Biochemistry and Chemical Biology

Ion Channels: Keeping a lid on calcium uptake

Jun 3, 2016

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University of California, San Francisco, United States

Mitochondria are often referred to as the “powerhouses” of eukaryotic cells because they supply most of the energy that the cells need. In the 1960s it was discovered that active mitochondria, when isolated from the cell and studied “in a test-tube”, accumulate large quantities of calcium ions (Ca²⁺). However, the importance of this phenomenon was not immediately clear. Later, in the 1990s, it was revealed that mitochondria inside eukaryotic cells also take up Ca²⁺ ions (Rizzuto et al., 1998).

The uptake of Ca²⁺ by mitochondria stimulates certain enzymes to regulate energy production in order to match the cell’s activity. However, if too much Ca²⁺ enters, the mitochondria can malfunction which often kills the cell. The uptake of Ca²⁺ by mitochondria must therefore be tightly controlled. Now, in eLife, Christopher Miller and colleagues at Brandeis University – including Ming-Feng Tsai and Charles Phillips as joint first authors – report how this control might be achieved (Tsai et al., 2016).

Each mitochondrion has an inner membrane and an outer membrane. Small molecules and ions (including Ca²⁺ ions) can pass freely through the outer membrane, but not the inner one. The transport of Ca²⁺ through the inner membrane depends on an ion channel called the “mitochondrial Ca²⁺ uniporter” (or MCU channel for short). This channel is the most selective Ca²⁺ channel currently known (Kirichok et al., 2004).

The MCU channel is actually a protein complex made from multiple subunits. The Ca²⁺ ions pass through a pore-forming subunit (Baughman et al., 2011; De Stefani et al., 2011) that spans the inner membrane and is surrounded by five other subunits. These other subunits regulate the pore-forming subunit, but how they do this and how they are all assembled into the channel complex are still topics of active debate.

The pore-forming subunit plus two of the five regulatory subunits (proteins named EMRE and MICU1) form what can be referred to as the “core functional unit of the MCU” (Perocchi et al., 2010; Sancak et al., 2013). This stripped-down version of the complex acts much like the full channel and can be used to explain how mitochondria take up Ca²⁺. Tsai, Phillips and colleagues used biochemical assays to determine how these three subunits fit together within the core functional unit. They demonstrated that EMRE interacts with the pore-forming subunit via domains that span the inner membrane. They also found that the subunits could not form a working channel without this interaction. Furthermore, they showed that MICU1 binds to EMRE at the outer surface of the inner mitochondrial membrane (Figure 1).

Figure 1

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The core functional unit of the MCU channel complex.

The core functional unit spans the inner membrane of a mitochondrion and consists of three subunits: the pore-forming subunit (green), MICU1 (blue) and EMRE (red). Tsai, Phillips and colleagues show that the pore-forming subunit and EMRE interact within the inner membrane via their transmembrane domains. They also show that a negatively charged domain of EMRE (red circle) anchors MICU1 to the cytosolic face of the inner mitochondrial membrane. The concentration of calcium ions ([Ca²⁺]) in the cytosol of a resting cell is typically about ~100 nM (left). At this concentration, MICU1 does not bind to Ca²⁺ ions (gray circles), and MICU1 blocks the pore to prevent the flow of Ca²⁺ ions. In contrast, when the concentration of Ca²⁺ in the cytosol is elevated (right), MICU1 binds to two Ca²⁺ ions and dissociates from the pore. This allows Ca²⁺ ions to flow into the mitochondria (gray arrows).

