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Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor

Michael Gabl1, Martina Sundqvist1, Andre Holdfeldt1

  • 1Department of Rheumatology and Inflammation Research, University of Gothenburg, 41390 Gothenburg, Sweden.

Journal of Immunology (Baltimore, Md. : 1950)
|April 1, 2018
PubMed

Insights

Novel mitochondrial cryptic peptides (MCTs) activate neutrophils by binding to formyl peptide receptors (FPRs). This discovery sheds light on innate immune responses to endogenous danger signals.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Phagocytic neutrophils utilize formyl peptide receptors (FPRs) to detect N-formylated methionine (fMet)-containing peptides, a common bacterial motif.
  • Mitochondrial cryptic peptides (MCTs), derived from mitochondrial DNA-encoded proteins, also possess N-terminal fMet, suggesting a potential role in innate immunity.
  • Limited understanding exists regarding how the innate immune system recognizes and responds to these endogenous MCTs.

Purpose of the Study:

  • To investigate the neutrophil recognition profiles and functional outcomes of putative MCTs derived from human mitochondrial DNA-encoded proteins.
  • To determine the specific FPR (FPR1 and FPR2) engagement and activation patterns of these MCTs.
  • To elucidate the signaling pathways and downstream effects triggered by MCT-induced neutrophil activation.

Main Methods:

  • Synthesis and purification of thirteen putative MCTs from human mitochondrial DNA-encoded proteins.
  • Assessment of neutrophil activation using FPR-specific agonists and antagonists.
  • Analysis of FPR1 and FPR2 binding preferences and functional responses (e.g., superoxide generation, β-arrestin recruitment).
  • Evaluation of heterologous receptor desensitization and priming effects.

Main Results:

  • Six out of thirteen MCTs potently activated neutrophils via FPRs.
  • Specific MCTs exhibited distinct preferences for FPR1 (ND3, ND6) or FPR2 (ND4, ND5, cytochrome b).
  • MCT-COX1 acted as a dual FPR1/FPR2 agonist, while others showed weak or no FPR activity.
  • Activating MCTs induced biased signaling, favoring NADPH oxidase activation or β-arrestin recruitment, and modulated other receptor responses.

Conclusions:

  • Identification of novel FPR-activating peptides originating from mitochondrial proteins.
  • Elucidation of the molecular basis for neutrophil activation by specific MCTs.
  • Demonstration of biased signaling properties of MCTs, impacting innate immune responses to endogenous danger signals.

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