Abstract

Elevated mitochondrial matrix superoxide and/or hydrogen peroxide concentrations drive a wide range of physiological responses and pathologies. Concentrations of superoxide and hydrogen peroxide in the mitochondrial matrix are set mainly by rates of production, the activities of superoxide dismutase-2 (SOD2) and peroxiredoxin-3 (PRDX3), and by diffusion of hydrogen peroxide to the cytosol. These considerations can be used to generate criteria for assessing whether changes in matrix superoxide or hydrogen peroxide are both necessary and sufficient to drive redox signaling and pathology: is a phenotype affected by suppressing superoxide and hydrogen peroxide production; by manipulating the levels of SOD2, PRDX3 or mitochondria-targeted catalase; and by adding mitochondria-targeted SOD/catalase mimetics or mitochondria-targeted antioxidants? Is the pathology associated with variants in SOD2 and PRDX3 genes? Filtering the large literature on mitochondrial redox signaling using these criteria highlights considerable evidence that mitochondrial superoxide and hydrogen peroxide drive physiological responses involved in cellular stress management, including apoptosis, autophagy, propagation of endoplasmic reticulum stress, cellular senescence, HIF1α signaling, and immune responses. They also affect cell proliferation, migration, differentiation, and the cell cycle. Filtering the huge literature on pathologies highlights strong experimental evidence that 30-40 pathologies may be driven by mitochondrial matrix superoxide or hydrogen peroxide. These can be grouped into overlapping and interacting categories: metabolic, cardiovascular, inflammatory, and neurological diseases; cancer; ischemia/reperfusion injury; aging and its diseases; external insults, and genetic diseases. Understanding the involvement of mitochondrial matrix superoxide and hydrogen peroxide concentrations in these diseases can facilitate the rational development of appropriate therapies.

摘要

线粒体基质超氧化物和/或过氧化氢浓度升高会导致广泛的生理反应和病理。线粒体基质中超氧化物和过氧化氢的浓度主要由产生速率、超氧化物歧化酶 2 (SOD2) 和过氧化还原酶 3 (PRDX3) 的活性以及过氧化氢扩散到细胞质中决定。这些考虑可用于生成评估基质超氧化物或过氧化氢的变化是否是驱动氧化还原信号和病理的必要和足够的标准：是受抑制超氧化物和过氧化氢产生影响的表型；通过操纵 SOD2、PRDX3 或线粒体靶向过氧化氢酶的水平；并通过添加靶向线粒体的 SOD/过氧化氢酶模拟物或靶向线粒体的抗氧化剂？病理是否与 SOD2 和 PRDX3 基因的变异有关？使用这些标准过滤关于线粒体氧化还原信号的大量文献，突出了大量证据表明线粒体超氧化物和过氧化氢驱动参与细胞应激管理的生理反应，包括细胞凋亡、自噬、内质网应激的传播、细胞衰老、HIF1α 信号传导和免疫反应。它们还影响细胞增殖、迁移、分化和细胞周期。过滤大量关于病理的文献突出了强有力的实验证据，即 30-40 种病理可能由线粒体基质超氧化物或过氧化氢驱动。这些可以分为重叠和相互作用的类别：代谢、心血管、炎症和神经系统疾病；癌症; 缺血/再灌注损伤；衰老及其疾病；外来的侮辱和遗传病。了解线粒体基质超氧化物和过氧化氢浓度在这些疾病中的作用可以促进适当疗法的合理开发。