High Blood Sugar in Diabetes Disrupts Mitochondrial Enzyme Activity

The damage caused to the body by the high levels of blood sugar that characterize diabetes seems to be due to disturbances caused in the activity of a critical mitochondrial enzyme.

Investigators at Johns Hopkins University (Baltimore, MD, USA) worked with a rat diabetes model. They were particularly interested in the metabolic pathways involved in O-linked N-acetylglucosaminylation (O-GlcNAcylation), a reversible post-translational modification in which a sugar moiety is added to serine/threonine residues of cytosolic or nuclear proteins. Catalyzed by O-GlcNAc-transferase (OGT) and removed by O-GlcNAcase (OGA), this dynamic modification is dependent on environmental glucose concentration. O-GlcNAcylation regulates the activities of a wide panel of proteins involved in almost all aspects of cell biology.

The investigators reported in the April 27, 2015, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) that analyses of purified rat heart mitochondria from normal and streptozocin-treated diabetic rats showed strikingly different OGT and OGA localizations and expression levels. Live cell OGA activity assays established the presence of O-GlcNAcase within the mitochondria. Furthermore, the inner mitochondrial membrane transporter, pyrimidine nucleotide carrier, transported UDP-GlcNAc from the cytosol to the inside of the mitochondria. Knockdown of this transporter substantially lowered mitochondrial O-GlcNAcylation.

In addition, inhibition of OGT or OGA activity within neonatal rat cardiomyocytes significantly affected energy production, mitochondrial membrane potential, and mitochondrial oxygen consumption.

"Sugar itself is not toxic, so it has been a mystery why high blood sugar can have such a profound effect on the body," said senior author Dr. Gerald Hart, professor of biological chemistry at Johns Hopkins University. "The answer seems to be that high blood sugar disrupts the activity of a molecule that is involved in numerous processes within the cell. The net effect of the changes in O-GlcNAc-related activity is to make energy production in the mitochondria less efficient so that the mitochondria begin to produce more heat and damaging molecules as byproducts of the process."

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