Aberrant acetylation of mitochondrial proteins, due to loss of SIRT3, results in tumor permissive phenotypes and increases breast cancer malignancy risk

Xianghui Zou

doi:https://doi.org/10.21985/N2P41G

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Aberrant acetylation of mitochondrial proteins, due to loss of SIRT3, results in tumor permissive phenotypes and increases breast cancer malignancy risk

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SIRT3 is a mitochondrial-localized, NAD+-dependent deacetylase, tumor suppressor protein that functions to direct mitochondrial energy sensing and antioxidant proteins, increasing the efficiency of energy utilization, providing a redox balanced environment, and preventing aging-related diseases. One SIRT3 deacetylation target is NADP+-dependent isocitrate dehydrogenase 2 (IDH2), a key Krebs Cycle enzyme that produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In addition, IDH2 catalyzes the production of NADPH, a reducing reagent to maintain cellular redox balance. It has been shown that acetylation of IDH2 at lysine 413 decreases IDH2-dependent enzymatic activity. However, the mechanism by which acetylation of IDH2 inhibits activity, as well as the phenotypes due to its aberrant acetylation, remain unknown. In my thesis, we report that loss of SIRT3 increases IDH2 acetylation at lysine 413 (IDH2-K413-Ac) decreases IDH2 enzymatic activity via a mechanism that decreased IDH2 dimer formation. Native-PAGE analysis of eluted mutant IDH2 proteins (acetylation mimetic mutant, IDH2K413Q) showed a decreased IDH2 dimerization. Metabolically, expression of IDH2K413Q in cancer cells significantly decreased oxygen consumption, ATP turnover, mitochondrial respiration, and glutathione levels, and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism to an environment promoting oxidative stress. In addition, enforced expression of IDH2K413Q promoted in vitro transformation of NIH3T3 cells and tumorigenesis in nude mice. Finally, immunohistochemistry (IHC) staining showed that IDH2 acetylation was higher in high-risk Luminal B patients than low-risk Luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413-Ac and dimerization, and a transformation and/or carcinogenic permissive phenotype.

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