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.

线粒体质子动力（PMF）是一种跨线粒体内部的电化学梯度， 细胞膜，为ATP合成和其他线粒体信号提供动力。PMF在以下条件下自然可变 不同的情况下，并可能取决于营养状况，细胞或组织类型和许多其他因素。重要的是， 有证据表明，PMF随年龄增长而下降。从酵母菌到哺乳动物组织都是如此。 然而，目前还不清楚这种下降是衰老表型的原因还是结果。我们证明了 PMF随年龄增长而下降。线虫和人类细胞和饮食限制（DR），一个良好的特征， 长寿干预，防止这种损失。此外，PMF的损失抵消了DR对C的影响。elegans 这进一步表明PMF是生物衰老的基本调节剂。该提案旨在测试 并充分说明PMF是三种不同但相关的长寿范式的决定因素：规范性 衰老、DR和缺氧信号。DR是减少热量摄入而不引起营养不良， 中心blog缺氧和通过缺氧诱导因子（HIF）的信号传导延长寿命并促进健康， 不同的型号。有趣的是，虽然DR似乎保留PMF，但缺氧处理会急剧降低PMF。 这些相反的影响PMF在两个不同的范例，延长寿命必须进行调查 机械地。缺乏在活组织或完整生物体中隔离地特异性调节PMF的工具是一个困难的问题。 理解线粒体如何调节衰老的关键差距。该提案旨在利用已知的 通过DR和缺氧信号转导研究模型中代谢随年龄下降的新的保守机制 梭elegans长寿和人类细胞衰老。直到最近，还没有办法通过实验 与代谢和生理学的其它方面隔离地增加PMF。PMF现在可以被隔离为单个 通过光遗传学可变，使用光敏蛋白来增加或减少跨膜 体内电化学梯度。线粒体光遗传学允许我们控制线粒体直接离开 其他代谢途径完好我们认为，保存线粒体能量是一个共同的原因， DR介导的寿命和缺氧信号的因子。我们将使用最先进的 平行光遗传学技术C. elegans和细胞模型，这将确保严格的结果和有效的 翻译我们的发现的途径。我们将测试PMF如何在动物和细胞中补充DR。 水平，以及PMF如何与缺氧和HIF介导的寿命延长相互作用。我们将进一步测试 充分表征的营养感测信号由PMF调节以引起长寿。新的见解如何 PMF特异性控制衰老和长寿信号将是对PMF有效性的重要研究。 靶向代谢以保护人类免受疾病的侵害。了解基本参数 蠕虫和人类细胞中的代谢和PMF将为我们已经知道的东西提供新的见解， 将为发现线粒体PMF下游长寿的新机制铺平道路。