Skip to main content
SpringerLink
Log in

Mitochondrial Pruning by Nix and BNip3: An Essential Function for Cardiac-Expressed Death Factors

  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Programmed cardiac myocyte death via the intrinsic, or mitochondrial, pathway is a mechanism of pathological ventricular remodeling after myocardial infarction and during chronic pressure overload hypertrophy. Transcriptional upregulation of the closely related proapoptotic Bcl2 family members BNip3 in ischemic myocardium and Nix in hypertrophied myocardium suggested a molecular mechanism by which programmed cell death can be initiated by cardiac stress and lead to dilated cardiomyopathy. Studies using transgenic and gene knockout mice subsequently demonstrated that expression of BNip3 and Nix is both sufficient for cardiomyopathy development and necessary for cardiac remodeling after reversible coronary occlusion and transverse aortic banding, respectively. Here, these data are reviewed in the context of recent findings showing that Nix not only stimulates cardiomyocyte apoptosis but also induces mitochondrial autophagy (mitophagy) and indirectly activates the mitochondrial permeability transition pore, causing cell necrosis. New findings are presented suggesting that Nix and BNip3 have an essential function, “mitochondrial pruning,” that restrains mitochondrial proliferation in cardiomyocytes and without which an age-dependent mitochondrial cardiomyopathy develops.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Diwan, A., & Dorn, G. W., II. (2007). Decompensation of cardiac hypertrophy: Cellular mechanisms and novel therapeutic targets. Physiology (Bethesda), 22, 56–64.

    CAS  Google Scholar 

  2. Berry, J. J., Hoffman, J. M., Steenbergen, C., Baker, J. A., Floyd, C., Van Trigt, P., et al. (1993). Human pathologic correlation with PET in ischemic and nonischemic cardiomyopathy. Journal of Nuclear Medicine, 34, 39–47.

    PubMed  CAS  Google Scholar 

  3. Olivetti, G., Abbi, R., Quaini, F., Kajstura, J., Cheng, W., Nitahara, J. A., et al. (1997). Apoptosis in the failing human heart. Journal of Nuclear Medicine, 336, 1131–1141.

    CAS  Google Scholar 

  4. Francis, G. S. (1998). Changing the remodeling process in heart failure: Basic mechanisms and laboratory results. Current Opinion in Cardiology, 13, 156–161.

    PubMed  CAS  Google Scholar 

  5. Olivetti, G., Capasso, J. M., Sonnenblick, E. H., & Anversa, P. (1990). Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circulation Research, 67, 23–34.

    PubMed  CAS  Google Scholar 

  6. Rubart, M., & Field, L. J. (2006). Cardiac regeneration: Repopulating the heart. Annual Review of Physiology, 68, 29–49.

    Article  PubMed  CAS  Google Scholar 

  7. Hayakawa, Y., Chandra, M., Miao, W., Shirani, J., Brown, J. H., Dorn, G. W., II, et al. (2003). Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. Circulation, 108, 3036–3041.

    Article  PubMed  CAS  Google Scholar 

  8. Foo, R. S., Mani, K., & Kitsis, R. N. (2005). Death begets failure in the heart. Journal of Clinical Investigation, 115, 565–571.

    PubMed  CAS  Google Scholar 

  9. Dorn, G. W., II. (2009). Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovascular Research, 81, 465–473.

    Article  PubMed  CAS  Google Scholar 

  10. Youle, R. J., & Strasser, A. (2008). The BCL-2 protein family: Opposing activities that mediate cell death. Nature Reviews. Molecular Cell Biology, 9, 47–59.

    Article  PubMed  CAS  Google Scholar 

  11. Chen, Z., Chua, C. C., Ho, Y. S., Hamdy, R. C., & Chua, B. H. (2001). Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. American Journal of Physiology. Heart and Circulatory Physiology, 280, H2313–H2320.

    PubMed  CAS  Google Scholar 

  12. Condorelli, G., Morisco, C., Stassi, G., Notte, A., Farina, F., Sgaramella, G., et al. (1999). Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation, 99, 3071–3078.

    PubMed  CAS  Google Scholar 

  13. Yussman, M. G., Toyokawa, T., Odley, A., Lynch, R. A., Wu, G., Colbert, M. C., et al. (2002). Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nature Medicine, 8, 725–730.

    PubMed  CAS  Google Scholar 

  14. Regula, K. M., Ens, K., & Kirshenbaum, L. A. (2002). Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes. Circulation Research, 91, 226–231.

