Metabolic Impact and Mechanism of Enhanced Mitochondrial Calcium Uptake in Mitochondrial Cardiomyopathies

线粒体钙摄取增强对线粒体心肌病的代谢影响和机制

基本信息

批准号：
10753651
负责人：
Dipayan Chaudhuri
金额：
$ 60.42万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753651
关键词：
ATP Synthesis Pathway Address Adenine Affect Animals Antioxidants Binding Bioenergetics Biological Assay Biology Calcium Calcium Signaling Carbon Cardiac Cardiomyopathies Child Childhood Complex Cytoprotection Dependovirus Dinucleoside Phosphates Disease Drosophila genus Enzymes Equilibrium Functional disorder Heart Heart Injuries Heart failure Homeostasis Human Impairment Inborn Errors of Metabolism Infant Link Mediating Metabolic Metabolism Mitochondria Mitochondrial DNA Mitochondrial Matrix Modeling Mus Mutation N-terminal NADH NADH dehydrogenase (ubiquinone)NADP Niacinamide Organ Outcome Oxidation-Reduction Oxidative Phosphorylation Pathologic Pathologic Processes Pathology Pathway interactions Physiological Physiology Prevalence Production Prognosis Proteins Reactive Oxygen Species Regulation Regulatory Pathway Signal Transduction Testing Therapeutic Up-Regulation Work calcium uniporter disease-causing mutation functional improvement heart function heart metabolism heart preservation improved mitochondrial cardiomyopathies mitochondrial metabolism mortality mouse model neonatal mice novel novel therapeutics preservation prevent protein degradation transcription factor transgene expression uptake virtual

项目摘要

PROJECT SUMMARY Diseases that arise from mutations in components of mitochondrial oxidative phosphorylation can be devastating, as mitochondria are crucial for energy synthesis. These diseases occur predominantly in infants and children, with a prevalence of 1 in 5000. Though virtually any organ can be affected, the heart is frequently involved, because cardiac function has such high energy requirements. These mitochondrial cardiomyopathies have a particularly grim prognosis, with mortality rates increased nearly three-fold compared to children without cardiac involvement, and no specific therapies available. In linking cardiac function to mitochondrial metabolism, calcium signaling may be central to the pathological process. Calcium influx into the mitochondria can potently stimulate ATP synthesis. In the initial period of this application, we identified a regulatory mechanism by which dysfunction within Complex I of the electron transport chain causes a compensatory increase in activity of the mitochondrial calcium uniporter channel, preserving ATP synthesis. During normal physiology, Complex I promotes uniporter degradation via an interaction with the uniporter, a mechanism we term Complex I-induced protein turnover (CLIPT). During Complex I dysfunction, interaction with the uniporter is inhibited, preventing degradation and leading to a build-up in functional channels. This mechanism is widespread and was seen in fruit flies, mice, and humans. Moreover, while inhibiting the uniporter led to early demise in Complex I-deficient animals, enhancing uniporter stability rescued survival and function. In this project period, we propose the following three aims to further study this pathway and determine whether it can be exploited for potential therapeutic benefit. We focus on mitochondrial one-carbon (1C) metabolism, a producer of mitochondrial antioxidant species (NAPDH), because this pathway is substantially upregulated in mitochondrial cardiomyopathies. In the first aim, we will examine if adenine dinucleotides (NAD+/NADP+) regulate the uniporter, and if calcium regulates critical 1C metabolism enzymes. In the second aim, we will establish whether uniporter activity in mitochondrial cardiomyopathies extends beyond ATP synthesis to NADPH biology, affecting redox balance and one-carbon metabolism. In the third aim, we will test whether manipulation of the portion of the uniporter that interacts with Complex I, the uniporter N-terminal domain (NTD), can be exploited in mouse models as a potential therapy for mitochondrial cardiomyopathies.

