Targeting metabolic remodeling and mitochondrial dysfunction in the diabetic heart

糖尿病（DM）引起一种称为糖尿病性心肌病（DMCM）的心肌疾病，其进展为心力衰竭。DMCM的一个标志是代谢中断，这是由于ATP生产对脂肪酸氧化（FAO）的依赖性增加所致。FAO的增加导致线粒体应激并最终导致线粒体功能障碍，但其潜在的分子机制尚不清楚。酮化是一种脂肪酸氧化溢出途径，通过限速酶3-羟基-3-甲基戊二酰-CoA合成酶2（HMGCS 2）导致线粒体损伤。在DM心脏中，受损的线粒体自噬（受损线粒体的降解）进一步加重了线粒体损伤。此外，miR-133 a是一种高度丰富的心脏保护性miRNA，在DM心脏中下调。然而，目前尚不清楚miR-133 a如何调节糖尿病心肌病的代谢重塑和线粒体损伤。我的初步数据显示，miR-133 a的过表达阻止线粒体脂质积聚，上调脂肪酸转运蛋白，并下调HMGCS 2在1型糖尿病（T1 DM）心脏中的表达。此外，miR-133 a上调线粒体自噬相关蛋白Parkin，可能是通过靶向外胚层神经皮质1（ENC 1）-线粒体自噬抑制剂。因此，我们假设脂肪酸代谢减少诱导T1 DM心脏中生酮的溢出激活有助于线粒体功能障碍，线粒体功能障碍通过上调ENC 1受损而加剧，并通过糖尿病心肌病中miR-133 a表达增加而改善。我将检查T1 DM心脏中的生酮是否增加，以及miR-133 a是否通过制定两个特定的目标来减轻生酮并恢复线粒体自噬。目标1：检验以下假设：生酮激活导致DMCM中的线粒体功能障碍，这在一定程度上可通过T1 DM心脏中miR-133 a表达增加来缓解。目标二：为了检验ENC 1增加损害糖尿病心肌病中的线粒体自噬的假设，其部分通过T1 DM心脏中miR-133 a的上调而得到改善。这些研究将揭示DMCM中生酮和线粒体损伤的新调控机制，并提供基于miR-133 a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.