title: Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling.
abstract: Polymorphonuclear neutrophils (PMNs) form the first line of defense against invading microorganisms. We have shown previously that ATP release and autocrine purinergic signaling via P2Y2 receptors are essential for PMN activation. Here we show that mitochondria provide the ATP that initiates PMN activation. Stimulation of formyl peptide receptors increases the mitochondrial membrane potential (Δψm) and triggers a rapid burst of ATP release from PMNs. This burst of ATP release can be blocked by inhibitors of mitochondrial ATP production and requires an initial formyl peptide receptor-induced Ca(2+) signal that triggers mitochondrial activation. The burst of ATP release generated by the mitochondria fuels a first phase of purinergic signaling that boosts Ca(2+) signaling, amplifies mitochondrial ATP production, and initiates functional PMN responses. Cells then switch to glycolytic ATP production, which fuels a second round of purinergic signaling that sustains Ca(2+) signaling via P2X receptor-mediated Ca(2+) influx and maintains functional PMN responses such as oxidative burst, degranulation, and phagocytosis.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Yi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,; Paracelsus Medical University, Salzburg A-5020, Austria, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seier
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,; Paracelsus Medical University, Salzburg A-5020, Austria, and.
authors.forename: Amelie F
authors.initials: AF
authors.lastname: Graf
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Bianca
authors.initials: B
authors.lastname: Brix
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Eritza
authors.initials: E
authors.lastname: Chong
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,; Ludwig Boltzmann Institute for Traumatology, Vienna A-1200, Austria. Electronic address: wjunger@bidmc.harvard.edu.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology / Q000378:metabolism*; D019898:Autocrine Communication / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D015550:Cell Degranulation / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D018375:Neutrophil Activation / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis / Q000502:physiology; D058469:Receptors, Purinergic P2X / Q000276:immunology / Q000378:metabolism*; D016897:Respiratory Burst / Q000502:physiology
chemical_list: D058469:Receptors, Purinergic P2X; D000255:Adenosine Triphosphate
keywords: ATP; Calcium Signaling; Inflammation; Neutrophil; Purinergic Receptor
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