The role of mito-nuclear communication in the adaptation to mitochondrial dysfunction and stress resistance

线粒体核通讯在适应线粒体功能障碍和应激抵抗中的作用

• 批准号: 10713440
• 负责人: Alaattin Kaya
• 金额: $ 36.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713440
• 关键词: Age; Aging; Basic Science; Biological; Biological Process; Cell physiology; Cells; Cellular Stress; Communication; Cytoprotection; Disease; Foundations; Functional disorder; Gene Expression; Genetic; Genome; Genotype; Goals; Haplotypes; Hemostatic function; Homeostasis; Human; Human Pathology; Huntington Disease; Intervention; Knowledge; Laboratories; Leber' s Hereditary Optic Neuropathy; Link; Maintenance; Malignant Neoplasms; Metabolism; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Molecular; National Institute of General Medical Sciences; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathway interactions; Public Health; Research; Research Project Grants; Resistance; Role; Specificity; Stress; System; Testing; Yeasts; biological adaptation to stress; cellular engineering; fitness; heteroplasmy; human disease; innovation; mitochondrial dysfunction; new therapeutic target; novel; pharmacologic; response; stressor

PROJECT SUMMARY/ABSTRACT Interactions between mitochondrial (mtDNA) and nuclear (nDNA) genomes are essential for maintaining mitochondrial and cellular functions. However, an age- and disease-associated increase of heteroplasmic mtDNA (the presence of different mtDNA haplotypes) creates an inter-genomic mismatch that perturbs mitonuclear interaction efficiency. Disrupted mitonuclear interaction results in mitochondrial dysfunction, reduced organismal fitness, and initiation of various stress that has been associated with a plethora of many human diseases, such as Huntington's disease, Leber's hereditary optic neuropathy, and type 2 diabetes mellitus. In response to disrupted mitonuclear interactions, cells activate stress response pathways to remodel gene expression and metabolism, thereby maintaining mitochondrial function and alleviating cellular stress. However, a detailed molecular understanding of mitonuclear mechanisms linking activation of stress response pathways for maintaining mitochondrial function and stress resistance has been understudied, representing a significant knowledge gap. I hypothesize that distinct mismatched mitonuclear genomes maintain coordination of mitochondrial status with various stress response pathways to alleviate harmful consequences of suboptimal mitonuclear interactions. To test this hypothesis, we developed a novel yeast mitonuclear exchange model (cytoductants) by combining more than 100 mtDNA genotypes onto the same nDNA genetic background, thereby generating an elegant system with various degrees of perturbation in mitonuclear interaction and altered mitochondrial function. Overall, the main goal of our research is to mechanistically understand how perturbations in mitonuclear interaction are transduced into biological effects. My laboratory will build and sustain three research projects to accomplish this goal. We will first test the hypothesis that understanding mitonuclear communication at molecular level will uncover distinct mitonuclear responses to perturbed mitonuclear interactions. (Project 1). Secondly, we will identify the crosstalk between stress response pathways and their downstream effectors in protecting cells from various stress under the condition of perturbed mitonuclear interaction. Further, we will determine whether a specific type of stressor determines the specificity of the response or not (Project 2). Finally, with an innovative cell engineering approach, we will investigate the hypothesis that balancing cellular energy hemostasis can mitigate the effect of disrupted mitonuclear interaction (Project 3). The proposed research is significant because it will uncover how cells respond to disrupted mitonuclear interactions to maintain cellular homeostasis. Since many mitochondrial diseases are carried in heteroplasmy, this basic research into the maintenance of mitonuclear interaction will likely identify modulators of efficient mitochondrial interaction. It might be targeted pharmacologically to treat human pathologies associated with mitonuclear dysfunction, such as neurodegeneration and aging.

项目摘要/摘要 线粒体（mtDNA）与核（NDNA）基因组之间的相互作用对于 维持线粒体和细胞功能。但是，年龄和疾病相关的增加 异质mtDNA（存在不同mtDNA单倍型的存在）会产生一种基因组不匹配 perturbs Mitonaclear相互作用效率。线粒体中断的线粒体相互作用会导致线粒体 功能障碍，降低有机体适应性以及与A 许多人类疾病，例如亨廷顿氏病，列伯的遗传性视神经病变和 2型糖尿病。为了响应破坏的有线核相互作用，细胞激活应力反应 重塑基因表达和代谢的途径，从而维持线粒体功能和 减轻细胞应激。但是，对有联系机制的详细分子理解 激活应力反应途径以维持线粒体功能和抗压力抗性一直是 研究了，代表了一个重要的知识差距。我假设那些独特的不匹配的有线核 基因组维持线粒体状态的协调与各种应力反应途径减轻 次优的有核相互作用的有害后果。为了检验这一假设，我们开发了一种小说 通过将超过100 mtDNA基因型合并到该的酵母有线核交换模型（细胞染料） 相同的NDNA遗传背景，从而产生了一个具有不同程度扰动的优雅系统 线核相互作用和线粒体功能改变。总体而言，我们研究的主要目标是 机械学上了解有线核相互作用中的扰动是如何将其转化为生物学作用的。 我的实验室将建立和维持三个研究项目以实现这一目标。我们将首先测试 假设理解分子水平的有线核通信将发现不同的有线核 对扰动的有核相互作用的响应。 （项目1）。其次，我们将确定 压力响应途径及其下游效应子在保护细胞免受各种应力下的下游效应子 扰动的线核相互作用的条件。此外，我们将确定特定类型的压力源是否 确定响应是否特异性（项目2）。最后，有了创新的细胞工程 方法，我们将研究平衡细胞能量止血的假设可以减轻效果 有线核互动的中断（项目3）。拟议的研究很重要，因为它将发现 细胞如何应对干扰的有线核相互作用以维持细胞稳态。自从很多 线粒体疾病在异质中携带，这是维持线核的基础研究 相互作用可能会识别有效线粒体相互作用的调节剂。它可能是针对的 在药理上治疗与有线核功能障碍相关的人体病理，例如 神经变性和衰老。