Evolutionary Diversity of the Mitochondrial Calcium Uniporter
Alexander G. Bick1,*, Sarah E. Calvo1,*, and Vamsi K. Mootha1,§
1Departments of Molecular Biology and Medicine, Massachusetts General Hospital 02114 USA;
Department of Systems Biology, Harvard Medical School, Boston, MA 02115 USA; Broad
Institute, Cambridge, MA 02139 USA
Calcium uptake into mitochondria occurs via a recently identified ion channel called the uniporter.
Here, we characterize the phylogenomic distribution of the uniporter’s membrane-spanning pore
subunit (MCU) and regulatory partner (MICU1). Homologs of both components tend to co-occur
in all major branches of eukaryotic life, but both have been lost along certain protozoan and fungal
lineages. Several bacterial genomes also contain putative MCU homologs that may represent
prokaryotic calcium channels. The analyses indicate that the uniporter may have been an early
feature of mitochondria.
Vertebrate mitochondria store large amounts of calcium taken up through a channel called
the calcium uniporter. The uniporter, combined with additional intake, buffering, and efflux
mechanisms (1), is hypothesized to regulate signaling, energy metabolism, and cell death.
Although uniporter activity was documented nearly 50 years ago (2, 3), its molecular
identity remained elusive until comparative genomics revealed its regulatory partner,
MICU1, and pore-forming subunit, MCU (4–6). MCU represents a fundamentally new class
of calcium channels, while MICU1 is a peripheral membrane protein with two EF-hand
motifs, resembling known calcium-sensing regulators. Molecular identification of the
uniporter machinery, combined with the recent availability of diverse genomes, offers an
opportunity to explore this channel’s evolutionary history.
We examined the distribution of MCU and MICU1 across 138 fully sequenced eukaryotic
organisms (7). We used sequence similarity followed by inspection of protein domains to
annotate organisms that harbor one or more homologs of MCU or of MICU1, and visualized
the data on a phylogenomic tree constructed using standard maximum likelihood methods
Homologs of MCU are distributed widely across all major branches of eukaryotic life,
present in nearly all plants and metazoa, but with apparent loss events in certain protozoan
and fungal lineages (Fig. 1A). MCU homologs have highly conserved acidic residues in the
vicinity of a “DIME” motif flanked by two transmembrane and coiled coil domains (Fig.
1B). Within protozoa, MCU homologs are found in organisms from diverse clades including
kinetoplasts (Trypanosoma cruzi), heterolobosea (Naegleria gruberi), oomycetes
(Phytophthora infestans), and ciliates (Tetrahymena thermophila), but they are absent from
other major lineages including apicomplexa (Plasmodium falciparum) and mitosome-
§Correspondence to: email@example.com.
*These authors contributed equally.
Supporting Online Material
Materials and Methods
References 9 to 28
NIH Public Access
Science. Author manuscript; available in PMC 2012 December 11.
Published in final edited form as:
Science. 2012 May 18; 336(6083): 886. doi:10.1126/science.1214977.