constantly active mouse heart and liver have essentially identical enzyme activities. An intermediate animal, the rabbit, showed intermediate values between the pig and mouse. These studies suggest that an inherent post-translational throttle on oxidative phosphorylation enzymes is present likely preventing the buildup of potential energy and associated reactive oxygen species under resting conditions.

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National Heart, Lung, and Blood Institute
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Kuzmiak-Glancy, Sarah; Covian, Raúl; Femnou, Armel N et al. (2018) Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. Am J Physiol Heart Circ Physiol 314:H704-H715
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Chen, Zhe; Qi, Yun; French, Stephanie et al. (2015) Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. Mol Biol Cell 26:674-84
Kooragayala, Keshav; Gotoh, Norimoto; Cogliati, Tiziana et al. (2015) Quantification of Oxygen Consumption in Retina Ex Vivo Demonstrates Limited Reserve Capacity of Photoreceptor Mitochondria. Invest Ophthalmol Vis Sci 56:8428-36

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