Metabolic Rewiring of the Heart Through Reductive Carboxylation

通过还原羧化重塑心脏的代谢

• 批准号: 10401521
• 负责人: Anja Karlstaedt
• 金额: $ 24.9万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-11 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401521
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Acute Myelocytic Leukemia; Address; Adult; Amino Acids; Atrophic; Autophagocytosis; Branched-Chain Amino Acids; Cancer Survivor; Cardiac Myocytes; Cardiotoxicity; Cardiovascular Diseases; Cause of Death; ChIP-seq; Chemistry; Chronic; Citrates; Citric Acid Cycle; Cytosol; Cytostatics; Data; Decarboxylation; Dilated Cardiomyopathy; Energy Metabolism; Epigenetic Process; Experimental Models; Functional disorder; Future; Gene Expression; Genetic; Glucose; Glutamine; Goals; Heart; Heart failure; Histones; Impairment; Isocitrate Dehydrogenase; Isocitrates; Label; Lead; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Modification; Mus; Muscle Cells; Mutate; Mutation; Myocardial dysfunction; Myocardium; NADH; NADP; Oxidation-Reduction; Oxidoreductase; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmacology; Phase; Process; Production; Protein Biosynthesis; Protein Isoforms; Proteins; Proteome; Proteomics; Research; Research Personnel; Risk; Role; Stress; Structure; Survivors; Testing; Tracer; Training; Tumor Biology; Work; alpha ketoglutarate; amino acid metabolism; base; cancer cell; carboxylation; cardiogenesis; chemotherapeutic agent; chemotherapy; disability; experimental study; heart function; heart metabolism; high risk; insight; ketoglutarate dehydrogenase; leukemia; mathematical model; mutant; novel therapeutic intervention; oxidation; response; self-renewal; skeletal muscle wasting; skills; transcriptome sequencing; tumor; tumor metabolism; tumorigenesis

Summary The term “cancer and the heart” traditionally refers to the cardiotoxic effects of chemotherapeutic agents. However, independent of any cytostatic treatment, cancer survivors have a five-fold higher risk for developing heart failure. Therefore, new therapeutic strategies must consider tumor biology when aiming at protecting the heart. For example, it has been observed that in isocitrate dehydrogenase (IDH) 1 and 2 mutant tumors, the elevated production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with systemic effects, including dilated cardiomyopathy. About 20% of acute myeloid leukemia cases harbor mutations of the IDH. These mutations lead to significantly reduced patient survival and cause metabolic dysfunction which are associated with high levels of the oncometabolite D2-HG. However, the extent to which D2-HG can directly impair cardiac function and metabolism, and which processes are involved, is still unknown. Recently I discovered that D2-HG mediates cardiac dysfunction by inhibiting α-ketoglutarate dehydrogenase, which leads to redirection of Krebs cycle intermediates, increased ATP citrate lyase activity, and increased histone 3 pan- acetylation. Furthermore, chronic treatment with D2-HG causes heart and skeletal muscle atrophy, suggesting that IDH mutation also stimulates structural remodeling. I now propose that inhibition of α-KG dehydrogenase by the oncometabolite D2-HG induces reductive carboxylation of α-KG in the heart resulting in pathologic structural remodeling. My goal is to determine the role of oncometabolism in the pathogenesis of heart failure. In the K99 phase, Specific Aim 1 will define the role of reductive carboxylation as a mediator for metabolic remodeling of the heart using the oncometabolite D2-HG as a model. Specific Aim 2 will define the role of reductive citrate metabolism as a link between energy substrate metabolism and epigenetic remodeling by lysine acetylation. These experiments will transition into the R00 phase, which in Specific Aim 3 will extend the findings to address the impact of branched chain amino acid metabolism and autophagy on proteomic remodeling in the metabolically deregulated state of D2-HG. Collectively, this project will advance the hypothesis that oncometabolic stress drives development of heart failure. These new insights ultimately change the way cancer and heart failure patients are treated.

总结 术语“癌症和心脏”传统上是指化疗剂的心脏毒性作用。 然而，独立于任何细胞抑制治疗，癌症幸存者有五倍高的风险发展为 心衰因此，新的治疗策略必须考虑肿瘤生物学时，旨在保护肿瘤细胞， 心例如，已经观察到在异柠檬酸脱氢酶（IDH）1和2突变肿瘤中， 癌代谢物D-2-羟基戊二酸（D2-HG）的产生增加与全身效应有关， 包括扩张型心肌病大约20%的急性髓细胞白血病病例携带IDH突变。 这些突变导致患者生存率显著降低，并引起代谢功能障碍， 与高水平的癌代谢物D2-HG有关。然而，D2-HG可以直接 受损心脏功能和代谢以及涉及哪些过程仍然是未知的。最近我 发现D2-HG通过抑制α-酮戊二酸脱氢酶介导心功能不全， Krebs循环中间体的重定向，增加ATP柠檬酸裂解酶活性，并增加组蛋白3泛- 乙酰化此外，用D2-HG长期治疗引起心脏和骨骼肌萎缩，这表明 IDH突变也会刺激结构重塑我现在提出抑制α-KG 癌代谢物D2-HG脱氢酶诱导心脏α-KG还原羧化 导致病理性结构重塑。我的目标是确定肿瘤在 心力衰竭的发病机制。在K99阶段，特异性目标1将确定还原羧化的作用 使用癌代谢物D2-HG作为模型作为心脏代谢重塑的介质。具体 目标2将确定还原性柠檬酸盐代谢的作用，作为能量底物代谢和 赖氨酸乙酰化的表观遗传重塑。这些实验将过渡到R 00阶段， 具体目标3将扩展研究结果，以解决支链氨基酸代谢的影响， 自噬对D2-HG代谢失调状态下蛋白质组重构的影响。总的来说，这个项目 将推进肿瘤代谢应激驱动心力衰竭发展的假设。这些新见解 最终改变癌症和心力衰竭患者的治疗方式。