Mitochondrial Dysfunction in Airway Disease

Abstract

There is increasing appreciation that mitochondria serve cellular functions beyond oxygen sensing and energy production. Accordingly, it has become important to explore noncanonical roles of mitochondria in normal and pathophysiological processes that influence airway structure and function in the context of diseases such as asthma and COPD. Mitochondria can sense upstream processes such as inflammation, infection, tobacco smoke, and environmental insults important in these diseases and in turn can respond to such stimuli through altered mitochondrial protein expression, structure, and resultant dysfunction. Conversely, mitochondrial dysfunction has downstream influences on cytosolic and mitochondrial calcium regulation, airway contractility, gene and protein housekeeping, responses to oxidative stress, proliferation, apoptosis, fibrosis, and certainly metabolism, which are all key aspects of airway disease pathophysiology. Indeed, mitochondrial dysfunction is thought to play a role even in normal processes such as aging and senescence and in conditions such as obesity, which impact airway diseases. Thus, understanding how mitochondrial structure and function play central roles in airway disease may be critical for the development of novel therapeutic avenues targeting dysfunctional mitochondria. In this case, it is likely that mitochondria of airway epithelium, smooth muscle, and fibroblasts play differential roles, consistent with their contributions to disease biology, underlining the challenge of targeting a ubiquitous cellular element of existential importance. This translational review summarizes the current state of understanding of mitochondrial processes that play a role in airway disease pathophysiology and identifying areas of unmet research need and opportunities for novel therapeutic strategies.

Keywords: COPD; asthma; metabolism; oxidative stress; remodeling.

Figure 1

Mitochondrial structure and energetic function. Mitochondria have a cytoplasm-facing outer membrane and a highly folded inner membrane that contains the enzymes of the ETC and oxidative phosphorylation, as well as mtDNA. ROS are a normal byproduct of mitochondrial respiration. Insults such as cigarette smoke and inflammation in the context of diseases such as COPD and asthma differentially influence elements of mitochondrial respiration, overall increasing ROS production, which has downstream consequences on inflammation itself, mtDNA integrity, cytosolic Ca²⁺ ([Ca²⁺]_cyt) regulation, cell proliferation, and apoptosis (especially when severe stress induces the PTP), and in a feedback fashion, mitochondrial structure and function. β-Oxid = β-oxidation; CytC = cytochrome C; ETC = electron transport chain; IV = complex IV of the ETC; mtDNA = mitochondrial DNA; PTP = permeability transition pore; ROS = reactive oxygen species.

Figure 2

Mitochondrial fission and fusion. Under conditions of cellular stability, mtDNA form extensive contiguous networks facilitated by the mitofusin proteins and Opa1 that promote fusion of mitochondrial membranes. Conditions of cellular stress promote mitochondrial fragmentation/fission orchestrated by multiple proteins including Drp1 and Fis1. Insults such as cigarette smoke and inflammation usually promote mitochondrial fission. CS = cigarette smoke; Drp1 = dynamin-related protein 1; ER = endoplasmic reticulum; Fis1 = fission 1; Mfn1/2 = mitofusin 1 and 2. See Figure 1 legend for expansion of other abbreviations.

Figure 3

Mitochondrial motility and organelle interactions. Mitochondrial movement occurs along cytoskeletal proteins, facilitated by elements such as Miro, Milton, and Mfn. Mitochondrial proximity to the ER or the PM can help with buffering of Ca²⁺ fluxes and thus regulation of [Ca²⁺]_cyt. Impairment of mitochondrial motility due to cigarette smoke or in asthma can lead to [Ca²⁺]_cyt dysregulation and other downstream consequences. PM = plasma membrane. See Figure 2 legend for expansion of other abbreviations.

Figure 4

Mitophagy and mitochondrial damage-associated molecular patterns (DAMPs). Insults such as cigarette smoke and inflammation promote mitochondrial destruction through autophagy mechanisms involving lysosomes. Mitochondrial dysfunction can also result from release of DAMPs such as mtDNA fragments and ATP that have autocrine/paracrine effects including activating the inflammasome, with downstream consequences on inflammation itself, cell proliferation, and apoptosis. ATP = adenosine triphosphate; TLR = toll-like receptor. See Figure 1 legend for expansion of other abbreviations.

Figure 5

Mitochondrial dysfunction resulting from cigarette smoke and inflammation effects on various aspects of mitochondrial structure, localization, metabolism, and other mitochondrial functions contributes to asthma and COPD. Novel therapeutic approaches for airway diseases should consider mitochondria-targeted antioxidants and methods to modulate mitochondrial fission/fusion, motility, mitophagy, and other processes. See Figure 1 legend for expansion of abbreviations.