Mitochondrial Mechanisms in Asthma

ABSTRACT One of the most prevalent chronic diseases globally, asthma is characterized by airway inflammation and hyper- reactivity. Alterations in mitochondrial metabolism and bioenergetics are evident in asthma, but the mitochondrial genome (mtDNA) has historically been excluded from genome-wide association studies of asthma due to technical constraints. Mitochondria possess their own circular mtDNA, encoding crucial components of the Electron Transport Chain (ETC), i.e., Complex I (CI), CIII, CIV, and CV. Unlike nuclear DNA, mtDNA is exclusively maternally inherited and exhibits a high mutation rate. This leads to accumulation of single nucleotide variants (SNVs) along maternal lineages, many of which are nonsynonymous in coding regions, resulting in amino acid changes. While these variants historically played a role in adaptation, changes in modern lifestyles and longevity compared to our ancestors have shifted their impact towards altering susceptibility to complex traits and diseases. We hypothesize that homoplasmic SNVs in mtDNA alter bioenergetic capacities and induce epigenetic changes, collectively influencing asthma risk and pathophysiology. Strong supportive data include the identification of specific asthma-risk SNVs in population studies and confirmation of physiological differences among individuals stratified by risk-variant, e.g. CV (A8701G). In mechanistic investigations, trans-mitochondrial cells in which mtDNA are experimentally exchanged, the cells that harbor an asthma-risk variant have epigenetic changes linked to nuclear differential expression of asthma-related genes. Similarly, using a Mitochondrial-Nuclear eXchange (MNX) model with swapped mtDNA and nuclear DNA from two mouse strains, SNVs in CI (T9461C) and CIV (G9348A) are mechanistically linked to changes in lung gene expression, higher pro-inflammatory cytokine levels, and mucus metaplasia. In Aim 1, we explore the role of the mitochondrial genome in asthma. First, we identify associations of mtDNA SNVs with asthma risk and traits [Aim1A]. Subsequently, we investigate whether risk variants influence mitochondrial functions in circulating cells and platelets of asthmatics and healthy controls, and determine underlying mechanisms using trans- mitochondrial cybrids [Aim1B]. In Aim 2, we investigate mitochondrial mechanisms driving asthma using the MNX genetic mouse model. We examine how SNVs regulate expression of nuclear genes and lung physiological traits using MNX and wild-type mice under baseline conditions [Aim2A], and assess the impact of MNX mtDNA variants on lung inflammation, airway reactivity, and mucus metaplasia in an allergen-induced airway inflammation model [Aim2B]. Together, these studies will enhance our understanding of how mtDNA variants affect bioenergetics and epigenetics, and contribute to the origins and progression of asthma.