SYMPOSIUM Mitochondrial Mechanisms Underlying Tolerance to Fluctuating Oxygen Conditions: Lessons from Hypoxia-Tolerant Organisms Inna M. Sokolova, 1,*,† Eugene P. Sokolov ‡ and Fouzia Haider * *Department of Marine Biology, University of Rostock, Rostock, Germany; † Department of Maritime Systems, Interdisciplinary Faculty, University of Rostock, Rostock, Germany; ‡ Leibniz Institute for Baltic Sea Research, Leibniz ScienceCampus Phosphorus Research Rostock, Warnemu ¨nde, Germany From the symposium “Beyond the powerhouse: integrating mitonuclear evolution, physiology, and theory in comparative biology” presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7, 2019 at Tampa, Florida. 1 E-mail: Inna.Sokolova@uni-rostock.de Synopsis Oxygen (O 2 ) is essential for most metazoan life due to its central role in mitochondrial oxidative phosphor- ylation (OXPHOS), which generates >90% of the cellular adenosine triphosphate. O 2 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 O 2 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), sulphide 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 reactive oxygen species (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 com- plicated 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 phylogenet- ically diverse hypoxia-tolerant species could reveal novel solutions to the ubiquitous and metabolically severe problem of O 2 deficiency and would have important implications for understanding the evolution of hypoxia tolerance and the potential mitigation of pathological states caused by O 2 fluctuations. Oxygen (O 2 ) is essential for metazoan life due to its central role in mitochondrial oxidative phosphoryla- tion (OXPHOS), which generates >90% of the cel- lular adenosine triphosphate (ATP) in aerobic organisms. Most extant metazoans depend on O 2 at least at some stage of their life cycles, and O 2 fluctuations are intrinsically stressful to aerobic organisms. In terrestrial environments, hypoxia (O 2 deficiency) is uncommon and found at high altitudes where low barometric pressure results in the permanently decreased partial pressure of O 2 (P O2 ), and in some underground habitats where organism- mediated O 2 consumption exceeds O 2 influx by air exchange. In contrast, aquatic environments often experience O 2 fluctuations (ranging from >400% to 0% of air saturation) reflecting the dynamics of photosynthesis, respiration, and gas exchange with the atmosphere (Burnett 1997; Richards 2011). In estuaries and deep temperate lakes, benthic habitats might become hypoxic in summer when water Advance Access publication May 31, 2019 ß The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com. Integrative and Comparative Biology Integrative and Comparative Biology, volume 59, number 4, pp. 938–952 doi:10.1093/icb/icz047 Society for Integrative and Comparative Biology Downloaded from https://academic.oup.com/icb/article-abstract/59/4/938/5497799 by guest on 04 July 2020