MOLECULAR ORCHESTRATION OF MITOCHONDRIAL FITNESS VIA REPLACEMENT OR REPAIR

通过替换或修复进行线粒体适应性的分子排列

• 批准号: 9101442
• 负责人: Gerald W. Dorn
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9101442
• 关键词: Ablation; Adult; Apoptotic; Applied Genetics; Attention; Autophagocytosis; Back; Basal metabolic rate; Bioenergetics; Biogenesis; Birth; Carbohydrates; Cardiac; Cardiac Myocytes; Cell Death; Cells; Clinical; Complement; Coupling; Data; Development; Disease; Disease Progression; Eating; Excision; Exhibits; Failure; Fatty acid glycerol esters; Fetal Heart; Gene Expression; Genetic Models; Germ Lines; Glucose; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart Mitochondria; Heart failure; Human; Hypertrophy; Individual; Injury; Interruption; Knockout Mice; Life; Mediating; Metabolic; Metabolism; Mitochondria; Modality; Modeling; Molecular; Mus; Mutation; Myocardial; Necrosis; Operative Surgical Procedures; Organelles; Outer Mitochondrial Membrane; PINK1 gene; Parkin gene; Parkinson Disease; Pathway interactions; Pattern; Perinatal; Phenotype; Play; Positioning Attribute; Process; Proteins; Quality Control; Reactive Oxygen Species; Research; Role; Signal Transduction; Source; Staging; Stress; Testing; Therapeutic; Time; Ubiquitination; base; cost; fatty acid metabolism; fetal; genetic approach; heart metabolism; in vivo; mitochondrial fitness; mutant; novel; novel strategies; novel therapeutics; overexpression; parkin gene/protein; postnatal; preference; pressure; prevent; programs; public health relevance; receptor; repaired; stomach cardia; therapeutic target

 DESCRIPTION (provided by applicant): Mitochondria are the essential sources of most ATP that fuels excitation-contraction coupling in the heart. They are also major sources of toxic reactive oxygen species (ROS). To maintain overall mitochondrial and metabolic health, cells rely upon surveillance, pre-emptive sequestration, and targeted removal of damaged organelles while retaining healthy mitochondria. Selective mitochondrial culling in this manner utilizes the cellular autophagy apparatus, and is therefore designated "mitophagy." The integrated process of identification, sequestration, and mitophagic removal of damaged mitochondria is commonly referred to as "mitochondrial quality control." The best understood cellular mechanism for mitochondrial quality control depends upon mitochondrial localization of, and protein ubiquitination by, the Parkinson's disease factor Parkin. The novel concept underlying this proposal is that "mitochondrial quality" is not a specific condition. Because metabolic demands and substrate availability fluctuate based on cardiac developmental and pathophysiological status, the highest quality mitochondria in one condition may be sub-optimal or detrimental in another. Examples of mitochondrial plasticity include the normal perinatal transition from glycolytic to fatty acid metabolism, and the pathological reversal of this metabolic transition in diseased adult hearts. Conventional wisdom is that mitochondria are genetically "reprogrammed" during these metabolic transformations, but we believe this to be overly simplistic. Our intercurrent experimental data reveal that pre-existing mitochondria must first be removed in a Parkin-dependent manner before biogenesis and mitochondrial fusion can accomplish their replacement by metabolically distinct successors. Thus, we hypothesize that the Parkin mitophagy pathway serves two distinct roles in hearts: the canonical function of selecting and removing individual damaged mitochondria, and a previously undescribed function evoking generalized mitochondrial turnover essential to biogenic mitochondrial replacement during metabolic transitions. Our research efforts have produced a completely novel approach to modulating Parkin signaling specifically at its mitochondrial molecular interface by expressing dominantly active or inhibitory mitochondrial outer membrane Parkin receptors (PINK1-phosphorylated Mfn2). We will use this approach to manipulate Parkin signaling in the in vivo mouse heart and evaluate the consequences on mitochondrial quality and metabolic remodeling during the normal perinatal transition to fatty acid metabolism, after surgical induction of cardia pressure overload (TAC), and during hypertrophy reverse remodeling in TAC/de-TAC studies. If our hypothesis is correct, then enhancing Parkin signaling will facilitate early culling of damaged organelles at the cost of accelerating delayed metabolic remodeling back to the glycolytic fetal phenotype, whereas interrupting Parkin-mediated mitophagy will cause early accumulation of damaged organelles, but delay the maladaptive reversion to fetal-like metabolism. Thus, we will establish the optimal times, relative to disease progression, for conditional enhancement or suppression of Parkin-mediated mitophagy to best complement mitochondrial function and metabolism in different pathophysiological states. Together, our studies will rigorously evaluate the concept that manipulating Parkin signaling at its mitochondrial receptor (an interaction that i pharmacologically targetable) can both promote culling of damaged organelles and correct mismatches between mitochondrial metabolic preference and myocardial demand.

