Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content
Springer Nature Link
Log in

Metabolic adaptation to chronic hypoxia in cardiac mitochondria

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11 % oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17–18 %, and with pyruvate were decreased by 29–15 %, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bizeau ME, Willis WT, Hazel JR (1998) Differential responses to endurance training in subsarcolemmal and intermyofibrillar mitochondria. J Appl Physiol 85:1279–1284

    PubMed  CAS  Google Scholar 

  2. Boengler K, Schulz R, Heusch G (2009) Loss of cardioprotection with ageing. Cardiovasc Res 83:247–261. doi:10.1093/cvr/cvp033

    Article  PubMed  CAS  Google Scholar 

  3. Boengler K, Stahlhofen S, van de Sand A, Gres P, Ruiz-Meana M, Garcia-Dorado D, Heusch G, Schulz R (2009) Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res Cardiol 104:141–147. doi:10.1007/s00395-009-0007-5

    Article  PubMed  CAS  Google Scholar 

  4. Boveris A, Oshino R, Erecinska M, Chance B (1971) Reduction of mitochondrial components by durohydroquinone. Biochim Biophys Acta 245:1–16. doi:0005-2728(71)90002-8

    Article  PubMed  CAS  Google Scholar 

  5. Bulteau AL, Lundberg KC, Ikeda-Saito M, Isaya G, Szweda LI (2005) Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion. Proc Natl Acad Sci USA 102:5987–5991. doi:10.1073/pnas.0501519102/0501519102

    Article  PubMed  CAS  Google Scholar 

  6. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J (2009) MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron–sulfur cluster assembly proteins ISCU1/2. Cell Metab 10:273–284. doi:10.1016/j.cmet.2009.08.015

    Article  PubMed  CAS  Google Scholar 

  7. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2008) Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria. Am J Physiol Cell Physiol 294:C460–C466. doi:10.1152/ajpcell.00211.2007

    Article  PubMed  CAS  Google Scholar 

  8. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031. doi:10.1074/jbc.M304854200

    Article  PubMed  CAS  Google Scholar 

  9. Chernyak BV, Bernardi P (1996) The mitochondrial permeability transition pore is modulated by oxidative agents through both pyridine nucleotides and glutathione at two separate sites. Eur J Biochem 238:623–630. doi:10.1111/j.1432-1033.1996.0623w.x

    Article  PubMed  CAS  Google Scholar 

  10. Cole MA, Murray AJ, Cochlin LE, Heather LC, McAleese S, Knight NS, Sutton E, Jamil AA, Parassol N, Clarke K (2011) A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. Basic Res Cardiol 106:447–457. doi:10.1007/s00395-011-0156-1

    Article  PubMed  CAS  Google Scholar 

  11. Dabkowski ER, Baseler WA, Williamson CL, Powell M, Razunguzwa TT, Frisbee JC, Hollander JM (2010) Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes. Am J Physiol Heart Circ Physiol 299:H529–H540. doi:10.1152/ajpheart.00267.2010

    Article  PubMed  CAS  Google Scholar 

  12. Darley-Usmar VM, Rickwood D, Wilson MT (1987) Mitochondria, a practical approach. IRL Press, Oxford

    Google Scholar 

  13. Essop MF, Razeghi P, McLeod C, Young ME, Taegtmeyer H, Sack MN (2004) Hypoxia-induced decrease of UCP3 gene expression in rat heart parallels metabolic gene switching but fails to affect mitochondrial respiratory coupling. Biochem Biophys Res Commun 314:561–564

    Article  PubMed  CAS  Google Scholar 

  14. Favaro E, Ramachandran A, McCormick R, Gee H, Blancher C, Crosby M, Devlin C, Blick C, Buffa F, Li JL, Vojnovic B, Pires das Neves R, Glazer P, Iborra F, Ivan M, Ragoussis J, Harris AL (2010) MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. PLoS ONE 5:e10345. doi:10.1371/journal.pone.0010345

    Article  PubMed  Google Scholar 

  15. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613

    PubMed  CAS  Google Scholar 

  16. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129:111–122. doi:10.1016/j.cell.2007.01.047

    Article  PubMed  CAS  Google Scholar 

  17. Gomez L, Paillard M, Price M, Chen Q, Teixeira G, Spiegel S, Lesnefsky EJ (2011) A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection. Basic Res Cardiol 106:1341–1353. doi:10.1007/s00395-011-0223-7

    Article  PubMed  CAS  Google Scholar 

  18. Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1:401–408. doi:10.1016/j.cmet.2005.05.001

