SIRT5 in cancer metabolic reprogramming

The sirtuins are a family of NAD + ‐dependent protein deacylases that regulate metabolism and other diverse aspects of cell biology. Three sirtuins (SIRT3, SIRT4, and SIRT5) are present in the mitochondrial matrix. SIRT5 is an inefficient deacetylase, instead removing succinyl, malonyl, and glutaryl groups from lysines of its target proteins. To provide insight into SIRT5 functions, together with Dr. Yingming Zhao's group, we previously carried out proteomics profiling of the cellular succinylome (Park et al. , Mol. Cell 2013). This revealed potential impacts of succinylation on enzymes involved in diverse aspects of mitochondrial metabolism. We tested the impact of SIRT5 on two substrates identified in our studies, Pyruvate Dehydrogenase Complex (PDC) and Succinate Dehydrogenase (SDH). SIRT5 inhibited biochemical activities of both complexes, and suppressed overall mitochondrial respiration in the presence of glucose, pyruvate, and succinate. Metabolism in tumor cells is “reprogrammed” to meet the anabolic demands of uncontrolled cellular proliferation. Reprogramming of mitochondrial metabolism represents a key element of this metabolic rewiring. PDC and SDH are both implicated in neoplasia and cancer cell metabolic reprogramming. In particular, activation of PDC activity in cancer cells reverts tumor cell metabolism, inhibits malignant behavior, and induces apoptosis in diverse cancer types. Given the role of SIRT5 in regulating PDC and SDH, we hypothesized that SIRT5 might play a role in metabolic reprogramming in cancer. Our progress in testing this idea will be discussed. Support or Funding Information NIH R01GM101171 and UL1TR000433, DoD OC140123, the Glenn Foundation for Medical Research, the John S. and Suzanne C. Munn Cancer Fund of the University of Michigan Comprehensive Cancer Center, and the University of Michigan Department of Pathology.