Chlamydia trachomatis targets mitochondrial dynamics to promote intracellular survival and proliferation

Abstract

Chlamydia trachomatis is an obligate intracellular bacterium that scavenges host metabolic products for its replication. Mitochondria are the power plants of eukaryotic cells and provide most of the cellular ATP via oxidative phosphorylation. Several intracellular pathogens target mitochondria as part of their obligatory cellular reprogramming. This study was designed to analyse the mitochondrial morphological changes in response to C. trachomatis infection in HeLa cells. Mitochondrial elongation and fragmentationwere found at the early stages and late stages of C. trachomatis infection, respectively. C. trachomatis infection-induced mitochondrial elongation was associated with the increase of mitochondrial respiratory activity, ATP production, and intracellular growth of C. trachomatis. Silencing mitochondrial fusion mediator proteins abrogated the C. trachomatis infection-induced elevation in the oxygen consumption rate and attenuated chlamydial proliferation. Mechanistically, C. trachomatis induced the elevation of intracellular cAMP at the early phase of infection, followed by the phosphorylation of fission-inactive serine residue 637 (S637) of Drp1, resulting in mitochondrial elongation. Accordingly, treatment with adenylate cyclase inhibitor diminished mitochondrial elongation and bacterial growth in infected cells. Collectively, these results strongly indicate that C. trachomatis promotes its intracellular growth by targeting mitochondrial dynamics to regulate ATP synthesis via inhibition of the fission mediator Drp1.

Mitochondrial Functions in Infection and Immunity

“…C. trachomatis upregulates a host miRNA (miR-30c-5p), which is key in maintaining the mitochondrial structure and intracellular proliferation of the bacteria [21]. While during the early infection phase, C. trachomatis induces mitochondrial elongation, it does resort to enhancing mitochondrial fragmentation during the late phases of infection [22]. Mitochondrial elongation is associated with enhanced respiratory activity and increased ATP production, which in turn promotes bacterial proliferation, thus making mitochondria a critical focal point in the intracellular life-cycle of C. trachomatis [22] (Figure 1).…”

NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the�AMPK/Drp1/mitochondrial fission pathway

“…Mitochondrial dysfunction is implicated in the pathological progression of OA via a number of pathways, including oxidative stress, cartilage matrix synthesis and degradation disorder, cytokine mediated inflammatory response activation and chondrocyte death (10,11). Recent studies have highlighted an important role of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in mitochondrial homeostasis (12,13). Mechanistically, excessive mitochondrial fission contributes to mitochondrial dysfunction as indicated by loss of mitochondrial DNA integrity, reduction in ATP generation, mitochondrial ROS outburst, and loss of mitochondrial membrane potential (13).…”

Assaying Chlamydia pneumoniae persistence in monocyte-derived macrophages identifies schisandrin lignans as phenotypic switchers

“…As also total cellular ATP levels were elevated in the infected samples (supplementary fig. 1) but no increase in NADPH oxidase activity was observed (data not shown), this may reflect the manipulation of host cell mitochondrial function in a manner similar to a related pathogen C. trachomatis 31 . While NADPH oxidase is considered the major source of ROS in stimulated macrophages in general, previous studies have proposed that mitochondrial ROS production also takes part in macrophage responses to bacterial invaders 32 .…”