Abstract
Effective growth and replication of obligate intracellular pathogens depend on host cell metabolism. How this is connected to host cell mitochondrial function has not been studied so far. Recent studies suggest that growth of intracellular bacteria such as Chlamydia pneumoniae is enhanced in a low oxygen environment, arguing for a particular mechanistic role of the mitochondrial respiration in controlling intracellular progeny. Metabolic changes in C. pneumoniae infected epithelial cells were analyzed under normoxic (O2 ≈ 20%) and hypoxic conditions (O2 < 3%). We observed that infection of epithelial cells with C. pneumoniae under normoxia impaired mitochondrial function characterized by an enhanced mitochondrial membrane potential and ROS generation. Knockdown and mutation of the host cell ATP synthase resulted in an increased chlamydial replication already under normoxic conditions. As expected, mitochondrial hyperpolarization was observed in non-infected control cells cultured under hypoxic conditions, which was beneficial for C. pneumoniae growth. Taken together, functional and genetically encoded mitochondrial dysfunction strongly promotes intracellular growth of C. pneumoniae.
Highlights
Mitochondria play a major role in the generation of energy and regulate cell death, production of reactive oxygen species (ROS), and sensing of glucose and oxygen (Heikal, 2010)
C. pneumoniae infection resulted in a significantly decreased maximal respiration compared to non-infected control cells at 24 and 48 hpi (Figures 1A–C), which is characteristic for mitochondrial dysfunction
Abnormalities in the function of mitochondria are defining a mitochondrial dysfunction, such as impairment of the respiratory chain or mitochondrial hyperpolarization leading to increased mitochondrial membrane potential, preventing apoptosis (Michelakis, 2008; Brand and Nicholls, 2011)
Summary
Mitochondria play a major role in the generation of energy and regulate cell death, production of reactive oxygen species (ROS), and sensing of glucose and oxygen (Heikal, 2010). Thereby, cells need to metabolically adapt to hypoxia by switching the metabolism from oxidative phosphorylation (OXPHOS) to anaerobic glycolysis to maintain ATP supply. Mitochondrial dysfunction can be defined as abnormality in generation of ATP by Mitochondrial Dysfunction Supports C. pneumoniae Growth. OXPHOS, ROS production, regulation of apoptosis, regulation of cytoplasmic and mitochondrial matrix calcium, synthesis and catabolism of metabolites as well as mitochondrial trafficking (Brand and Nicholls, 2011). Impairment of the respiratory chain leads to an increased glycolysis, supporting tumor cell growth, and proliferation (Warburg, 1956). Activation of macrophages and dendritic cells by pro-inflammatory stimuli causes a metabolic switch away from OXPHOS toward glycolysis (Kelly and O’Neill, 2015)
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