Protein Phosphorylation and Prevention of Cytochrome Oxidase Inhibition by ATP: Coupled Mechanisms of Energy Metabolism Regulation
Open accessAbstract
Rapid regulation of oxidative phosphorylation is crucial for mitochondrial adaptation to swift changes in fuels availability and energy demands. An intramitochondrial signaling pathway regulates cytochrome oxidase (COX), the terminal enzyme of the respiratory chain, through reversible phosphorylation. We find that PKA-mediated phosphorylation of a COX subunit dictates mammalian mitochondrial energy fluxes and identify the specific residue (S58) of COX subunit IV-1 (COXIV-1) that is involved in this mechanism of metabolic regulation. Using protein mutagenesis, molecular dynamics simulations, and induced fit docking, we show that mitochondrial energy metabolism regulation by phosphorylation of COXIV-1 is coupled with prevention of COX allosteric inhibition by ATP. This regulatory mechanism is essential for efficient oxidative metabolism and cell survival. We propose that S58 COXIV-1 phosphorylation has evolved as a metabolic switch that allows mammalian mitochondria to rapidly toggle between energy utilization and energy storage.
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Mitochondrial dysfunction leads to tau phosphorylation and Aβ production.
“Increased stress signaling may also dysregulate mitochondrial function, which also leads to tau phosphorylation149 and Aβ production150 (Fig. 5, orange).”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [149]
The Abstract and Discussion (pages not provided) describe phosphorylation of a cytochrome oxidase subunit and regulation of mitochondrial energy metabolism, not tau phosphorylation or Aβ production. Searches for tau phosphorylation and amyloid-beta production found no passage linking either to mitochondrial dysfunction in our copy. (LLM, conf=0.76)
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Villani, G., Greco, M., Papa, S., & Attardi, G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.48.31829 · Cited by 225 · see citing works
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Research works printed but not linked: 39
- Acin-Perez R Salazar E Brosel S Yang H Schon EA Manfredi G Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects EMBO Mol Med 2009a 1 392 406 20049744 PMC2814779
- Acin-Perez R Salazar E Kamenetsky M Buck J Levin LR Manfredi G Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation Cell Metab 2009b 9 265 276 19254571 PMC2684673
- Arnold S Kadenbach B Cell respiration is controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase Eur J Biochem 1997 249 350 354 9363790
- Balaban RS The mitochondrial proteome: a dynamic functional program in tissues and disease states Environ Mol Mutagen 2010 51 352 359 20544878 PMC3209511
- Bender E Kadenbach B The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation FEBS Lett 2000 466 130 134 10648827
- Birch-Machin MA Turnbull DM Assaying mitochondrial respiratory complex activity in mitochondria isolated from human cells and tissues Methods Cell Biol 2001 65 97 117 11381612
- Bonne G Seibel P Possekel S Marsac C Kadenbach B Expression of human cytochrome c oxidase subunits during fetal development Eur J Biochem 1993 217 1099 1107 8223633
- Bowers KJ Chow E Xu H Dror RO Eastwood MP Gregerson BA Klepeis JL Kolossvary I Moraes MA Sacerdoti FD Salmon JK Shan Y Shaw DEN- ScalableAlgorithmsforMolecularDynamicsSimulationsonCommodity Clusters 2006 43 ACM/IEEE Conference on Supercomputing(SC06) Tampa, Florida IEEE Computer Society 2006
- Cho AE Guallar V Berne BJ Friesner R Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach J Comput Chem 2005 26 915 931 15841474 PMC3920598
- D’Aurelio M Pallotti F Barrientos A Gajewski CD Kwong JQ Bruno C Beal MF Manfredi G In vivo regulation of oxidative phosphorylation in cells harboring a stop-codon mutation in mitochondrial DNA-encoded cytochrome c oxidase subunit I J Biol Chem 2001 276 46925 46932 11595737
- Dalmonte ME Forte E Genova ML Giuffre A Sarti P Lenaz G Control of respiration by cytochrome c oxidase in intact cells: role of the membrane potential J Biol Chem 2009 284 32331 32335 19776013 PMC2781647
- Deng N Zhang J Zong C Wang Y Lu H Yang P Wang W Young GW Korge P Lotz C Doran P Liem DA Apweiler R Weiss JN Duan H Ping P Phosphoproteome analysis reveals regulatory sites in major pathways of cardiac mitochondria Mol Cell Proteomics 2010 PMC3033665 20495213
- Dey R Barrientos A Moraes CT Functional constraints of nuclear-mitochondrial DNA interactions in xenomitochondrial rodent cell lines J Biol Chem 2000 275 31520 31527 10908562
- Evans DJ Holian BL The Nose--Hoover thermostat The Journal of Chemical Physics 1985 83 4069 4074
- Fukuda R Zhang H Kim JW Shimoda L Dang CV Semenza GL HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells Cell 2007 129 111 122 17418790
- Helling S Vogt S Rhiel A Ramzan R Wen L Marcus K Kadenbach B Phosphorylation and kinetics of mammalian cytochrome c oxidase Mol Cell Proteomics 2008 PMC2556016 18541608
