Mitochondrial Unfolded Protein Response Under Hypoxic Conditions

Hypoxia is a critical condition affecting the physiological and pathophysiological processes in the cellular environment due to depleted oxygen levels. Under hypoxic conditions, cells undergo a series of changes to adapt to the lack of oxygen that is vital for cellular metabolism in higher organisms. Importantly, hypoxia may induce organelle-specific molecular alterations, including misfolded/unfolded proteins. As a fundamental response to these changes, the unfolded protein response (UPR) is triggered by organelles, including the endoplasmic reticulum (ER) and mitochondria. UPR in mitochondria (UPRmt) is a mitochondrial stress-adaptation pathway that communicates mitochondrial dysfunction to the nucleus to induce response genes such as chaperones and proteases, distinct from UPR in the endoplasmic reticulum (UPRer). Although UPR in the ER under hypoxic conditions has been well documented, the association of UPRmt has not been clearly evaluated. Given the fact that mitochondria are one of the pivotal organelles where oxygen consumption carries utmost importance, understanding the underlying mechanisms is crucial to overcoming hypoxic pathology and maintaining mitochondrial homeostasis. In this study, we reviewed the literature to dissect studies combining UPRmt under hypoxia in various physiological and pathophysiological conditions, including the regulation of tissue barrier homeostasis in diverse organisms, to present a comprehensive perspective. Accumulatively, the studies have revealed the protective effects of UPRmt under hypoxic conditions; yet some of them have reported that the association between hypoxia and UPRmt could be organism-specific. Even so, the number of studies is limited to systematically conclude the involvement of UPRmt in hypoxia. Therefore, further molecular studies are still needed.