Host and microbial regulation of mitochondrial reactive oxygen species during mycobacterial infections

Mycobacteria, including Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTM), pose challenges in treatment due to their increased resistance to antibiotics. Following infection, mycobacteria and their components trigger robust innate and inflammatory immune responses intricately associated with the modulation of mitochondrial functions, including oxidative phosphorylation (OXPHOS) and metabolism. Certainly, mitochondrial reactive oxygen species (mtROS) are an inevitable by-product of OXPHOS and function as a bactericidal weapon; however, an excessive accumulation of mtROS are linked to pathological inflammation and necroptotic cell death during mycobacterial infection. Despite previous studies outlining various host pathways involved in regulating mtROS levels during antimicrobial responses in mycobacterial infection, our understanding of the precise mechanisms orchestrating the fine regulation of this response remains limited. Emerging evidence suggests that mycobacterial proteins play a role in targeting the mitochondria of the host, indicating the potential influence of microbial factors on mitochondrial functions within host cells. In this review, we provide an overview of how both host and Mtb factors influence mtROS generation during infection. A comprehensive study of host and microbial factors that target mtROS will shed light on innovative approaches for effectively managing drug-resistant mycobacterial infections.