    Article  PubMed  CAS  Google Scholar 

  19. Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91:807–819. doi:10.1113/expphysiol.2006.033506

    Article  PubMed  CAS  Google Scholar 

  20. Heather LC, Carr CA, Stuckey DJ, Pope S, Morten KJ, Carter EE, Edwards LM, Clarke K (2010) Critical role of complex III in the early metabolic changes following myocardial infarction. Cardiovasc Res 85:127–136. doi:10.1093/cvr/cvp276

    Article  PubMed  CAS  Google Scholar 

  21. Heather LC, Cole MA, Lygate CA, Evans RD, Stuckey DJ, Murray AJ, Neubauer S, Clarke K (2006) Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc Res 72:430–437

    Article  PubMed  CAS  Google Scholar 

  22. Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, Garcia-Dorado D, Di Lisa F, Schulz R, Heusch G (2005) Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97:583–586. doi:10.1161/01.RES.0000181171.65293.65

    Article  PubMed  CAS  Google Scholar 

  23. Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the holy grail of cardioprotection. Basic Res Cardiol 105:151–154. doi:10.1007/s00395-009-0080-9

    Article  PubMed  Google Scholar 

  24. Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE, Codreanu I, Hopwood N, Johnson AW, Rider OJ, Levett DZ, Tyler DJ, Francis JM, Neubauer S, Grocott MP, Clarke K (2010) Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt Everest base camp. FASEB J 25:792–796. doi:10.1096/fj.10-172999

    Article  PubMed  Google Scholar 

  25. Iyer NV, Leung SW, Semenza GL (1998) The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. Genomics 52:159–165. doi:10.1006/geno.1998.5416

    Article  PubMed  CAS  Google Scholar 

  26. Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 549:513–524. doi:10.1113/jphysiol.2003.034231

    Article  PubMed  CAS  Google Scholar 

  27. Judge S, Jang YM, Smith A, Hagen T, Leeuwenburgh C (2005) Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J 19:419–421. doi:10.1096/fj.04-2622fje

    PubMed  CAS  Google Scholar 

  28. Lesnefsky EJ, Gudz TI, Migita CT, Ikeda-Saito M, Hassan MO, Turkaly PJ, Hoppel CL (2001) Ischemic injury to mitochondrial electron transport in the aging heart: damage to the iron–sulfur protein subunit of electron transport complex III. Arch Biochem Biophys 385:117–128. doi:10.1006/abbi.2000.2066

    Article  PubMed  CAS  Google Scholar 

  29. Magalhaes J, Ascensao A, Soares JM, Ferreira R, Neuparth MJ, Marques F, Duarte JA (2005) Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol 99:1247–1253. doi:10.1152/japplphysiol.01324.2004

    Article  PubMed  CAS  Google Scholar 

  30. Matsuyama D, Kawahara K (2011) Oxidative stress-induced formation of a positive-feedback loop for the sustained activation of p38 MAPK leading to the loss of cell division in cardiomyocytes soon after birth. Basic Res Cardiol 106:815–828. doi:10.1007/s00395-011-0178-8

    Article  PubMed  CAS  Google Scholar 

  31. Monette JS, Gomez LA, Moreau RF, Bemer BA, Taylor AW, Hagen TM (2010) Characteristics of the rat cardiac sphingolipid pool in two mitochondrial subpopulations. Biochem Biophys Res Commun 398:272–277. doi:10.1016/j.bbrc.2010.06.077

    Article  PubMed  CAS  Google Scholar 

  32. Mozaffari MS, Baban B, Liu JY, Abebe W, Sullivan JC, El-Marakby A (2011) Mitochondrial complex I and NAD(P) H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts. Basic Res Cardiol 106:287–297. doi:10.1007/s00395-011-0150-7

    Article  PubMed  CAS  Google Scholar 

  33. Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073. doi:10.1074/jbc.M407715200

    Article  PubMed  CAS  Google Scholar 

  34. Muller W (1976) Subsarcolemmal mitochondria and capillarization of soleus muscle fibers in young rats subjected to an endurance training. A morphometric study of semithin sections. Cell Tissue Res 174:367–389

    Article  PubMed  CAS  Google Scholar 

  35. Neely JR, Rovetto MJ, Oram JF (1972) Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 15:289–329. doi:0033-0620(72)90029-1

