SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells

Abstract

Pyruvate dehydrogenase E1 alpha (PDHE1α or PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex (PDC) that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321) and a PDHA1 mutant, mimicking a deacetylated lysine (PDHA1K321R) increases in PDH activity, as compared to the K321 acetylation mimic (PDHA1K321Q) or wild-type PDHA1. Finally, PDHA1K321Q exhibited a more transformed in vitro cellular phenotype as compared to PDHA1K321R. These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyl-lysine suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…The pyruvate dehydrogenase complex (PDC) catalyzes oxidative decarboxylation of pyruvate into acetyl-CoA, which is subsequently used in Krebs cycle to generate ATP (110,118). PDC plays a key role in glucose metabolism, linking glycolysis with the Krebs cycle.…”

“…Roughly half of all caloric intake passes through PDC (117). Phosphorylation of the PDC E1a subunit by pyruvate dehydrogenase kinases (PDK1-4) inhibits PDC activity, whereas dephosphorylation by pyruvate dehydrogenase phosphatases (PDP1 and 2) restores its activity (110). Reduced PDC activity and increased glycolysis are common in cancer cells, as a part of an overall metabolic reprograming associated with malignancy (179).…”

“…Decreased PDC activity promotes a switch of skeletal muscle metabolism from glucose oxidation toward lactate production and fatty acid utilization (74). Recently, a study by Ozden et al confirmed the role of SIRT3 in directly deacetylating PDC E1a (110). A PDC E1a mutant mimicking the deacetylated state showed increased activity as compared with an acetylation mimic.…”

Deacetylation of Androgen Receptor by SIRT2 and its Dysregulation Promotes Pathogenesis and Progression of Prostate Cancer

“…In vitro deacetylation assays was performed as published previously by our lab 17 . Briefly, 293T cells were transiently transfected with FLAG tagged-AR and one of the HATs (p300, P/CAF, and TIP60) with PEI.…”

Changes in the Expression and the Role of Sirtuin 3 in Cancer Cells and in Cardiovascular Health and Disease

“…Studying SIRT3 in these diseases may provide important mechanistic connection between the mitochondrial function and age-associated disorders [16][17][18][19][20]. SIRT3 expression is important for mitochondrial biogenesis, regulation of metabolism, ATP synthesis, suppression of reactive oxygen species (ROS), stress responses, and cell signaling [15,19,[21][22][23].…”