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.

项目总结/摘要 线粒体（mtDNA）和核（nDNA）基因组之间的相互作用是必不可少的， 维持线粒体和细胞功能。然而，与年龄和疾病相关的 异质性mtDNA（不同mtDNA单倍型的存在）产生基因组间错配， 干扰线粒体相互作用效率。线粒体相互作用中断导致线粒体 功能障碍，降低有机体适应性，并引发各种压力，这些压力与 过多的许多人类疾病，如亨廷顿病、莱伯遗传性视神经病变和 2型糖尿病为了响应被破坏的线粒体相互作用，细胞激活应激反应 重塑基因表达和代谢的途径，从而维持线粒体功能， 缓解细胞压力然而，对线粒体机制的详细分子理解， 激活应激反应途径以维持线粒体功能和应激抗性， 研究不足，代表着重大的知识差距。我假设明显不匹配的线粒体 基因组维持线粒体状态与各种应激反应途径的协调， 次优线粒体相互作用的有害后果。为了验证这一假设，我们开发了一种新的 酵母线粒体交换模型（cytoductants），将100多种mtDNA基因型结合到 相同的nDNA遗传背景，从而产生一个优雅的系统，在不同程度的扰动， 线粒体相互作用和线粒体功能改变。总的来说，我们研究的主要目标是 机械地理解线粒体相互作用中的扰动如何被转换成生物学效应。 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 在分子水平上理解线粒体通讯将揭示不同线粒体的假说 对干扰线粒体相互作用的反应。（项目1）。其次，我们将识别 应激反应途径及其下游效应物在保护细胞免受各种应激下的作用 微扰Mitsubishi相互作用的条件此外，我们将确定是否一种特定类型的压力源， 确定响应的特异性或不（项目2）。最后，通过创新的细胞工程 方法，我们将研究平衡细胞能量止血可以减轻效果的假设 破坏线粒体相互作用（项目3）。这项拟议中的研究意义重大，因为它将揭示 细胞如何对破坏的线粒体相互作用作出反应以维持细胞内稳态。由于许多 线粒体疾病是以异质性进行的，这项关于线粒体维持的基础研究 相互作用将可能鉴定有效线粒体相互作用的调节剂。可能是针对 用于治疗与线粒体功能障碍相关的人类病理，例如 神经变性和衰老。