Combined with relevant data from other groups (Mallilankaraman et al., 2012; Csordás et al., 2013; Patron et al., 2014), the results of Tsai, Phillips and colleagues provide a glimpse of how the MCU channel complex might work at the molecular level. EMRE anchors MICU1 near the pore-forming subunit, and MICU1 then blocks the pore when the Ca²⁺concentration in the cytosol is at its resting level. This stops Ca²⁺ ions from flowing into the mitochondria. However, when the Ca²⁺ concentration in the cytosol increases, Ca²⁺ ions bind to MICU1and cause it to dissociate from the pore to allow other Ca²⁺ ions to pass through (Figure 1). Thus MICU1 serves as a Ca²⁺-sensitive “lid” on the MCU channel complex, which closes and opens the channel in response to changes in the Ca²⁺ concentration in the cytosol. Notably, the pore-forming subunit cannot work without EMRE (Sancak et al., 2013). Thus it might be EMRE, and not the pore forming subunit, that controls how many of the MCU channels are active in various tissues.

Now that we know how the MCU core functional unit is assembled, the stage is set to explore how the structure of the MCU channel relates to its function. This will bring us closer to understanding the phenomenon of Ca²⁺ uptake by mitochondria and how it could be affected via drugs to control energy production in cells and cell death.

References

(2011) Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter
Nature 476:341–345.

https://doi.org/10.1038/nature10234
- Google Scholar
1. Csordás G
2. Golenár T
3. Seifert EL
4. Kamer KJ
5. Sancak Y
6. Perocchi F
7. Moffat C
8. Weaver D
9. de la Fuente Perez S
10. Bogorad R
11. Koteliansky V
12. Adijanto J
13. Mootha VK
14. Hajnóczky G
(2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter
Cell Metabolism 17:976–987.

https://doi.org/10.1016/j.cmet.2013.04.020
- Google Scholar
(2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter
Nature 476:336–340.

https://doi.org/10.1038/nature10230
- Google Scholar
(2012) MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca²⁺ uptake that regulates cell survival
Cell 151:630–644.

https://doi.org/10.1016/j.cell.2012.10.011
- Google Scholar
(2004) The mitochondrial calcium uniporter is a highly selective ion channel
Nature 427:360–364.

https://doi.org/10.1038/nature02246
- Google Scholar
(2014) MICU1 and MICU2 finely tune the mitochondrial Ca²⁺ uniporter by exerting opposite effects on MCU activity
Molecular Cell 53:726–737.

https://doi.org/10.1016/j.molcel.2014.01.013
- Google Scholar
1. Perocchi F
2. Gohil VM
3. Girgis HS
4. Bao XR
5. McCombs JE
6. Palmer AE
7. Mootha VK
(2010) MICU1 encodes a mitochondrial EF hand protein required for Ca²⁺ uptake
Nature 467:291–296.

https://doi.org/10.1038/nature09358
- Google Scholar
1. Rizzuto R
2. Pinton P
3. Carrington W
4. Fay FS
5. Fogarty KE
6. Lifshitz LM
7. Tuft RA
8. Pozzan T
(1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca²⁺ responses
Science 280:1763–1766.

https://doi.org/10.1126/science.280.5370.1763
- Google Scholar
1. Sancak Y
2. Markhard AL
3. Kitami T
4. Kovács-Bogdán E
5. Kamer KJ
6. Udeshi ND
7. Carr SA
8. Chaudhuri D
9. Clapham DE
10. Li AA
11. Calvo SE
12. Goldberger O
13. Mootha VK
(2013) EMRE is an essential component of the mitochondrial calcium uniporter complex
Science 342:1379–1382.

https://doi.org/10.1126/science.1242993
- Google Scholar
1. Tsai MF
2. Phillips CB
3. Ranaghan M
4. Tsai CW
5. Wu Y
6. Willliams C
7. Miller C
(2016) Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex
eLife 5:e15545.

https://doi.org/10.7554/eLife.15545
- Google Scholar

Article and author information

Author details

Vivek Garg

Department of Physiology, University of California, San Francisco, San Francisco, United States

For correspondence
vivek.garg@ucsf.edu

Competing interests
The authors declare that no competing interests exist.
Yuriy Kirichok

Department of Physiology, University of California, San Francisco, San Francisco, United States

For correspondence
yuriy.kirichok@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

Publication history

Version of Record published: June 3, 2016
Version of Record updated: June 7, 2016

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.