title: Mitochondrial protein-derived cryptides: Are endogenous N-formylated peptides including mitocryptide-2 components of mitochondrial damage-associated molecular patterns?
abstract: Recently, much attention has been paid to "nonclassical" bioactive peptides, which are fragmented peptides simultaneously produced during maturation and degradation of various functional proteins. We identified many fragmented peptides derived from various mitochondrial proteins including mitocryptide-1 and mitocryptide-2 that efficiently activate neutrophils. These endogenous, functionally active, fragmented peptides are referred to as "cryptides." Among them, mitocryptide-2 is an N-formylated cryptide cleaved from mitochondrial cytochrome b that is encoded in mitochondrial DNA (mtDNA). It is known that 13 proteins encoded in mtDNA are translated in mitochondria as N-formylated forms, suggesting the existence of endogenous N-formylated peptides other than mitocryptide-2. Here, we investigated the effects of N-formylated peptides presumably cleaved from mtDNA-encoded proteins other than cytochrome b on the functions of neutrophilic cells to elucidate possible regulation by endogenous N-formylated cryptides. Four N-formylated cryptides derived from cytochrome c oxidase subunit I and NADH dehydrogenase subunits 4, 5, and 6 among 12 peptides from mtDNA-encoded proteins efficiently induced not only migration but also β-hexosaminidase release, which is an indicator of neutrophilic phagocytosis, in HL-60 cells differentiated into neutrophilic cells. These activities were comparable to or higher than those induced by mitocryptide-2. Although endogenous N-formylated peptides that are contained in mitochondrial damage-associated molecular patterns (DAMPs) have yet to be molecularly identified, they have been implicated in innate immunity. Thus, N-formylated cryptides including mitocryptide-2 are first-line candidates for the contents of mitochondrial DAMPs to promote innate immune responses. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 580-587, 2016.
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Marutani
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Tsutsumi
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Koike
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Harada
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.affiliation: Laboratory of Peptide Science, Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, 526-0829, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Mukai
mesh_terms: D000818:Animals; D045303:Cytochromes b / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D010455:Peptides; D045303:Cytochromes b; D042967:Electron Transport Complex I
keywords: formyl-peptide receptor; formyl-peptide receptor-like 1; mitochondrial DAMPs; mitocryptide; neutrophil-activating peptide