    Article  PubMed  CAS  Google Scholar 

  36. Oktay Y, Dioum E, Matsuzaki S, Ding K, Yan LJ, Haller RG, Szweda LI, Garcia JA (2007) Hypoxia-inducible factor 2alpha regulates expression of the mitochondrial aconitase chaperone protein frataxin. J Biol Chem 282:11750–11756. doi:10.1074/jbc.M611133200

    Article  PubMed  CAS  Google Scholar 

  37. Palmer JW, Tandler B, Hoppel CL (1985) Biochemical differences between subsarcolemmal and interfibrillar mitochondria from rat cardiac muscle: effects of procedural manipulations. Arch Biochem Biophys 236:691–702

    Article  PubMed  CAS  Google Scholar 

  38. Palmer JW, Tandler B, Hoppel CL (1977) Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 252:8731–8739

    PubMed  CAS  Google Scholar 

  39. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM (2001) Reactive oxygen species generated by the mitochondrial respiratory chain affect the complex III activity via cardiolipin peroxidation in beef-heart submitochondrial particles. Mitochondrion 1:151–159. doi:10.1016/S1567-7249(01)00011-3

    Article  PubMed  CAS  Google Scholar 

  40. Petronilli V, Cola C, Bernardi P (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. J Biol Chem 268:1011–1016

    PubMed  CAS  Google Scholar 

  41. Qanud K, Mamdani M, Pepe M, Khairallah RJ, Gravel J, Lei B, Gupte SA, Sharov VG, Sabbah HN, Stanley WC, Recchia FA (2008) Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure. Am J Physiol Heart Circ Physiol 295:H2098–H2105. doi:10.1152/ajpheart.00471.2008

    Article  PubMed  CAS  Google Scholar 

  42. Riva A, Tandler B, Loffredo F, Vazquez E, Hoppel C (2005) Structural differences in two biochemically defined populations of cardiac mitochondria. Am J Physiol Heart Circ Physiol 289:H868–H872. doi:10.1152/ajpheart.00866.2004

    Article  PubMed  CAS  Google Scholar 

  43. Rosca MG, Okere IA, Sharma N, Stanley WC, Recchia FA, Hoppel CL (2009) Altered expression of the adenine nucleotide translocase isoforms and decreased ATP synthase activity in skeletal muscle mitochondria in heart failure. J Mol Cell Cardiol 46:927–935. doi:10.1016/j.yjmcc.2009.02.009

    Article  PubMed  CAS  Google Scholar 

  44. Rosca MG, Vazquez EJ, Kerner J, Parland W, Chandler MP, Stanley W, Sabbah HN, Hoppel CL (2008) Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovasc Res 80:30–39. doi:10.1093/cvr/cvn184

    Article  PubMed  CAS  Google Scholar 

  45. Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G (2002) No ischemic preconditioning in heterozygous connexin43-deficient mice. Am J Physiol Heart Circ Physiol 283:H1740–H1742. doi:10.1152/ajpheart.00442.2002

    PubMed  CAS  Google Scholar 

  46. Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordonez A, Corral-Escariz M, Soro I, Lopez-Bernardo E, Perales-Clemente E, Martinez-Ruiz A, Enriquez JA, Aragones J, Cadenas S, Landazuri MO (2011) Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting complex I activity. Cell Metab 14:768–779. doi:10.1016/j.cmet.2011.10.008

    Article  PubMed  CAS  Google Scholar 

  47. Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Suat-Cheng Tan, Anassuya Ramachandran and Linda O’Flaherty for their technical advice. This work was supported by funding from the British Heart Foundation (grant number RG/07/004/22659) and Diabetes UK (grant number 11/0004175).

Conflict of interest

There are no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK

    Lisa C. Heather, Mark A. Cole, Jun-Jie Tan, Lucy J. A. Ambrose, Amira H. Abd-Jamil, Emma E. Carter, Michael S. Dodd & Kieran Clarke

  2. Institute of Neurology, University College London, London, UK

    Simon Pope

  3. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

    Kar Kheng Yeoh & Christopher J. Schofield

Authors
  1. Lisa C. Heather
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark A. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun-Jie Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucy J. A. Ambrose
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simon Pope
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amira H. Abd-Jamil
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emma E. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael S. Dodd
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kar Kheng Yeoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher J. Schofield
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kieran Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisa C. Heather.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 108 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heather, L.C., Cole, M.A., Tan, JJ. et al. Metabolic adaptation to chronic hypoxia in cardiac mitochondria. Basic Res Cardiol 107, 268 (2012). https://doi.org/10.1007/s00395-012-0268-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-012-0268-2

Keywords

Search

Navigation