Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity

Martha M Monick; Linda S Powers; Christopher W Barrett; Sara Hinde; Alix Ashare; Dayna J Groskreutz; Toru Nyunoya; Mitchell Coleman; Douglas R Spitz; Gary W Hunninghake

doi:10.4049/jimmunol.180.11.7485

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Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity

Journal article

Peer reviewed

Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity

Martha M Monick, Linda S Powers, Christopher W Barrett, Sara Hinde, Alix Ashare, Dayna J Groskreutz, Toru Nyunoya, Mitchell Coleman, Douglas R Spitz and Gary W Hunninghake

The Journal of immunology (1950), Vol.180(11), pp.7485-7496

06/01/2008

DOI: 10.4049/jimmunol.180.11.7485

PMCID: PMC2410094

PMID: 18490749

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Abstract

A unique feature of human alveolar macrophages is their prolonged survival in the face of a stressful environment. We have shown previously that the ERK MAPK is constitutively active in these cells and is important in prolonging cell survival. This study examines the role of the ERK pathway in maintaining mitochondrial energy production. The data demonstrate that ATP levels in alveolar macrophages depend on intact mitochondria and optimal functioning of the electron transport chain. Significant levels of MEK and ERK localize to the mitochondria and inhibition of ERK activity induces an early and profound depletion in cellular ATP coincident with a loss of mitochondrial transmembrane potential. The effect of ERK suppression on ATP levels was specific, since it did not occur with PI3K/Akt, p38, or JNK suppression. ERK inhibition led to cytosolic release of mitochondrial proteins and caspase activation. Both ERK inhibition and mitochondrial blockers induced loss of plasma membrane permeability and cell death. The cell death induced by ERK inhibition had hallmarks of both apoptotic (caspase activation) and necrotic (ATP loss) cell death. By blocking ERK inhibition-induced reactive oxygen species, caspase activation was prevented, although necrotic pathways continued to induce cell death. This suggests that mitochondrial dysfunction caused by ERK inhibition generates both apoptotic and necrotic cell death-inducing pathways. As a composite, these data demonstrate a novel mitochondrial role for ERK in maintaining mitochondrial membrane potential and ATP production in human alveolar macrophages.

Microscopy, Electron, Transmission

Reactive Oxygen Species - metabolism

Humans

Cells, Cultured

Adenosine Triphosphatases - metabolism

Mitochondria - immunology

Mitochondria - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Adenosine Triphosphatases - immunology

Macrophages, Alveolar - ultrastructure

Macrophages, Alveolar - metabolism

Macrophages, Alveolar - immunology

Phagocytosis

Details

Title: Subtitle: Constitutive ERK MAPK activity regulates macrophage ATP production and mitochondrial integrity
Creators: Martha M Monick - Department of Medicine, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242, USA. martha-monick@uiowa.edu
Linda S Powers
Christopher W Barrett
Sara Hinde
Alix Ashare
Dayna J Groskreutz
Toru Nyunoya
Mitchell Coleman
Douglas R Spitz
Gary W Hunninghake
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.180(11), pp.7485-7496
DOI: 10.4049/jimmunol.180.11.7485
PMID: 18490749
PMCID: PMC2410094
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: K08 HL089392 / NHLBI NIH HHS R01 HL077431 / NHLBI NIH HHS R01 HL077431-04 / NHLBI NIH HHS RR00059 / NCRR NIH HHS R01 HL079901 / NHLBI NIH HHS R01 HL073967-04 / NHLBI NIH HHS HL-077431 / NHLBI NIH HHS P30 CA086862 / NCI NIH HHS R01 HL073967 / NHLBI NIH HHS HL079901-01A1 / NHLBI NIH HHS M01 RR000059 / NCRR NIH HHS CA-086862 / NCI NIH HHS HL-60316 / NHLBI NIH HHS UL1 RR024979 / NCRR NIH HHS
Language: English
Date published: 06/01/2008
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Pathology; Orthopedics and Rehabilitation; Radiation Oncology; Internal Medicine
Record Identifier: 9984040529002771

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