    Article  PubMed  CAS  Google Scholar 

  15. Galvez, A. S., Brunskill, E. W., Marreez, Y., Benner, B. J., Regula, K. M., Kirschenbaum, L. A., et al. (2006). Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress. Journal of Biological Chemistry, 281, 1442–1448.

    Article  PubMed  CAS  Google Scholar 

  16. Yurkova, N., Shaw, J., Blackie, K., Weidman, D., Jayas, R., Flynn, B., et al. (2008). The cell cycle factor E2F-1 activates Bnip3 and the intrinsic death pathway in ventricular myocytes. Circulation Research, 102, 472–479.

    Article  PubMed  CAS  Google Scholar 

  17. Bruick, R. K. (2000). Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 97, 9082–9087.

    Article  PubMed  CAS  Google Scholar 

  18. Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H., & Harris, A. L. (2001). HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Research, 61, 6669–6673.

    PubMed  CAS  Google Scholar 

  19. Birse-Archbold, J. L., Kerr, L. E., Jones, P. A., McCulloch, J., & Sharkey, J. (2005). Differential profile of Nix upregulation and traslocation during hypxia/ischaemia in vivo versus in vitro. Journal of Cerebral Blood Flow and Metabolism, 25, 1356–1365.

    Article  PubMed  CAS  Google Scholar 

  20. Syed, F., Odley, A., Hahn, H. S., Brunskill, E. W., Lynch, R. A., Marreez, Y., et al. (2004). Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circulation Research, 95, 1200–1206.

    Article  PubMed  CAS  Google Scholar 

  21. Dorn, G. W., II. (2005). Physiologic growth and pathologic genes in cardiac development and cardiomyopathy. Trends in Cardiovascular Medicine, 15, 185–189.

    Article  PubMed  CAS  Google Scholar 

  22. Diwan, A., Krenz, M., Syed, F. M., Wansapura, J., Ren, X., Koesters, A. G., et al. (2007). Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. Journal of Clinical Investigation, 117, 2825–2833.

    Article  PubMed  CAS  Google Scholar 

  23. Kubasiak, L. A., Hernandez, O. M., Bishopric, N. H., & Webster, K. A. (2002). Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proceedings of the National Academy of Sciences of the United States of America, 99, 12825–12830.

    Article  PubMed  CAS  Google Scholar 

  24. Kubli, D. A., Quinsay, M. N., Huang, C., Lee, Y., & Gustafsson, A. B. (2008). Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion. American Journal of Physiology. Heart and Circulatory Physiology, 295, H2025–H2031.

    Article  PubMed  CAS  Google Scholar 

  25. Schmidt-Kastner, R., Aguirre-Chen, C., Kietzmann, T., Saul, I., Busto, R., & Ginsberg, M. D. (2004). Nuclear localization of the hypoxia-regulated pro-apoptotic protein BNIP3 after global brain ischemia in the rat hippocampus. Brain Research, 1001, 133–142.

    Article  PubMed  CAS  Google Scholar 

  26. Burton, T. R., Henson, E. S., Baijal, P., Eisenstat, D. D., & Gibson, S. B. (2005). The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survivial under hypoxia. International Journal of Cancer, 118, 1660–1669.

    Article  CAS  Google Scholar 

  27. Diwan, A., Koesters, A. G., Odley, A. M., Pushkaran, S., Baines, C. P., Spike, B. T., et al. (2007). Unrestrained erythroblast development in Nix−/− mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proceedings of the National Academy of Sciences of the United States of America, 104, 6794–6799.

    Article  PubMed  CAS  Google Scholar 

  28. Schweers, R. L., Zhang, J., Randall, M. S., Loyd, M. R., Li, W., Dorsey, F. C., et al. (2007). NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proceedings of the National Academy of Sciences of the United States of America, 104, 19500–19505.

    Article  PubMed  Google Scholar 

  29. Sandoval, H., Thiagarajan, P., Dasgupta, S. K., Schumacher, A., Prchal, J. T., Chen, M., et al. (2008). Essential role for Nix in autophagic maturation of erythroid cells. Nature, 454, 232–235.

    Article  PubMed  CAS  Google Scholar 

  30. Diwan, A., Wansapura, J., Syed, F. M., Matkovich, S. J., Lorenz, J. N., & Dorn, G. W., II. (2008). Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation, 117, 396–404.

    Article  PubMed  CAS  Google Scholar 

  31. Diwan, A., Matkovich, S. J., Yuan, Q., Zhao, W., Yatani, A., Brown, J. H., et al. (2009). Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death. Journal of Clinical Investigation, 119, 203–212.

