Divergences in the mitochondrial oxidative phosphorylation process and the role they play on reactive oxygen species production and aging

线粒体氧化磷酸化过程的差异及其对活性氧产生和衰老的作用

• 批准号: RGPIN-2021-02924
• 负责人: Lemieux, Hélène
• 金额: $ 3.06万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746469
• 关键词: Divergences; mitochondrial; oxidative; phosphorylation; process

Mitochondria provide energy through a process called oxidative phosphorylation. This process is fed by multiple pathways of electrons converging at the ubiquinone junction of the electron transfer system. By using oxygen as the final electron acceptor, oxidative phosphorylation also produces highly reactive derivatives of oxygen, i.e., reactive oxygen species. Reactive oxygen species have a dual role. At low doses, these molecules are beneficial, acting as triggers to activate cellular signal pathways and prepare the cell to defend itself against stressful events. However, at higher doses, they attack the proteins, lipids and DNA causing oxidative stress, cellular dysfunction and aging. My research indicates large variations in oxidative phosphorylation pathway utilization and regulation mechanisms among species, tissues, and sexes. To further understand the role of mitochondria in aging, we have to consider the mitochondrial diversity and its impact on reactive oxygen species production. The global objective of my research program is to investigate the consequences of heterogeneity in oxidative phosphorylation efficiency, substrates utilization and regulatory mechanisms on cellular homeostasis and aging through reactive oxygen species production. For this, we need to determine (A) how the activated pathway(s) and the regulatory mechanism(s) modulate energy production and reactive oxygen species efflux by the mitochondria, (B) how this relationship varies between species, tissues, sex and age, and (C) how it is linked with longevity. We will address these questions both at the macroevolutionary and microevolutionary scales by comparing various animal models from diverse taxa, from planarian worm to human. Our comparison will include species with similar oxidative phosphorylation regulation mechanisms, i.e., control by the phosphorylation system in the planarian worm and human heart, and species with contrasting regulation mechanisms, i.e., control by the electron transfer system in the beetle, rat and mice hearts. Furthermore, by having access to lines of beetles with large differences in longevity, we will verify, at the microevolutionary level, if the selection of oxidative phosphorylation pathways or regulatory mechanism is an efficient way to modulate aging. The results obtained through this research program will broaden our current knowledge of how variability in mitochondrial metabolism, at different time points during the course of life, affects animal cellular health and aging. Understanding these fluctuations and their impacts is crucial to pinpoint the role of mitochondria in aging, and to design strategies to protect mitochondria during the aging process.

线粒体通过氧化磷酸化过程提供能量。这一过程是由电子转移系统的泛素结处聚集的多种电子途径提供的。通过使用氧作为最终的电子受体，氧化磷酸化也产生高活性的氧衍生物，即活性氧。活性氧具有双重作用。在低剂量下，这些分子是有益的，作为触发器激活细胞信号通路，并准备细胞保护自己免受压力事件。然而，在高剂量下，它们会攻击蛋白质、脂质和DNA，导致氧化应激、细胞功能障碍和衰老。我的研究表明，在物种、组织和性别之间，氧化磷酸化途径的利用和调节机制存在很大差异。为了进一步了解线粒体在衰老中的作用，我们必须考虑线粒体多样性及其对活性氧产生的影响。我的研究计划的全球目标是研究氧化磷酸化效率、底物利用和通过活性氧产生的细胞稳态和衰老的调节机制的异质性的后果。为此，我们需要确定(A)激活的途径和调节机制如何通过线粒体调节能量产生和活性氧的外排，(B)这种关系如何在物种、组织、性别和年龄之间变化，以及(C)它如何与长寿联系在一起。我们将通过比较从涡虫到人类等不同类群的各种动物模型，从宏观进化和微观进化两方面来解决这些问题。我们的比较将包括具有相似氧化磷酸化调节机制的物种，即涡虫和人类心脏中的磷酸化系统控制，以及具有不同调节机制的物种，即甲虫、大鼠和小鼠心脏中的电子传递系统控制。此外，通过接触寿命差异较大的甲虫系，我们将在微观进化水平上验证氧化磷酸化途径或调节机制的选择是否是调节衰老的有效方法。通过这项研究项目获得的结果将拓宽我们目前对线粒体代谢在生命过程中不同时间点的变异性如何影响动物细胞健康和衰老的认识。了解这些波动及其影响对于确定线粒体在衰老中的作用以及设计在衰老过程中保护线粒体的策略至关重要。