Mitochondria: Powering the Innate Immune Response to Mycobacterium tuberculosis Infection

Abstract

Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for cross talk or synergy between bacterium- and mitochondrion-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking, and intriguing, in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages, leading to metabolic changes and triggering potent innate immune responses. Research from our laboratories and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyperactivating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrion-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

Keywords: LRRK2; Mycobacterium tuberculosis; cytosolic DNA sensing; innate immunity; macrophage; mtDNA; type I interferon.

FIG 1

Both mtDNA and Mtb DNA engage cytosolic DNA surveillance pathways to activate type I interferon expression. Mtb infection can stimulate type I IFN expression by activating both cGAS, via Mtb dsDNA, and STING, via secretion of cyclic-di-AMP. To date, mtDNA has been shown to engage cGAS and TLR9. While TLR9 has been shown to play a role in determining Mtb infection outcomes in vivo, it remains unclear whether the endosomal receptor actually directly binds to Mtb-derived dsDNA during Mtb infection of macrophages (represented by the question mark). The figure was created with BioRender.

FIG 2

Cross talk between Mycobacterium tuberculosis and mitochondria can influence cytosolic sensing pathways. Schematic representation of molecular interplay between Mtb and mitochondria in infected cells. Yellow question marks indicate several phenomena whose mechanisms/consequences are unclear, namely, whether PDIM (phthiocerol dimycocerosates) and/or ESAT-6 (6-kDa early secretory antigenic target 6) directly alter the mitochondrial membrane, what secretion systems introduce mitochondrion-modulating Mtb effectors into host cells, how Mtb infection generally affects mitochondrial metabolism, and whether mtDNA engages with cGAS (cyclic GMP-AMP synthase) and AIM2 (absent in melanoma) simultaneously (and, if so, what the outcomes for an Mtb-infected cell are). Secreted Mtb virulence factors that have been shown to alter mitochondrial homeostasis are colored in shades of purple. The figure was created with BioRender.

FIG 3

Mutations in functionally diverse mitochondrial proteins confer susceptibility to mycobacterial disease. Shown is a representation of proteins associated with leprosy/tuberculosis susceptibility via either GWAS or direct experimental investigation. From left to right, proteins are Presenilins-associated rhomboid-like protein (PARL), Parkinson’s disease 2 (PARK2), PTEN-induced kinase 1 (PINK1), leucine-rich repeat kinase 2 (LRRK2), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), fatty acid metabolism-immunity nexus (FAMIN), mitochondrial transcription factor A (TFAM), and mitochondrial DNA polymerase gamma (POLG). The figure was created with BioRender.