Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils.

Abstract

Mitochondria synthesize several hydrophobic proteins. Like bacteria, mitochondria initiate protein synthesis with an N-formylmethionine residue. Because N-formylmethionyl peptides are chemotactic for polymorphonuclear leukocytes (PMN), mitochondria isolated from cultured human cells and purified bovine mitochondria proteins were tested for PMN chemotactic activity in vitro. Isolated mitochondria, following disruption, stimulated PMN migration in vitro. Nondisrupted mitochondria were not chemotactic. Intact mitochondria that had been incubated with a lysosomal lysate stimulated PMN migration. Antibodies directed against 2 mitochondrial enzymes, cytochrome oxidase and ATPase, which contain mitochondrially synthesized subunits, decreased mitochondrially derived chemotactic activity. Antibodies directed against C3 (complement component 3) did not decrease mitochondrially derived chemotactic activity. Purified bovine mitochondrial N-formylmethionyl proteins stimulated PMN migration in vitro, whereas nonformylated mitochondrial proteins did not. The chemotactic activity of purified mitochondrial proteins and disrupted mitochondria was decreased by the formyl peptide antagonist butyloxycarbonyl-phenylalanine-leucine-phenylalanine-leucine-phenylalanine. Disrupted mitochondrial and purified mitochondrial proteins stimulated PMN-directed migration (chemotaxis), according to accepted criteria. In addition to other chemotactic factors, release of N-formylmethionyl proteins from mitochondria at sites of tissue damage may play a role in the accumulation of inflammatory cells at these sites.