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Constitutive ERK MAPK Activity Regulates Macrophage ATP Production and Mitochondrial Integrity¹

Martha M. Monick^2,*, Linda S. Powers^*, Christopher W. Barrett^*, Sara Hinde^*, Alix Ashare^*, Dayna J. Groskreutz^*, Toru Nyunoya^*, Mitchell Coleman, Douglas R. Spitz and Gary W. Hunninghake^*

^* Department of Medicine and Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Veterans Affairs Merit Review grant, National Institutes of Health Grants HL-60316, HL-077431, HL079901-01A1 (to G.W.H.), and CA-086862 (to D.R.S.), and Grant RR00059 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Martha M. Monick, Room 100 Eckstein Medical Research Building, Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail address: martha-monick{at}uiowa.edu

³ Abbreviations used in this paper: ROS, reactive oxygen species; ETC, electron transport chain; mit, mitochondrial membrane potential; CCCP, carbonyl cyanide m-chlorophenylhydrazone; PVDF, polyvinylidene difluoride; PARP, poly(ADP-ribose) polymerase; VDAC, voltage-dependent anion channel; AIF, apoptosis-inducing factor; LDH, lactate dehydrogenase; GSH, reduced glutathione; GSSH, oxidized GSH; NAC, N-acetylcysteine; PDC, pyruvate dehydrogenase complex; EthD-1, ethidium homodimer.