Skip to main content
SpringerLink
Log in

Nuclear-mitochondrial cross-talk in global myocardial ischemia. A time-course analysis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Myocardial ischemia results in early and progressive damage to mitochondrial structure and function, but the molecular events leading to these changes have not been clearly established. We hypothesized that mitochondrial dysfunction and a coordinated expression of nuclear and mitochondrial genes occur in a time-dependent manner by relating the time courses of changes in parameters of mitochondrial bioenergetics after ischemia–reperfusion. Using a Langendorff rat heart model, mitochondrial bioenergetics and protein levels were assessed at different times of ischemia and ischemia/reperfusion. Mitochondrial and nuclear gene expression (super array analysis) and mitochondrial DNA levels were evaluated after late ischemia. Ischemia induced progressive and marked decreases in complex I, III, and V activities. Reperfusion (15, 30, and 60 min) after 45 min of ischemia had little further effect on enzyme activities or respiration. Super array analysis after 45 min ischemia revealed increased levels of the proteins with more pronounced increases in the corresponding mRNAs. Expression of mitochondrial and nuclear genes involved in oxidative phosphorylation increased after 45 min of ischemia but not after reperfusion. Myocardial ischemia induces mitochondrial dysfunction and differential but coordinated expression of nuclear and mitochondrial genes in a time-dependent manner. Our observations are pertinent to the search for molecular stimuli that generate mitochondrial defects and alter mitochondrial and nuclear transcriptional responses that may impact ischemic preconditioning and cardioprotection.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Murry CE, Richard VJ, Reimer KA, Jennings RB (1990) Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 66:913–931

    PubMed  CAS  Google Scholar 

  2. Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL (1997) Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol 273:H1544–H1554

    PubMed  CAS  Google Scholar 

  3. Rouslin W, Millard RW (1981) Mitochondrial inner membrane enzyme defects in porcine myocardial ischemia. Am J Physiol 240:H308–H313

    PubMed  CAS  Google Scholar 

  4. Rouslin W (1983) Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. Am J Physiol 244:H743–H748

    PubMed  CAS  Google Scholar 

  5. Ylitalo K, Ala-Rami A, Vuorinen K, Peuhkurinen K, Lepojarvi M, Kaukoranta P, Kiviluoma K, Hassinen I (2001) Reversible ischemic inhibition of F(1)F(0)-ATPase in rat and human myocardium. Biochim Biophys Acta 1504:329–339

    Article  PubMed  CAS  Google Scholar 

  6. Borutaite V, Mildaziene V, Brown GC, Brand MD (1995) Control and kinetic analysis of ischemia-damaged heart mitochondria: which parts of the oxidative phosphorylation system are affected by ischemia? Biochim Biophys Acta 1272:154–158

    PubMed  Google Scholar 

  7. Petrosillo G, Di Venosa N, Ruggiero FM et al (2005) Mitochondrial dysfunction associated with cardiac ischemia/reperfusion can be attenuated by oxygen tension control. Role of oxygen-free radicals and cardiolipin. Biochim Biophys Acta 1710:78–86

    Article  PubMed  CAS  Google Scholar 

  8. Marín-García J, Goldenthal MJ (2004) Mitochondria play a critical role in cardioprotection. J Card Fail 10:55–66

    Article  PubMed  Google Scholar 

  9. Ning XH, Chen SH, Xu CS et al (2003) Hypothermia preserves myocardial function and mitochondrial protein gene expression during hypoxia. Am J Physiol Heart Circ Physiol 285:H212–H219

    PubMed  CAS  Google Scholar 

  10. Ning XH, Chen SH, Xu CS, Li L, Yao LY, Qian K et al (2002) Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis. J Appl Physiol 92:2200–2207

    PubMed  CAS  Google Scholar 

  11. Marin-Garcia J, Goldenthal JM, Moe GW (2001) Abnormal cardiac and skeletal muscle mitochondrial function in pacing induced cardiac failure. Cardiovasc Res 52:103–110

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  14. Lucas D, Szweda L (1999) Declines in mitochondrial respiration during cardiac reperfusion: age-dependent inactivation of [alpha]-ketoglutarate dehydrogenase. Proc Natl Acad Sci USA 96:6689–6693

