Studies on the mitochondria-derived N-formyl peptide in the regulation of anti-pathogenic responses

Abstract

Multicellular organisms possess several lines of cellular defense system, among which the earliest is an innate immunity. In order to operate this system accurately, cells must recognize a unique pattern of danger and transmit a cognate signal to the nucleus. Mitochondrion, a dynamic double-membrane organelle, plays a central role by behaving as a signaling platform during this process. A maintenance of healthy mitochondria, therefore, is important for eukaryotic cells to get prepared for further pathogenic infections. In this study, I investigated a protective function of mitochondrial protein, methionyl-tRNA formyltransferase (MTFMT) in the regulation of innate immune responses. In this regard, MTFMT seems to function in a maintenance of mitochondrial integrity rather than a mitochondrial translation. A transient deficiency of MTFMT is associated with a disruption of mitochondrial structural- and functional integrity, which eventually results in a reduction of cellular susceptibility against pathogenic infections. What brings such reduction can be explained by two ways. First is an attenuated accumulation of signaling molecule on the disrupted mitochondria. A subset of an evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) protein is located in the mitochondria and participates in an activation of NF-κB signaling pathway. I found mitochondrial accumulation of ECSIT was highly reduced in MTFMT-deficient condition. Such attenuated accumulation of ECSIT could not activate downstream pathways mainly including NF-κB signaling pathway. Second is a release of mitochondrial N-formyl peptide from the disrupted mitochondria. I found an increase of cytosolic concentration of N-formyl peptide in MTFMT-deficient condition. A cytosolic, but mitochondria-derived N-formyl peptide suppressed anti-bacterial responses by directly enhancing bacterial virulence. Additionally, I found that S.flexneri infection could induce a release of mitochondrial N-formyl peptide into the cytoplasm. In this process, ATP-binding cassette sub-family B member 10 (ABCB10) protein might function as a mitochondrial peptide exporter. Taken together, I described an importance of mitochondria in a regulation of innate immune response and suggested a novel function of cytosolic mitochondria-derived N-formyl peptide during bacterial infection.