Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondrial Ca2+ uniporter and CaMKII in heart



Arising from M. A. Joiner et al. Nature 491, 269–273 (2012); doi:10.1038/nature1023410.1038/nature11444

The influx of cytosolic Ca2+ into mitochondria is mediated primarily by the mitochondrial calcium uniporter (MCU)1, a small-conductance, Ca2+-selective channel2,3,4,5,6—MCU modulates intracellular Ca2+ transients and regulates ATP production and cell death1. Recently, Joiner et al. reported that MCU is regulated by mitochondrial CaMKII, and this regulation determines stress response in heart7. They reported a very large current putatively mediated by MCU that was about two orders of magnitude greater than the MCU current (IMCU) that we previously measured in heart mitochondria3; furthermore, the current traces presented by Joiner et al. showed unusually high fluctuations incompatible with the low single-channel conductance of MCU. Here we performed patch-clamp recordings from mouse heart mitochondria under the exact conditions used by Joiner et al.7, and confirm that IMCU in cardiomyocytes is very small and is not directly regulated by CaMKII; thus, the currents presented by Joiner et al. do not appear to correspond to MCU, and there is no direct electrophysiological evidence that CaMKII regulates MCU. There is a Reply to this Brief Communication Arising by Joiner, M. A. et al. Nature 513, (2014).

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Heart MCU current and CaMKII.


  1. Rizzuto, R., Bernardi, P. & Pozzan, T. Mitochondria as all-round players of the calcium game. J. Physiol. 529, 37–47 (2000)

    CAS  Article  Google Scholar 

  2. Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004)

    ADS  CAS  Article  Google Scholar 

  3. Fieni, F., Bae Lee, S., Jan, Y. N. & Kirichok, Y. Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nature Commun. 3, 1317 (2012)

    ADS  Article  Google Scholar 

  4. Chaudhuri, D., Sancak, Y., Mootha, V. K. & Clapham, D. E. MCU encodes the pore conducting mitochondrial calcium currents. eLife 2, e00704 (2013)

    Article  Google Scholar 

  5. De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011)

    ADS  CAS  Article  Google Scholar 

  6. Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011)

    ADS  CAS  Article  Google Scholar 

  7. Joiner, M. A. et al. CaMKII determines mitochondrial stress responses in heart. Nature 491, 269–273 (2012)

    ADS  CAS  Article  Google Scholar 

  8. Page, E. Quantitative ultrastructural analysis in cardiac membrane physiology. Am. J. Physiol. 235, C147–C158 (1978)

    CAS  Article  Google Scholar 

  9. Smith, H. E. & Page, E. Morphometry of rat heart mitochondrial subcompartments and membranes: application to myocardial cell atrophy after hypophysectomy. J. Ultrastruct. Res. 55, 31–41 (1976)

    CAS  Article  Google Scholar 

  10. Williams, G. S., Boyman, L., Chikando, A. C., Khairallah, R. J. & Lederer, W. J. Mitochondrial calcium uptake. Proc. Natl Acad. Sci. USA 110, 10479–10486 (2013)

    ADS  CAS  Article  Google Scholar 

  11. O'Rourke, B. & Maack, C. The role of Na dysregulation in cardiac disease and how it impacts electrophysiology. Drug Discov. Today Dis. Models 4, 207–217 (2007)

    Article  Google Scholar 

  12. Maack, C. et al. Elevated cytosolic Na+ decreases mitochondrial Ca2+ uptake during excitation-contraction coupling and impairs energetic adaptation in cardiac myocytes. Circ. Res. 99, 172–182 (2006)

    CAS  Article  Google Scholar 

  13. Ashpole, N. M. & Hudmon, A. Excitotoxic neuroprotection and vulnerability with CaMKII inhibition. Mol. Cell. Neurosci. 46, 720–730 (2011)

    CAS  Article  Google Scholar 

  14. Rokita, A. G. & Anderson, M. E. New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII). Circulation 126, 2125–2139 (2012)

    Article  Google Scholar 

  15. Pusch, M. & Neher, E. Rates of diffusional exchange between small cells and a measuring patch pipette. Pflugers Archiv. 411, 204–211 (1988)

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations



F.F. and Y.K. conceived the project. F.F. performed electrophysiological experiments. D.E.J. and A.H. generated recombinant CAMKII and determined its activity under various conditions. All authors contributed to experimental design, discussed the results, and wrote the manuscript.

Corresponding author

Correspondence to Yuriy Kirichok.

Ethics declarations

Competing interests

Declared none.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fieni, F., Johnson, D., Hudmon, A. et al. Mitochondrial Ca2+ uniporter and CaMKII in heart. Nature 513, E1–E2 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing