Alternative Oxidase Attenuates Cigarette Smoke–induced Lung Dysfunction and Tissue Damage

Abstract

Cigarette smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide. We aimed to elucidate whether mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology. In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow using alternative oxidase (AOX), which bypasses the cytochrome segment of the respiratory chain. AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS for 9 months. It preserved the cell viability of isolated mouse embryonic fibroblasts treated with CS condensate, limited the induction of apoptosis, and decreased the production of reactive oxygen species (ROS). In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e., infiltration by macrophages and neutrophils and adverse signaling, was unaffected. The use of AOX allowed us to obtain novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production, and lung remodeling. Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung. We propose AOX as a novel tool to study CS-related lung remodeling and potentially to counteract CS-induced ROS production and cell damage.

Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

“…In fruit flies, AOX complemented ETC defects in vivo and restored viability . Global expression in the mouse protected against cyanide toxicity decreased lethality from endotoxemia and alleviated cigarette smoke‐induced lung remodelling and cell death . AOX was demonstrated to effectively decrease RET‐induced ROS driven by succinate.…”

“…31 Global expression in the mouse protected against cyanide toxicity 32,33 decreased lethality from endotoxemia 34 and alleviated cigarette smoke-induced lung remodelling and cell death. 35 AOX was demonstrated to effectively decrease RET-induced ROS 36,37 driven by succinate. Most importantly, however, expression of AOX prevented the development of a lethal cardiomyopathy in a cIII mouse mutant strain 38 indicating sufficient expression for full respiratory restoration in the stressed heart.…”

Phenotypic effects of dietary stress in combination with a respiratory chain bypass in mice

“…Similarly, two different lines of mice ubiquitously expressing AOX (El‐Khoury et al ; Szibor et al ) showed no significant deviations from controls, even when over 350 physiological, behavioral and metabolic parameters were measured. Nevertheless, AOX was able to confer protection against various kinds of physiological stress, ranging from exposure to respiratory poisons such as cyanide or antimycin A (Fernandez‐Ayala et al ; El‐Khoury et al ; Szibor et al ), genetically engineered OXPHOS deficiency (Kemppainen et al 2014; Rajendran et al ) pathological models related to oxidative, proteotoxic, nutritional, and proinflammatory stress (Fernandez‐Ayala et al ; Humphrey et al ; El‐Khoury et al ; Mills et al ; Giordano et al ), or disturbed nuclear‐receptor and Jun‐kinase signaling (Andjelković et al, ; Andjelković et al, ).…”

Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing

“…Despite its enzymatic function, AOX expression alone does not disturb normal mouse physiology (10,13). However, it is able to correct pathological states associated with respiratory inhibition, notably those affecting cIII and/or cIV (10,(13)(14)(15)(16). This makes AOX a valuable tool to study the involvement of mitochondria and their hierarchy in physiological and pathophysiological processes affecting health and disease (17)(18)(19).…”