 描述（由适用提供）：线粒体是大多数ATP的基本来源，这些ATP为心脏中兴奋而兴奋的耦合。它们也是有毒活性氧（ROS）的主要来源。为了维持总体线粒体和代谢健康，细胞依赖于监视，先发制人的隔离以及靶向去除受损的细胞器，同时保留健康的线粒体。选择性线粒体以这种方式使用细胞自噬设备，因此被指定为“线粒体”。识别，隔离和线粒体的线粒体的综合过程通常称为“线粒体质量控制”。线粒体质量控制的最佳理解的细胞机制取决于帕金森氏病因子帕金的线粒体定位和蛋白质泛素化。该提议的基础的新颖概念是“线粒体质量”不是特定条件。由于代谢需求和底物的可用性会根据心脏发育和病理生理状况而波动，因此在一种情况下，最高质量的线粒体在另一种情况下可能是最佳或有害的。线粒体可塑性的例子包括正常的围产期过渡，从糖酵解到脂肪酸代谢，以及这种新陈代谢转变的病理逆转。传统的智慧是，在这些代谢转化期间，线粒体在遗传上是“重编程”的，但我们认为这过于简单。我们的互动实验数据表明，在生物发生和线粒体融合可以通过代谢不同的后继者替代其替代者之前，必须首先以帕金依赖性方式去除先前存在的线粒体。这就是我们假设，parkin线粒体途径在心脏中起两个不同的作用：选择和去除个体损坏的线粒体的规范功能，以及先前未描述的功能，引起了代谢过渡期间生物线粒体替换所必需的广义性线粒体转换。我们的研究工作已经产生了一种完全新颖的方法，可以通过表达显着的活性或抑制性线粒体外膜帕克蛋白受体（PINK1-磷酸化的MFN2）来调节其线粒体分子界面。我们将使用这种方法来操纵体内小鼠心脏中的Parkin信号传导，并评估在正常的围产期过渡到脂肪酸代谢的过程中对线粒体质量和代谢重塑的后果，在心脏抗体压力超负荷（TAC）手术诱导后，以及在TAC/DEDAC研究中进行肥大反向重塑期间。如果我们的假设正确，则增强Parkin信号传导将有助于提前淘汰损害 细胞器是以加速延迟代谢重塑回到糖酵解胎儿表型的成本，而中断Parkin介导的线粒体会导致受损细胞器的早期加速，但会延迟适应性的逆转为胎儿样细胞代谢。这是，我们将建立相对于疾病进展的最佳时间，以增强或抑制帕金介导的线粒体，以最佳完成线粒体功能和不同病理生理状态的代谢。总之，我们的研究将严格评估这样的概念，即在其线粒体受体处操纵Parkin信号传导（我可以在药物方面具有目标的相互作用）既可以促进受损细胞器的剔除，又可以促进线粒体代谢偏好和心肌需求之间的不匹配。