    Article  PubMed  CAS  Google Scholar 

  15. Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ (2000) Heart mitochondrial DNA and enzyme changes during early human development. Mol Cell Biochem 210:47–52

    Article  PubMed  CAS  Google Scholar 

  16. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  17. Barbu V, Dautry F (1989) Northern blot normalization with a 28S rRNA oligonucleotide probe. Nucleic Acids Res 17:7115

    Article  PubMed  CAS  Google Scholar 

  18. Knight RJ, Kofoed KF, Schelbert HR, Buxton DB (1996) Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium. Cardiovasc Res 32:1016–1023

    Article  PubMed  CAS  Google Scholar 

  19. Tanaka R, Mochizuki H, Suzuki A, Katsube N, Ishitani R, Mizuno Y, Urabe T (2002) Induction of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in rat brain after focal ischemia/reperfusion. J Cereb Blood Flow Metab 22:280–288

    Article  PubMed  CAS  Google Scholar 

  20. Tsao PS, Aoki N, Lefer DJ, Johnson G 3rd, Lefer AM (1990) Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82:1402–1412

    Article  PubMed  CAS  Google Scholar 

  21. Hanaki Y, Sugiyama S, Taki K, Kato T, Suzuki S, Ozawa T (1988) Differing time courses between delta lactate and mitochondrial respiration during coronary occlusion and after reperfusion in canine hearts. Heart Vessels 4:149–152

    Article  PubMed  CAS  Google Scholar 

  22. Marín-García J, Goldenthal MJ, Damle S, Pi Y, Moe GW (2009) Regional distribution of mitochondrial dysfunction and apoptotic remodeling in pacing-induced heart failure. J Card Fail 15:700–708

    Article  PubMed  Google Scholar 

  23. Copeland WC (2008) Inherited mitochondrial diseases of DNA replication. Annu Rev Med 59:131–146

    Article  PubMed  CAS  Google Scholar 

  24. Heddi A, Stepien G, Benke PJ, Wallace DC (1999) Coordinate induction of energy gene expression in tissues of mitochondrial disease patients. J Biol Chem 274:22968–22976

    Article  PubMed  CAS  Google Scholar 

  25. Wiesner RJ, Hornung TV, Garman JD, Clayton DA, O’Gorman E, Wallimann TJ (1999) Stimulation of mitochondrial gene expression and proliferation of mitochondria following impairment of cellular energy transfer by inhibition of the phosphocreatine circuit in rat hearts. J Bioenerg Biomembr 31:559–567

    Article  PubMed  CAS  Google Scholar 

  26. Yu Q, Nguyen T, Ogbi M, Caldwell RW, Johnson JA (2008) Differential loss of cytochrome-c oxidase subunits in ischemia–reperfusion injury: exacerbation of COI subunit loss by PKC-epsilon inhibition. Am J Physiol 294:H2637–H2645

    CAS  Google Scholar 

  27. He H, Chen M, Scheffler NK, Gibson BW, Spremulli LL, Gottlieb RA (2001) Phosphorylation of mitochondrial elongation factor Tu in ischemic myocardium: basis for chloramphenicol-mediated cardioprotection. Circ Res 89:461–467

    Article  PubMed  CAS  Google Scholar 

  28. Wells J, Henkler F, Leversha M, Koshy R (1995) A mitochondrial elongation factor-like protein is over-expressed in tumours and differentially expressed in normal tissues. FEBS Lett 23:119–125

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Molecular Cardiology and Neuromuscular Institute, 75 Raritan Avenue, Highland Park, NJ, 08904, USA

    José Marín-García & Shirish Damle

  2. Division of Cardiology, Department of Medicine, University of Alberta and Hospitals, Edmonton, AB, Canada

    Bodh I. Jugdutt

  3. Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto,, Toronto, ON, Canada

    Gordon W. Moe

Authors
  1. José Marín-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shirish Damle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bodh I. Jugdutt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gordon W. Moe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Marín-García.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marín-García, J., Damle, S., Jugdutt, B.I. et al. Nuclear-mitochondrial cross-talk in global myocardial ischemia. A time-course analysis. Mol Cell Biochem 364, 225–234 (2012). https://doi.org/10.1007/s11010-011-1221-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-1221-7

Keywords

Search

Navigation