- Hofhaus G Shakeley RM Attardi G Use of polarography to detect respiration defects in cell cultures Methods Enzymol 1996 264 476 483 8965720
- Hopper RK Carroll S Aponte AM Johnson DT French S Shen RF Witzmann FA Harris RA Balaban RS Mitochondrial matrix phosphoproteome: effect of extra mitochondrial calcium Biochemistry 2006 45 2524 2536 16489745 PMC1415274
- Horvat S Beyer C Arnold S Effect of hypoxia on the transcription pattern of subunit isoforms and the kinetics of cytochrome c oxidase in cortical astrocytes and cerebellar neurons J Neurochem 2006 99 937 951 16981895
- Huttemann M Kadenbach B Grossman LI Mammalian subunit IV isoforms of cytochrome c oxidase Gene 2001 267 111 123 11311561
- Huttemann M Lee I Liu J Grossman LI Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element FEBS J 2007 274 5737 5748 17937768
- Jorgensen WL Maxwell DS Tirado-Rives J Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids Journal of the American Chemical Society 1996 118 11225 11236
- Kadenbach B Intrinsic and extrinsic uncoupling of oxidative phosphorylation Biochim Biophys Acta 2003 1604 77 94 12765765
- Lee I Salomon AR Ficarro S Mathes I Lottspeich F Grossman LI Huttemann M cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity J Biol Chem 2005 280 6094 6100 15557277
- Li Y Park JS Deng JH Bai Y Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complex J Bioenerg Biomembr 2006 38 283 291 17091399 PMC1885940
- Lomax MI Grossman LI Tissue-specific genes for respiratory proteins Trends Biochem Sci 1989 14 501 503 2560276
- Martyna GJ Tobias DJ Klein ML Constant pressure molecular dynamics algorithms The Journal of Chemical Physics 1994 101 4177 4189
- Metoki K Hommes FA The pH of mitochondria of fibroblasts from a hyperornithinaemia, hyperammonaemia, homocitrullinuria-syndrome patient J Inherit Metab Dis 1984 7 9 11 6429444
- Miyazaki T Neff L Tanaka S Horne WC Baron R Regulation of cytochrome c oxidase activity by c-Src in osteoclasts J Cell Biol 2003 160 709 718 12615910 PMC2173369
- Napiwotzki J Kadenbach B Extramitochondrial ATP/ADP-ratios regulate cytochrome c oxidase activity via binding to the cytosolic domain of subunit IV Biol Chem 1998 379 335 339 9563830
- Napiwotzki J Shinzawa-Itoh K Yoshikawa S Kadenbach B ATP and ADP bind to cytochrome c oxidase and regulate its activity Biol Chem 1997 378 1013 1021 9348111
- Pagliarini DJ Dixon JE Mitochondrial modulation: reversible phosphorylation takes center stage? Trends Biochem Sci 2006 31 26 34 16337125
- Papa S De Rasmo D Scacco S Signorile A Technikova-Dobrova Z Palmisano G Sardanelli AM Papa F Panelli D Scaringi R Santeramo A Mammalian complex I: a regulable and vulnerable pacemaker in mitochondrial respiratory function Biochim Biophys Acta 2008 1777 719 728 18455500
- Samavati L Lee I Mathes I Lottspeich F Huttemann M TNFalpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase J Biol Chem 2008 PMC3258931 18534980
- Schagger H von Jagow G Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form Anal Biochem 1991 199 223 231 1812789
- Sherman W Day T Jacobson MP Friesner RA Farid R Novel procedure for modeling ligand/receptor induced fit effects J Med Chem 2006 49 534 553 16420040
- Shirts MR Bair E Hooker G Pande VS Equilibrium Free Energies from Nonequilibrium Measurements Using Maximum-Likelihood Methods Physical Review Letters 2003 91 140601 14611511
- Steenaart NA Shore GC Mitochondrial cytochrome c oxidase subunit IV is phosphorylated by an endogenous kinase FEBS Lett 1997 415 294 298 9357986
- Thomson M Evidence of undiscovered cell regulatory mechanisms: phosphoproteins and protein kinases in mitochondria Cell Mol Life Sci 2002 59 213 219 11915939 PMC11146121
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- Authors
- Acin-Perez, R., Gatti, D. L., Bai, Y., & Manfredi, G.
- Affiliations
- Wayne State University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Cornell University (US)
- Corresponding author
- Manfredi, Giovanni
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 13
- Issue
- 6
- Pages
- 712-719
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3118639
- OpenAlex
- W2010061651
- Cited by
- 190
- References
- 1
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 11 · 2023: 5 · 2022: 9 · 2021: 12 · 2020: 16 · 2019: 11 · 2018: 13 · 2017: 14 · 2016: 18 · 2015: 13 · 2014: 18 · 2013: 15 · 2012: 18
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 777 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (GM69840, R01 GM088999)
- Muscular Dystrophy Association
- United Mitochondrial Disease Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- cytochrome c oxidase, protein phosphorylation, protein kinase A, mitochondrial bioenergetics, metabolic switch
- MeSH terms
- Adenosine Triphosphate, Allosteric Regulation, Animals, Binding Sites, Cell Line, Electron Transport Complex IV, Energy Metabolism, Oxidative Phosphorylation, Phosphorylation, Protein Processing, Post-Translational, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Cyclic AMP-Dependent Protein Kinases, Mutant Proteins, Rats, Molecular Dynamics Simulation
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