Mitochondrial mechanisms underlying tolerance to fluctuating oxygen conditions: Lessons from hypoxia-tolerant organisms.

Oxygen (O2) is essential for most metazoan life due to its central role in in mitochondrial oxidative phosphorylation (OXPHOS), which generates >90% of the cellular ATP. Oxygen fluctuations are an ultimate mitochondrial stressor resulting in mitochondrial damage, energy deficiency and cell death. This work provides an overview of the known and putative mechanisms involved in mitochondrial tolerance to fluctuating oxygen conditions in hypoxia-tolerant organisms including aquatic and terrestrial vertebrates and invertebrates. Mechanisms of regulation of the mitochondrial OXPHOS and electron transport system (ETS) (including alternative oxidases), sulfide tolerance, regulation of redox status and mitochondrial quality control, and the potential role of hypoxia-inducible factor (HIF) in mitochondrial tolerance to hypoxia are discussed. Mitochondrial phenotypes of distantly related animal species reveal common features including conservation and/or anticipatory upregulation of ETS capacity, suppression of ROS-producing electron flux through ubiquinone, reversible suppression of OXPHOS activity, and investment into the mitochondrial quality control mechanisms. Despite the putative importance of oxidative stress in adaptations to hypoxia, establishing the link between hypoxia tolerance and mitochondrial redox mechanisms is complicated by the difficulties of establishing the species-specific concentration thresholds above which the damaging effects of ROS outweigh their potentially adaptive signaling function. The key gaps in our knowledge about the potential mechanisms of mitochondrial tolerance to hypoxia include regulation of mitochondrial biogenesis and fusion/fission dynamics, and HIF-dependent metabolic regulation that require further investigation in hypoxia-tolerant species. Future physiological, molecular and genetic studies of mitochondrial responses to hypoxia and reoxygenation in phylogenetically diverse hypoxia-tolerant species could reveal novel solutions to the ubiquitous and metabolically severe problem of O2 deficiency and would have important implications for understanding the evolution of hypoxia tolerance and the potential mitigation of pathological states caused by O2 fluctuations.