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 onlung 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 earlyphase 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 pathogenicmechanism 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
