Mitochondria are semi-autonomous organelles and according to the endosymbiotic theory it is of bacterial origin (purple photosynthetic bacteria) and a symbiotic relationship developed between the host cell and the mitochondria (Roger et al., 2017). So, it is obvious that with time both the members of the symbiotic relation have developed an evolutionary dependent pattern to survive in challenging conditions. It is known for long that mitochondria are the power house of the cell as it produces ATP via oxidative phosphorylation. Recent studies showed the role of mitochondria in production of cytokines, reactive oxygen species (ROS) (Murphy, 2009), maintaining of calcium homeostasis for cell signaling, programmed cell death and apoptosis. In addition, mitochondrial dynamics plays a very critical role for the development of immune response against infectious pathogens by various mechanisms like production of anti-bacterial effector proteins and metabolic pathways. Some of these includes production of reactive oxygen species (ROS) (Lahiri et al., 2017), cytokines, iNOS, modulation in mitochondrial fission or fusion or mitophagy, apoptosis, release of mitochondrial DNA (mtDNA) which further activates cyclic GMP–AMP synthase (cGAS) receptor (Ishikawa et al., 2009) and NLRP3 inflammasome. On binding of bacterial ligand (like LPS), TLR signaling activates the downstream molecule NF-kB which leads to the assembly of NLRP3-inflammasome (Zhou et al., 2011) [including NLRP3, apoptosis associated speck-like protein (ASC) and procaspase-1]. This leads to caspase-1 activation and subsequent maturation of the inflammatory cytokines pro-IL-1β and pro-IL-18 to IL-1β and IL-18 respectively and finally results in the removal of the bacterial pathogens (Meyer et al., 2018). It has been found that mitochondria can regulate immunity in different ways mainly by altering the metabolic pathways or by changing its shape or structure. Mitochondria being double-membrane organelle, its outer membrane contain signaling proteins important for anti-viral signaling, anti-apoptotic proteins, mitochondrial fusion proteins (Mitofusin 1 and 2—MFN1 and MFN-2) (Liesa et al., 2009). Study shows that bacteria like Helicobacter, Shigella, Vibrio, Pseudomonas and Legionella produces virulence factors that are involved in mitochondrial fission (fragmentation) whereas bacteria like Chlamydia produces effector proteins that promotes mitochondrial fusion (Tiku et al., 2020).

Under physiologic condition, glucose is converted to pyruvate by glycolysis in the cytosol and then pyruvate is transported to the mitochondria where it enters tricarboxylic acid (TCA) cycle and then to oxidative phosphorylation for the production of energy in the form of ATP, NADH2 and FADH (Fig. 1). During hypoxia, mitochondrial functions are reduced and ATP is produced via Glycolysis. This metabolic alteration observed in the cancer cells is known as Warburg effect (Vander Heiden et al., 2009). Bacterial infection and pathogen associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) induce ‘pseudo hypoxia’ and Warburg effect kind of situation in the infected cells. Bacterial PAMPs like LPS, Lipoteichoic acid (LTA) stimulation also produced mitochondrial ROS (mitoROS) from immune cells which can directly kill pathogens (Angajala et al., 2018). MitoROS is even important in deciding the cytokine profile of an infected macrophage and decides the autophagy potential of the cell. Mitochondria further serve as a docking platform for NLRP3 inflammasome activation which is crucial in the production of IL1b and pyroptotic cell death after infection. Bacteria like Staphylococcus, Salmonella produce virulence factors that are involved in the NLRP3 inflammasome activation which finally release the pro-inflammatory cytokines like IL-1β, IL-18 and leads to either dissemination of the bacteria or killing of the infected cells. Mitochondria additionally forms connection with other organelle and these inter-organellar connections serve as site for NLRP3 inflammasome activation (Kim et al., 2016). During bacterial infection, even these contact sites might be altered which in turn can dictate the inflammatory potential of the cell.

Thus, mitochondria mediated ROS and cytokine signaling can decide the fate of any infection. Importantly, human polymorphisms altering the ROS or inflammasome activation leads to aberrant infection. Further, mitochondrial TCA cycle intermediates are released in the cytosol during PAMP stimulation and/or bacterial infection (Liu et al., 2021). This TCA cycle break leads to accumulation of metabolites like citrate, succinate and itaconate which can kill the pathogen directly or indirectly by changing the immuno-inflammatory status of the infected cells. TCA cycle intermediates which are released in the cytosol can lead to production of inflammatory cytokines like IL6 and IL-1β which will decide the fate of any infection (O'Neill, 2015). The detailed study of the interaction between the host mitochondria and pathogens during bacterial infection can open new pathways to defeat various multi-drug resistant bacteria which target the mitochondria for their pathogenicity.

In this review, we will discuss in detail how mitochondrial immune-metabolism and dynamics (fusion, fission and mitophagy) are altered during bacterial infection in order to cope up with the insult. Then, we will describe how mitochondria help the cell to fight against pathogen attack. Some examples of mitochondria-mediated immune response elicited against specific bacteria will be elaborated. Finally, we will also touch base on the bacterial strategies to counteract the mitochondria mediated immunity during infection to facilitate their own survival within the host cell. We will initiate the chapter with a detailed description of mitochondria associated immune responses (Fig. 2).