Mitochondrial fission is increased in macrophages during mROS production in response to S. pneumoniae

Abstract

Immunometabolism and regulation of mitochondrial reactive oxygen species (mROS) are critical determinants of the immune effector phenotype of differentiated macrophages. Mitochondrial function requires dynamic fission and fusion, but whether effector function is associated with altered dynamics during bacterial responses is unknown. We show that macrophage mitochondria undergo fission after 12 h of progressive ingestion of live Streptococcus pneumoniae (pneumococci). Fission is associated with progressive reduction in oxidative phosphorylation but increased mROS generation. Fission is enhanced by mROS production, PI3K{gamma} signaling and by cathepsin B, but not by inflammasome activation or IL-1{beta} generation. Reduced fission following PI3K{gamma} or cathepsin B inhibition is associated with reduced mROS generation and bacterial killing. Fission is associated with Parkin recruitment to mitochondria, but not mitophagy. Fission occurs upstream of apoptosis induction and independently of caspase activation. During macrophage innate responses to live bacteria mitochondria shift from oxidative phosphorylation and ATP generation to mROS production and microbicidal responses with a progressive shift towards mitochondrial fission.