Multimodal control of mitochondrial energetics to shape biological aging

线粒体能量的多模式控制塑造生物衰老

• 批准号: 10864185
• 负责人: Alessandro Bitto
• 金额: $ 31.63万
• 依托单位: UNIVERSITY OF ROCHESTER
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10864185
• 关键词: 5' -AMP-activated protein kinase; ATP Synthesis Pathway; Acute; Address; Age; Aging; Animals; Apoptosis; Biological Aging; Biological Models; Biology; Caenorhabditis elegans; Calcium; Cell Aging; Cell Culture Techniques; Cell model; Cell physiology; Cells; Communication; Complement; Cues; Development; Dietary Intervention; Disease; Electron Transport; Energy Intake; Ensure; FRAP1 gene; Generations; Genetic; Health Promotion; Homeostasis; Human; Human Pathology; Hypoxia; Hypoxia Inducible Factor; Inner mitochondrial membrane; Intervention; Investigation; Light; Longevity; Longevity Pathway; Malnutrition; Measures; Mediating; Mediator; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Nematoda; Nutrient; Organism; Oxidation-Reduction; Oxygen; Pathway interactions; Phenotype; Physiology; Process; Proteins; Proton Pump; Proton-Motive Force; Protons; Reaction; Reactive Oxygen Species; Regimen; Regulation; Risk Factors; Role; Shapes; Signal Pathway; Signal Transduction; Techniques; Technology; Testing; Tissues; Translations; Yeasts; detection of nutrient; dietary requirement; dietary restriction; healthspan; healthy aging; hypoxia inducible factor 1; in vivo; insight; mitochondrial autophagy; mitochondrial dysfunction; model organism; multimodality; novel; novel strategies; nutrient metabolism; optogenetics; pharmacologic; preservation; prevent; protective pathway; proteostasis; response; senescence; tool; uptake

The mitochondrial protonmotive force (PMF) is an electrochemical gradient across the inner mitochondrial membrane that powers ATP synthesis and other mitochondrial signaling. PMF is naturally variable under different situations, and can depend on nutrient status, cell or tissue type, and many other factors. Importantly, evidence suggests that PMF declines with age. This observation holds from yeast to mammalian tissues. However, it is still unclear whether this decline is a cause or a consequence of aging phenotypes. We show that PMF declines with age in C. elegans and human cells and that Dietary Restriction (DR), a well-characterized longevity intervention, prevents this loss. Furthermore, loss of PMF negates the effects of DR on C. elegans longevity, further suggesting that PMF is a fundamental regulator of biological aging. This proposal aims to test and fully characterize how PMF is a determinant of three different, but related, longevity paradigms: normative aging, DR, and hypoxia signaling. DR is a reduction in caloric intake without causing malnutrition that results in longevity. Hypoxia and signaling through hypoxia-inducible factor (HIF) extend lifespan and promotes health in different models. Interestingly, while DR seems to preserve PMF, hypoxia treatment decreases PMF acutely. These opposite effects on PMF in two different paradigms that extend lifespan must be investigated mechanistically. Lack of tools to specifically modulate PMF in isolation in living tissue or intact organisms is a critical gap in understanding how mitochondria regulate aging. This proposal aims to leverage what is known through DR and hypoxia signaling to study new, conserved mechanisms of metabolic decline with age in models of C. elegans longevity and human cell senescence. Until recently, there were no means to experimentally increase PMF in isolation from other aspects of metabolism and physiology. PMF can now be isolated as a single variable through optogenetics, the use of light-sensitive proteins to increase or decrease transmembrane electrochemical gradients in vivo. Mitochondrial optogenetics allows us to control mitochondria directly leaving other metabolic pathways intact. We propose that preserved mitochondrial energetics is a common causal factor for both DR-mediated longevity and hypoxia signaling. We will test our models using cutting-edge optogenetic techniques in parallel C. elegans and cellular models, which will ensure rigorous results and efficient pathways for translation of our findings. We will test how PMF complements DR in animals and at the cellular level, as well as how PMF interacts with hypoxia and HIF-mediated lifespan extension. We will further test how well-characterized nutrient sensing signaling is regulated by PMF to cause longevity. New insight into how the PMF specifically controls aging and longevity signaling will be an important investigation into the efficacy of targeting metabolism for protection against disease in humans. Understanding the fundamental parameters of metabolism and PMF in both worms and human cells will offer novel insights into what we already know, and will pave the way for discovering new mechanisms of longevity downstream of mitochondrial PMF.

线粒体质子运动力（PMF）是内部线粒体的电化学梯度 膜，可以为ATP合成和其他线粒体信号传导提供动力。 PMF自然是可变的 不同的情况，可以取决于营养状况，细胞或组织类型以及许多其他因素。重要的是， 证据表明，PMF随着年龄的增长而下降。该观察结果从酵母到哺乳动物组织。 但是，尚不清楚这种下降是衰老表型的原因还是结果。我们表明 PMF随着秀丽隐杆线虫和人类细胞的年龄而下降 寿命干预，防止这种损失。此外，PMF的丧失否定了DR对秀丽隐杆线虫的影响 寿命，进一步表明PMF是生物衰老的基本调节剂。该建议旨在测试 并完全表征PMF的决定因素的三种不同但相关的寿命范式：规范 衰老，DR和缺氧信号传导。 DR是降低热量摄入量而不会导致营养不良的 长寿。缺氧和通过低氧诱导因子（HIF）发出信号传导延长寿命并促进健康 不同的模型。有趣的是，尽管DR似乎保留了PMF，但缺氧治疗急性降低。 必须研究两个延长寿命的两个不同范式中对PMF的相反影响 机械上。缺乏在生物组织或完整生物中孤立调节PMF的工具是一种 理解线粒体如何调节衰老的关键差距。该建议旨在利用已知的 通过DR和缺氧信号传导，研究新的，保守的代谢下降机制，随着年龄的增长 秀丽隐杆线虫的寿命和人类细胞衰老。直到最近，还没有实验的方法 与新陈代谢和生理学的其他方面孤立地增加PMF。现在可以将PMF隔离为单个 通过光遗传学可变，使用光敏蛋白增加或减少跨膜 体内电化学梯度。线粒体光遗传学使我们能够直接控制线粒体 其他代谢途径完好无损。我们建议保留的线粒体能量是一种常见的因果关系 DR介导的寿命和缺氧信号传导的因子。我们将使用前沿测试我们的模型 秀丽隐杆线虫和细胞模型中的光遗传技术，这将确保严格的结果和有效 翻译我们发现的途径。我们将测试PMF如何补充动物中的DR和在细胞中 水平以及PMF如何与缺氧和HIF介导的寿命扩展相互作用。我们将进一步测试如何 特征良好的营养感应信号受PMF调节，以导致寿命。关于如何 PMF专门控制衰老和寿命信号将是对 靶向代谢以保护人类的疾病。了解 蠕虫和人类细胞中的代谢和PMF将提供有关我们已经知道的事物的新见解，并且 将为发现线粒体PMF下游寿命的新机制铺平道路。