    PubMed  CAS  Google Scholar 

  32. Foyouzi-Youssefi, R., Arnaudeau, S., Borner, C., Kelley, W. L., Tschopp, J., Lew, D. P., et al. (2000). Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proceedings of the National Academy of Sciences of the United States of America, 97, 5723–5728.

    Article  PubMed  CAS  Google Scholar 

  33. Nutt, L. K., Pataer, A., Pahler, J., Fang, B., Roth, J., McConkey, D. J., et al. (2002). Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores. Journal of Biological Chemistry, 277, 9219–9225.

    Article  PubMed  CAS  Google Scholar 

  34. Scorrano, L., Oakes, S. A., Opferman, J. T., Cheng, E. H., Sorcinelli, M. D., Pozzan, T., et al. (2003). BAX and BAK regulation of endoplasmic reticulum Ca2+: A control point for apoptosis. Science, 300, 135–139.

    Article  PubMed  CAS  Google Scholar 

  35. Rizzuto, R., & Pozzan, T. (2006). Microdomains of intracellular Ca2+: Molecular determinants and functional consequences. Physiological Reviews, 86, 369–408.

    Article  PubMed  CAS  Google Scholar 

  36. Henriquez, M., Armisen, R., Stutzin, A., & Quest, A. F. G. (2008). Cell death by necrosis, a regulated way to go. Current Molecular Medicine, 8, 187–206.

    Article  PubMed  CAS  Google Scholar 

  37. Nakayama, H., Chen, X., Baines, C. P., Klevitsky, R., Zhang, X., Zhang, H., et al. (2007). Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failure. Journal of Clinical Investigation, 117, 2431–2444.

    Article  PubMed  CAS  Google Scholar 

  38. Dorn, G. W., II, & Kirshenbaum, L. A. (2008). Cardiac reanimation: Targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L. Oncogene, 27(Suppl 1), S158–S167.

    Article  PubMed  CAS  Google Scholar 

  39. Zhang, J., & Ney, P. A. (2009). Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death and Differentiation, 16, 939–946.

    Article  PubMed  CAS  Google Scholar 

  40. Lehman, J. J., Barger, P. M., Kovacs, A., Saffitz, J. E., Medeiros, D., & Kelly, D. P. (2000). PPARg coactivator-1 (PGC-1) promotes cardiac mitochondrial biogenesis. Journal of Clinical Investigation, 106, 847–856.

    Article  PubMed  CAS  Google Scholar 

  41. Russell, L. K., Mansfield, C. M., Lehman, J. J., Kovacs, A., Courtois, M., Saffitz, J. E., et al. (2004). Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor g coactivator-1a promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circulation Research, 94, 525–533.

    Article  PubMed  CAS  Google Scholar 

  42. Zhang, J., & Ney, P. A. (2008). NIX induces mitochondrial autophagy in reticulocytes. Autophagy, 4, 354–356.

    PubMed  Google Scholar 

  43. Schwarten, M., Mohrluder, J., Ma, P., Stoldt, M., Thielmann, Y., Stangler, T., et al. (2009). Nix directly binds to GABARAP: A possible crosstalk between apoptosis and autophagy. Autophagy, 5, 690–698.

    Article  PubMed  CAS  Google Scholar 

  44. Novak, I., Kirkin, V., McEwan, D. G., Zhang, J., Wild, P., Rozenknop, A., et al. (2010). Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep, 11, 45–51.

    Article  PubMed  CAS  Google Scholar 

  45. Goffart, S., Kleist-Retzow, J. C., & Wiesner, R. J. (2004). Regulation of mitochondrial proliferation in the heart: Power-plant failure contributes to cardiac failure in hypertrophy. Cardiovascular Research, 64, 198–207.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by NIH HL059888. The author would like to express his deep appreciation to the many members of his laboratory who contributed in various ways to the Nix story over the past decade, especially to those who were tolerant of the idea that we should maintain some mice for long periods of time just to see what might develop.

Author information

Authors and Affiliations

  1. Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Gerald W. Dorn II

  2. Washington University Center for Pharmacogenomics, 660 S. Euclid Ave., Campus Box 8086, St. Louis, MO, 63110, USA

    Gerald W. Dorn II

Authors
  1. Gerald W. Dorn II
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald W. Dorn II.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dorn, G.W. Mitochondrial Pruning by Nix and BNip3: An Essential Function for Cardiac-Expressed Death Factors. J. of Cardiovasc. Trans. Res. 3, 374–383 (2010). https://doi.org/10.1007/s12265-010-9174-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-010-9174-x

Keywords

Search

Navigation