Meyer Joel N, Leuthner Tess C, Luz Anthony L
Nicholas School of the Environment and Integrated Toxicology and Environmental Health Program, Duke University, Durham, NC 27708-0328, United States.
Toxicology. 2017 Nov 1;391:42-53. doi: 10.1016/j.tox.2017.07.019. Epub 2017 Aug 5.
Mitochondrial dynamics are regulated by two sets of opposed processes: mitochondrial fusion and fission, and mitochondrial biogenesis and degradation (including mitophagy), as well as processes such as intracellular transport. These processes maintain mitochondrial homeostasis, regulate mitochondrial form, volume and function, and are increasingly understood to be critical components of the cellular stress response. Mitochondrial dynamics vary based on developmental stage and age, cell type, environmental factors, and genetic background. Indeed, many mitochondrial homeostasis genes are human disease genes. Emerging evidence indicates that deficiencies in these genes often sensitize to environmental exposures, yet can also be protective under certain circumstances. Inhibition of mitochondrial dynamics also affects elimination of irreparable mitochondrial DNA (mtDNA) damage and transmission of mtDNA mutations. We briefly review the basic biology of mitodynamic processes with a focus on mitochondrial fusion and fission, discuss what is known and unknown regarding how these processes respond to chemical and other stressors, and review the literature on interactions between mitochondrial toxicity and genetic variation in mitochondrial fusion and fission genes. Finally, we suggest areas for future research, including elucidating the full range of mitodynamic responses from low to high-level exposures, and from acute to chronic exposures; detailed examination of the physiological consequences of mitodynamic alterations in different cell types; mechanism-based testing of mitotoxicant interactions with interindividual variability in mitodynamics processes; and incorporating other environmental variables that affect mitochondria, such as diet and exercise.
线粒体融合与分裂、线粒体生物发生与降解（包括线粒体自噬）以及细胞内运输等过程。这些过程维持线粒体稳态，调节线粒体形态、体积和功能，并且越来越被认为是细胞应激反应的关键组成部分。线粒体动力学因发育阶段、年龄、细胞类型、环境因素和遗传背景而异。事实上，许多线粒体稳态基因都是人类疾病基因。新出现的证据表明，这些基因的缺陷往往会使人对环境暴露敏感，但在某些情况下也可能具有保护作用。抑制线粒体动力学也会影响不可修复的线粒体DNA（mtDNA）损伤的消除以及mtDNA突变的传递。我们简要回顾线粒体动力学过程的基础生物学，重点关注线粒体融合与分裂，讨论这些过程如何应对化学和其他应激源的已知和未知情况，并综述线粒体毒性与线粒体融合和分裂基因遗传变异之间相互作用的文献。最后，我们提出未来研究的方向，包括阐明从低水平到高水平暴露、从急性暴露到慢性暴露的线粒体动力学反应的全貌；详细研究不同细胞类型中线粒体动力学改变的生理后果；基于机制测试线粒体毒性物质与线粒体动力学过程个体间变异性的相互作用；以及纳入影响线粒体的其他环境变量，如饮食和运动。
