Abstract 3719: ATF4-regulated Metabolic Shift Towards Phgdh-mediated Serine Synthesis Enhances Cardioprotection Against Oxidative Stress
Introduction Aldehydes are the major end-product of lipid peroxidation and their accumulation has been linked to a variety of heart diseases including ischemia-reperfusion injury. This study investigated how the heart accommodates for the accelerated accumulation of aldehydes under oxidative stress condition.
Methods and Results We generated transgenic mice that accumulate aldehydes due to a lack of aldehyde dehydrogenase (Aldh) activities. Despite the substantial oxidative damage in the mitochondrial matrix, the hearts of Aldh-deficient mice maintained normal contractile function and exhibited resistance to acute oxidative stress induced by ischemia-reperfusion. Gene chip analysis revealed that 3-phosphoglycerate dehydrogenase (Phgdh), which encodes the rate-limiting enzyme involved in the three-step conversion of serine biosynthesis from 3-phosphoglycerate (glycolytic intermetabolite), was up-regulated by ≥100-fold in the Aldh-deficient hearts. The in vivo pulse-chase analysis of 13C-labeled glucose using capillary electrophoresis-mass spectrometry showed that 13C-labeled glucose was converted to 13C-labeled serine in these mice hearts but not in wild-type control hearts. Increased phosphorylation of Gcn2 kinase and eIF2α, as well as increased protein expression of Atf4 and Phgdh, was observed in the Aldh-deficient hearts. Disruption of Atf4 blunted the increment of Phgdh in this heart. In cultured cardiomyocytes, aldehydes activated the eIF2α-Atf4 pathway via Gcn2 kinase and induced Phgdh expression. Phgdh knockout reduced the intracellular glutathione level, and abrogated the oxidative stress resistance of the aldehydes-preconditioning cardiomyocytes. In adult hearts, Phgdh induction was accompanied by aldehyde accumulation in the peri-infarcted myocardium following ischemia-reperfusion injury. Moreover, Phgdh gene abrogation rendered the heart vulnerable to infarction.
Conclusions Heart shifts glucose biotransformation from glycolysis towards Phgdh-mediated serine synthesis under oxidative stress condition. Thus, Aldehydes act as a second messenger to induce Phgdh-mediated serine biosynthesis, thereby conferring the cardioprotection against oxidative stress.