项目概要由线粒体氧化磷酸化成分突变引起的疾病可能是毁灭性的，因为线粒体对于能量合成至关重要。这些疾病主要发生在婴儿身上和儿童，患病率为五千分之一。虽然几乎任何器官都可能受到影响，但心脏经常受到影响涉及，因为心脏功能有如此高的能量需求。这些线粒体心肌病的预后尤其严峻，死亡率增加近三倍与没有心脏受累的儿童相比，并且没有可用的特定治疗方法。在连接心脏钙信号传导对线粒体代谢发挥重要作用，可能是病理过程的核心。钙流入线粒体可以有效刺激 ATP 合成。在本申请的初期，我们确定了电子传递链复合物 I 内功能障碍的调节机制导致线粒体钙单向通道活性代偿性增加，从而保留 ATP 合成。在正常生理过程中，复合物 I 通过与单向转运蛋白，我们称之为复合物 I 诱导的蛋白质周转 (CLIPT) 的机制。在复合体 I 功能障碍期间，与单向转运蛋白的相互作用被抑制，防止降解并导致功能性蛋白的积累渠道。这种机制很普遍，在果蝇、小鼠和人类中都有发现。此外，虽然抑制单向转运蛋白会导致复合物 I 缺陷动物的早期死亡，从而增强单向转运蛋白的稳定性挽救了生存和功能。在本项目期间，我们提出以下三个目标来进一步研究这一问题途径并确定它是否可以用于潜在的治疗益处。我们专注于线粒体一碳 (1C) 代谢，线粒体抗氧化剂 (NAPDH) 的产生者，因为该途径在线粒体心肌病中显着上调。在第一个目标中，我们将检查腺嘌呤二核苷酸 (NAD+/NADP+) 是否调节单向转运蛋白，以及钙是否调节关键 1C 代谢酶。在第二个目标中，我们将确定线粒体中的单转运蛋白活性是否心肌病从 ATP 合成延伸到 NADPH 生物学，影响氧化还原平衡和一碳代谢。在第三个目标中，我们将测试是否操纵相互作用的单向端口部分与复合物 I 一样，单向转运蛋白 N 末端结构域 (NTD) 可以在小鼠模型中作为潜在的线粒体心肌病的治疗。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanisms of EMRE-Dependent MCU Opening in the Mitochondrial Calcium Uniporter Complex.

线粒体钙单向转运蛋白复合物中 EMRE 依赖性 MCU 打开的机制。

DOI：
发表时间：
2020
期刊：
影响因子：
8.8
作者：
Van Keuren, Anna M;Tsai, Chen;Balderas, Enrique;Rodriguez, Madison X;Chaudhuri, Dipayan;Tsai, Ming
通讯作者：
Tsai, Ming

Mitochondria possess a large, non-selective ionic current that is enhanced during cardiac injury.

线粒体具有大量的非选择性离子电流，在心脏损伤期间会增强。

DOI：
发表时间：
2023-11-16
期刊：
影响因子：
0
作者：
Balderas, Enrique;Lee, Sandra H J;Shankar, Thirupura S;Yin, Xue;Balynas, Anthony M;Kyriakopoulos, Christos P;Selzman, Craig H;Drakos, Stavros G;Chaudhuri, Dipayan
通讯作者：
Chaudhuri, Dipayan

Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.

超越 TCA 循环：线粒体钙氧化磷酸化调节的新见解。

DOI：
发表时间：
2023-08-31
期刊：
影响因子：
3.9
作者：
Lee, Sandra H;Duron, Hannah E;Chaudhuri, Dipayan
通讯作者：
Chaudhuri, Dipayan

MitoBKCa channel is functionally associated with its regulatory β1 subunit in cardiac mitochondria.

MitoBKCa 通道在功能上与其在心脏线粒体中的调节β1 亚基相关。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Balderas, Enrique;Torres, Natalia S;Rosa;Chaudhuri, Dipayan;Toro, Ligia;Stefani, Enrico;Olcese, Riccardo
通讯作者：
Olcese, Riccardo

TRPswitch-A Step-Function Chemo-optogenetic Ligand for the Vertebrate TRPA1 Channel.

TRPswitch-脊椎动物 TRPA1 通道的阶梯功能化学光遗传学配体。

DOI：
发表时间：
2020
期刊：
影响因子：
15
作者：
Lam, Pui;Thawani, Aditya R;Balderas, Enrique;White, Andrew J P;Chaudhuri, Dipayan;Fuchter, Matthew J;Peterson, Randall T
通讯作者：
Peterson, Randall T