On the offense and defense: mitochondrial recovery programs amidst targeted pathogenic assault

Abstract

Bacterial pathogens employ a variety of tactics to persist in their host and promote infection. Pathogens often target host organelles in order to benefit their survival, either through manipulation or subversion of their function. Mitochondria are regularly targeted by bacterial pathogens owing to their diverse cellular roles, including energy production and regulation of programmed cell death. However, disruption of normal mitochondrial function during infection can be detrimental to cell viability because of their essential nature. In response, cells use multiple quality control programs to mitigate mitochondrial dysfunction and promote recovery. In this review, we will provide an overview of mitochondrial recovery programs including mitochondrial dynamics, the mitochondrial unfolded protein response (UPR^mt ), and mitophagy. We will then discuss the various approaches used by bacterial pathogens to target mitochondria, which result in mitochondrial dysfunction. Lastly, we will discuss how cells leverage mitochondrial recovery programs beyond their role in organelle repair, to promote host defense against pathogen infection.

Keywords: UPRmt; defense; infection; mitochondria; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitophagy; pathogen.

Fig. 1.

Mitochondrial recovery pathways. Cells engage multiple pathways to restore mitochondrial function during stress. Mitochondrial fusion involves the merging of distinct mitochondria with the help of protein regulators at the outer and inner membrane, including the GTPases MFN1/2 and OPA1, respectively. Mitochondrial fission involves the division of mitochondria. ER tubules mark the future scission site, and the constrictive forces of DRP1 GTPase mediate the actual division. DRP1 was proposed to function with DNM2 for mitochondrial fission, although this relationship is somewhat controversial. UPR^mt regulation is mediated by the transcription factor ATFS-1 in Caenorhabditis elegans (ATF5 in mammals) that contains a mitochondrial targeting sequence directing its localization to healthy mitochondria for degradation by the protease LONP. Stressed mitochondria display reduced mitochondrial protein import, allowing ATFS-1 to translocate to the nucleus in order to regulate mitochondrial protective gene expression. Various regulators of the UPR^mt have been discovered and are shown in the boxed region. Mitophagy is a specialized form of autophagy that removes damaged mitochondria. Two main players in mitophagy are PINK1 and Parkin. In healthy mitochondria, PINK1 is degraded by the protease PARL. However, mitochondrial import efficiency of PINK1 is reduced in dysfunctional mitochondria, resulting in its presentation at the outer membrane. Here, PINK1 recruits the E3 ubiquitin ligase Parkin that ubiquitinates various substrates ultimately marking the damaged organelle for removal by an autophagic mechanism.

Fig. 2.

Bacterial pathogens and their target: the mitochondrion. Mitochondria are double-membrane organelles. Complex transport systems mediate the import of mitochondrial proteins to specific subcompartments. At the mitochondrial outer membrane, the TOM complex is first to recognize incoming mitochondrial proteins present in the cytosol and transfers these proteins to various compartments depending on their specific signal sequences. The SAM complex mediates the transfer of proteins into the outer membrane. The TIM22 and TIM23 complex regulate the transport of proteins into the mitochondrial inner membrane, while TIM23 mediates the transit of proteins into the matrix interior. The Mia40/Erv1 mediate the transport of proteins into the intermembrane space. The mitochondrial processing peptidase MPP cleaves the amino-terminal signal sequence of nuclear-encoded mitochondrial proteins. Bacterial pathogens target various mitochondrial functions to promote their survival and infectivity. Shown here are extracellular and intracellular pathogens and their respective virulence factors that alter mitochondrial functions. OM, outer membrane; IM, inner membrane; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane.

Fig. 3.

Engagement and subversion of mitochondrial recovery pathways during bacterial pathogen infection. (A) The MAVS pathway responds to viral and bacterial RNA via the RLR RIG-1, which associate with MAVS protein at the mitochondrial outer membrane once activated. The RIG-1/MAVS complex becomes ubiquitinated, leading to the activation of the immune response regulators IFR3 and NF-κB via the kinases TBK1 and IKKε. (B) The UPR^mt is activated by toxins produced by Pseudomonas aeruginosa, involving the translocation of ATFS-1 into the nucleus and the regulation of gene expression related to mitochondrial recovery and pathogen defense. P. aeruginosa also represses the UPR^mt via its metabolic enzyme FadE2 through an unresolved mechanism. In addition, P. aeruginosa manipulates the host transcription factor ZIP-3 to repress UPR^mt activity. (C) The ubiquitin ligase Parkin, involved in the clearance of damaged mitochondria by mitophagy, mediates the removal of intracellular pathogens such as Mycobacterium tuberculosis. Parkin mediates the ubiquitination of M. tuberculosis, which marks it for delivery to the autophagosome and eventual degradation by the lysosome.