Targeting metabolic remodeling and mitochondrial dysfunction in the diabetic heart

糖尿病(DM)会导致一种称为糖尿病心肌病(DMCM)的心肌疾病，进而发展为心力衰竭。DMCM的一个特点是代谢紊乱，这是由于对脂肪酸氧化(FAO)产生ATP的依赖增加所致。粮农组织的增加导致线粒体应激，最终导致线粒体功能障碍，然而其潜在的分子机制尚不清楚。酮体生成是一种通过限速酶3-羟基-3-甲基戊二酰辅酶A合成酶2(HMGCS2)导致线粒体损伤的脂肪酸氧化溢出途径。糖尿病患者心脏线粒体吞噬功能受损，也就是受损线粒体的降解，进一步加重了线粒体损伤。此外，miR-133a是一种高度丰富的、对心脏具有保护作用的miRNA，在糖尿病心脏中下调。然而，目前尚不清楚miR-133a如何调控糖尿病心肌病的代谢重构和线粒体损伤。我的初步数据显示，在1型糖尿病(T1 DM)心脏中，miR-133a的过表达阻止了线粒体脂质积累，上调了脂肪酸运输蛋白，下调了HMGCS2的表达。此外，miR-133a上调吞丝分裂相关蛋白Parkin，似乎是通过靶向外胚层神经皮质1(ENC1)-一种吞丝分裂抑制因子。因此，我们假设脂肪酸代谢降低导致T1 DM心脏中酮生成的外溢激活有助于线粒体功能障碍，而线粒体功能障碍通过上调ENC1而受到丝裂原吞噬的损害而加剧，而在糖尿病心肌病中miR-133a的表达增加则得到改善。我将通过制定两个特定的目标来检验酮的生成是否在T1 DM的心脏中增加，以及miR-133a是否通过制定两个特定的目标来减缓酮的生成和恢复有丝分裂。目的：验证酮生成激活导致DMCM线粒体功能障碍的假说，这一假说可通过增加T1 DM心脏miR-133a的表达而部分缓解。目的：验证ENC1增加损害糖尿病心肌病有丝分裂功能的假说，该假说可通过上调T1 DM心脏miR-133a的表达而部分改善。这些研究将揭开DMCM中酮的发生和线粒体损伤的新的调控机制，并提供基于miR-133a的治疗方法来改善DMCM中的心脏代谢紊乱和线粒体功能障碍。

Diabetes mellitus (DM) induces a cardiac muscle disorder known as diabetic cardiomyopathy (DMCM) that progresses to heart failure. A hallmark of DMCM is disrupted metabolism, resulting from increased dependency on fatty acid oxidation (FAO) for ATP production. Increased FAO results in mitochondrial stress and ultimately mitochondrial dysfunction, however the underlying molecular mechanisms are unclear. Ketogenesis is a fatty acid oxidation spillover pathway that contributes to mitochondrial damage via the rate limiting enzyme 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2). Mitochondrial damage is further compounded by impaired mitophagy, the degradation of damaged mitochondria, in the DM heart. Furthermore, miR-133a, a highly abundant and cardioprotective miRNA, is downregulated in the DM heart. However, it is unclear how miR-133a regulates metabolic remodeling and mitochondrial damage in diabetic cardiomyopathy. My preliminary data shows that overexpression of miR-133a prevents mitochondrial lipid accumulation, upregulates fatty acid transport proteins, and downregulates HMGCS2 expression in the Type 1 DM (T1DM) heart. Moreover, miR-133a upregulated the mitophagy associated protein Parkin, plausibly by targeting Ectoderm Neural Cortex 1 (ENC1) - an inhibitor of mitophagy. Thus, we hypothesize that decreased fatty acid metabolism induces spillover activation of ketogenesis in the T1DM heart contributes to mitochondrial dysfunction, which is exacerbated by impaired mitophagy via upregulated ENC1 and ameliorated by increased expression of miR-133a in diabetic cardiomyopathy. I will examine whether ketogenesis is increased in the T1DM heart, and if miR-133a mitigates ketogenesis and restores mitophagy by formulating two specific Aims. Aim 1: To test the hypothesis that activation of ketogenesis leads to mitochondrial dysfunction in DMCM, which is mitigated in part by increased expression of miR-133a in the T1DM heart. Aim 2: To test the hypothesis that increased ENC1 impairs mitophagy in diabetic cardiomyopathy, which is ameliorated in part by upregulation of miR-133a in the T1DM heart. These studies will unravel a novel regulatory mechanism of ketogenesis and mitochondrial damage in DMCM and provide a miR-133a-based therapeutic approach to ameliorate cardiac metabolic derangement and mitochondrial dysfunction in DMCM.