Autophagy, TERT, and mitochondrial dysfunction in hyperoxia

Am J Physiol Heart Circ Physiol. 2021 Sep 24. doi: 10.1152/ajpheart.00166.2021. Online ahead of print.ABSTRACTVentilation with gases containing enhanced fractions of oxygen is the cornerstone of therapy for patients with hypoxia and acute respiratory distress syndrome. Yet, hyperoxia treatment increases free reactive oxygen species (ROS)-induced lung injury, which is reported to disrupt autophagy/mitophagy. Altered extranuclear activity of the catalytic subunit of telomerase, TERT, plays a protective role in ROS injury and autophagy in the systemic and coronary endothelium. We investigated interactions between autophagy/mitophagy and TERT that contribute to mitochondrial dysfunction and pulmonary injury in cultured rat lung microvascular endothelial cells (RLMVECs) exposed in vitro, and rat lungs exposed in vivo to hyperoxia for 48 hours. Hyperoxia induced mitochondrial damage in rat lungs (TOMM20, MTT), which was paralleled by increased markers of inflammation (MPO, IL-1β, TLR9), impaired autophagy signaling (Beclin-1, LC3B-II/1, p62), and decreased the expression of TERT. Mitochondrial specific autophagy (mitophagy) was not altered as hyperoxia increased expression of Pink1 but not Parkin. Hyperoxia-induced mitochondrial damage (TOMM20) was more pronounced in rats that lack the catalytic subunit of TERT, and resulted in a reduction in cellular proliferation rather than cell death in RLMVECs. Activation of TERT or autophagy individually offset mitochondrial damage (MTT). Co...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research