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Macrophages utilize mitochondrial fission to enhance mROS production during responses to Streptococcus pneumoniae

By Mohammed Mohasin, Katharin Balbirnie-Cumming, Emily Fisk, Elizabeth C Prestwich, Clark D Russell, Jennifer Marshall, Clare Pridans, Scott P Allen, Pamela J. Shaw, Kurt J. De Vos, Christopher J Hill, Per Bullough, Alison M. Condliffe, Tim J Mitchell, Helen M Marriott, David H. Dockrell

Posted 02 Aug 2019
bioRxiv DOI: 10.1101/722603

Immunometabolism and regulation of mitochondrial reactive oxygen species (mROS) control the immune effector phenotype of differentiated macrophages. Mitochondrial function requires dynamic fission and fusion, but whether effector function is coupled to 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), without evidence of Drp-1 phosphorylation at S616. Fission is associated with progressive reduction in oxidative phosphorylation but increased mROS generation. Fission is enhanced by mROS production, PI3Kγ signaling and by cathepsin B, but is independent of inflammasome activation or IL-1β generation. Inhibition of fission reduces 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 bacteria mitochondria shift from oxidative phosphorylation and ATP generation to mROS production for microbicidal responses by undergoing fission.

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