Modulation of Mitofusin Activity to Treat Heart Disease

调节丝裂霉素活性治疗心脏病

基本信息

批准号：
10458699
负责人：
Richard N Kitsis
金额：
$ 64.76万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458699
关键词：
Adult Apoptotic Attenuated Binding Brain Ischemia Cardiac Myocytes Cell Death Cells Cellular Metabolic Process Cessation of life Collaborations Data Event Family Goals Guanosine Triphosphate Phosphohydrolases Heart Diseases Heart failure Individual Infarction Ischemia Knockout Mice Mediating Membrane Metabolism Mitochondria Modeling Molecular Conformation Mus Myocardial Infarction Myocardial Ischemia Necrosis Organelles Outer Mitochondrial Membrane Peptides Phenocopy Play Proteins Reperfusion Therapy Reporting Respiratory Chain Role Sarcoplasmic Reticulum Shapes Structure Testing Therapeutic experimental study genetic approach heart function heart metabolism in vivo inhibitor mitochondrial metabolism mouse model myocardial infarct sizing new therapeutic target novel therapeutic intervention overexpression small molecule

项目摘要

Mitochondrial “connectivity” and mitochondrial-endoplasmic/sarcoplasmic reticulum (ER/SR) “proximity” each potentiate mitochondrial-mediated metabolism and necrosis through a variety of mechanisms. Mitofusins (MFN) 1 and 2 are large GTPases that play critical roles in mitochondrial connectivity and mitochondrial-ER/SR proximity. MFN1 and MFN2 reside in the outer mitochondrial membrane where they mediate mitochondrial fusion. MFN2, but not MFN1, also resides in the ER/SR membrane, where it tethers ER/SR to mitochondria through interactions with mitochondrial-localized MFN1 or MFN2. Deletion of MFN1 or MFN2 reduces myocardial infarct (MI) size during ischemia/reperfusion (I/R). Conversely, MFN1 and MFN2 overexpression augment metabolism. Given this information, therapeutic inhibition of MFNs would be expected to reduce infarct size during MI, while therapeutic activation of MFNs might attenuate heart failure (HF) by augmenting metabolism. The challenge has been to find a means to manipulate the activities of endogenous MFNs. In collaboration with others, we created the first peptides and small molecules that modulate conformations of MFN1 and MFN2 and delineated the underlying structural basis for these effects. We reported previously that MFN activators increase, while MFN inhibitors decrease, mitochondrial fusion. These are direct effects that require binding of these agents to either MFN1 or MFN2. We present here new data showing that MFN activators increase, while MFN inhibitors decrease, mitochondrial-ER/SR proximity and Ca2+ transfer to mitochondria. Moreover, we observed that MFN activators exacerbate infarct size during myocardial I/R, while MFN inhibitors reduce infarct size in both heart and brain I/R models. Interestingly, these effects of the activators are dependent on MFN2, but not MFN1, suggesting the importance of mitochondrial-ER/SR proximity but not excluding the possibility that MFN2- dependent changes in mitochondrial connectivity and shape also contribute. Additionally, MFN activators promote cardiomyocyte metabolism. The goals of this project are to understand the mechanisms by which MFN modulators impact cardiomyocyte death and metabolism and to test whether these agents might provide novel therapeutic strategies for MI and HF. We propose: 1. To correlate changes in MFN activation/inhibition with mitochondrial connectivity, mitochondrial-ER/SR proximity, Ca2+ transfer, cell death, and metabolism in adult cardiomyocytes. 2. To delineate the individual contributions of mitochondrial connectivity and mitochondrial- ER/SR proximity to cell death and metabolism in cardiomyocytes in vivo. 3. To assess whether mitofusin modulators provide novel therapeutic strategies for MI and HF. This project breaks new ground in defining the mechanisms by which MFN modulators impact cardiomyocyte death and metabolism and whether MFNs provide an actionable target for novel therapies directed against MI and HF.

线粒体“连通性”和线粒体 - 内质/肌质网（ER/SR）“接近度” 潜在的线粒体介导的代谢和坏死通过多种机制。丝线（MFN） 1和2是在线粒体连接和线粒体-ER/SR中起关键作用的大型GTPase 接近。 MFN1和MFN2位于外部线粒体膜中，它们介导线粒体融合。 MFN2（而不是MFN1）也存在于ER/SR膜中，它将ER/SR置于线粒体通过与线粒体 - 定位的MFN1或MFN2的相互作用。 MFN1或MFN2的删除可降低心肌缺血/再灌注（I/R）期间的梗死（MI）大小。相反，MFN1和MFN2过表达增加代谢。鉴于此信息，理论抑制MFN将有望减小梗死大小在MI期间，MFN的热激活可能通过增加代谢来减轻心力衰竭（HF）。挑战是找到一种操纵内源性MFN活动的方法。与其他，我们创建了第一个肽和小分子，这些肽调节了MFN1和MFN2的构象描述了这些影响的基本结构基础。我们先前报道了MFN激活剂增加，尽管MFN抑制剂减少，但线粒体融合。这些是需要这些药物结合的直接效果到MFN1或MFN2。我们在这里介绍了新数据，显示MFN激活剂增加，而MFN抑制剂减少，线粒体-ER/SR接近和Ca2+转移到线粒体。而且，我们观察到MFN 激活剂加剧心肌I/R期间的梗死大小和大脑I/R模型。有趣的是，激活剂的这些影响取决于MFN2，而不是MFN1，暗示了线粒体-ER/SR接近性的重要性，但不排除MFN2-的可能性线粒体连通性和形状的依赖性变化也有助于。另外，MFN激活剂促进心肌细胞代谢。该项目的目标是了解MFN的机制调节剂会影响心肌细胞死亡和代谢，并测试这些药物是否可能提供新颖 MI和HF的治疗策略。我们提出：1。将MFN激活/抑制的变化与成人的线粒体连通性，线粒体-ER/SR接近，Ca2+转移，细胞死亡和代谢心肌细胞。 2。描述线粒体连通性和线粒体的个体贡献 ER/SR靠近体内心肌细胞中细胞死亡和代谢。 3。评估介脂蛋白是否调节剂为MI和HF提供新颖的治疗策略。该项目打破了定义的新基础 MFN调节剂会影响心肌细胞死亡和代谢以及MFN是否提供的机制针对MI和HF的新型疗法的可行靶标。