MCU (CG18769) encodes the pore-forming subunit of the Drosophila mitochondrial calcium uniporter, a two-transmembrane-helix protein of the inner mitochondrial membrane that oligomerizes to form a calcium-selective channel. Like other metazoan MCU proteins it requires the small subunit EMRE to conduct calcium, and its activity is gated by the EF-hand regulators MICU1 and MICU3. MCU mediates fast, ruthenium red-sensitive calcium uptake into the mitochondrial matrix, including endoplasmic reticulum-to-mitochondria calcium transfer through IP3 receptors. MCU null flies are viable but short-lived; MCU is needed for oxidative stress-induced mitochondrial calcium overload and cell death, and uniporter activity in mushroom body neurons during pupal development is required for normal adult olfactory memory.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005262 calcium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of calcium channel activity across the MCU family (human MCU Q8NE86, mouse, C. elegans, Arabidopsis, Dictyostelium donors) via PTN000335993. Reason: MCU is the conserved pore of the uniporter; fly MCU null mitochondria lack fast calcium uptake and fly MCU conducts calcium when co-expressed with EMRE. Supporting Evidence: PMID:31042479 Altogether, these data show that MCU1 is a null mutant incapable of fast Ca2+ uptake. |
| GO:0005262 calcium channel activity | IDA PMID:33296646 Mechanisms of EMRE-Dependent MCU Opening in the Mitochondria... | ACCEPT | Summary: Functional expression of Drosophila MCU (with EMRE) in an assay of uniporter calcium transport. Reason: Direct assay of the fly MCU pore, which conducts calcium in an EMRE-dependent manner. Core molecular function. Supporting Evidence: PMID:33296646 Moreover, such an effect was not seen when using the JML from Drosophila melanogaster MCU, which requires EMRE to open |
| GO:0005262 calcium channel activity | IMP PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: MCU loss-of-function abolishes fast mitochondrial calcium uptake (annotated contributes_to). Reason: Mutant evidence that MCU is required for uniporter calcium conductance. MCU forms the pore itself, so the activity could equally be stated with enables; the term is correct. Supporting Evidence: PMID:31042479 While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake |
| GO:0005262 calcium channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of calcium channel activity from human MCU (Q8NE86). Reason: Consistent with direct fly evidence for MCU pore activity. Supporting Evidence: PMID:28726639 Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities |
| GO:0005739 mitochondrion | HDA PMID:25294944 Subcellular localisations of the CPTI collection of YFP-tagg... | MODIFY | Summary: High-throughput YFP protein-trap localization to mitochondria. Reason: Correct but general; MCU is an integral protein of the inner mitochondrial membrane, and the gene already carries GO:0005743 mitochondrial inner membrane. Proposed replacements: mitochondrial inner membrane Supporting Evidence: file:DROME/MCU/MCU-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | EXP PMID:27568554 Inhibiting the Mitochondrial Calcium Uniporter during Develo... | ACCEPT | Summary: Tagged MCU co-localizes with mitochondrial markers in mushroom body neurons. Reason: MCU is a multi-pass inner mitochondrial membrane protein; the experimental localization, together with conserved topology, supports this core location. Supporting Evidence: PMID:27568554 The punctate expression of the anti-FLAG epitope (Figure 2A) was coincident with mito-GFP (Figure 2C) |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping to mitochondrial inner membrane. Reason: Correct core location of the uniporter pore. Supporting Evidence: file:DROME/MCU/MCU-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | NAS PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: Author statement locating the uniporter in the inner mitochondrial membrane. Reason: Correct core location of the uniporter pore. Supporting Evidence: file:DROME/MCU/MCU-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IMP PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | MODIFY | Summary: Fly MCU requires EMRE to transport calcium in reconstitution assays. Reason: Correct but general; the transport measured is calcium uptake into the matrix, captured by the child term GO:0036444 calcium import into the mitochondrion, which the gene already carries. Proposed replacements: calcium import into the mitochondrion Supporting Evidence: PMID:27099988 metazoan MCU homologues from C. elegans and D. melanogaster require EMRE to transport Ca2+ |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IMP PMID:28726639 Mitochondrial calcium uniporter in Drosophila transfers calc... | MODIFY | Summary: MCU mutants lack mitochondrial calcium uptake after caffeine stimulation. Reason: Correct but general; refine to GO:0036444 calcium import into the mitochondrion, already annotated to MCU. Proposed replacements: calcium import into the mitochondrion Supporting Evidence: PMID:28726639 We generated Drosophila MCU loss-of-function mutants, which lacked mitochondrial calcium uptake in response to caffeine stimulation. |
| GO:0006979 response to oxidative stress | IMP PMID:28726639 Mitochondrial calcium uniporter in Drosophila transfers calc... | KEEP AS NON CORE | Summary: MCU mutants are protected from oxidative stress-induced mitochondrial calcium rise and cell death. Reason: Experimentally supported, but the response to oxidative stress is a consequence of MCU-mediated calcium overload rather than a core process of the channel. Supporting Evidence: PMID:28726639 oxidative stress-induced increases in mitochondrial calcium, mitochondrial membrane potential depolarization, and cell death were prevented in these mutants |
| GO:0007615 anesthesia-resistant memory | IMP PMID:27568554 Inhibiting the Mitochondrial Calcium Uniporter during Develo... | KEEP AS NON CORE | Summary: MCU silencing in mushroom body neurons impairs anesthesia-resistant memory. Reason: Robust behavioral phenotype, but memory is a downstream, developmental consequence of reduced mitochondrial calcium uptake in mushroom body neurons. Supporting Evidence: PMID:27568554 Three hour memory in MCU silenced flies after cold shock was statistically lower than the cold shocked controls, revealing that MCU expression in MBn neurons is required for ARM |
| GO:0015292 uniporter activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT inference of uniporter activity (human MCU Q8NE86, rat, Arabidopsis donors) via PTN000335993. Reason: Despite the protein's name, GO uniporter activity sits under secondary active (carrier) transmembrane transporter activity, whereas MCU is an ion channel. The transport function is correct, but the appropriate term is GO:0005262 calcium channel activity, which MCU already carries. Proposed replacements: calcium channel activity Supporting Evidence: PMID:28726639 Drosophila MCU contains evolutionarily conserved structures and requires essential MCU regulator (EMRE) for its calcium channel activities |
| GO:0015292 uniporter activity | ISS GO_REF:0000024 | MODIFY | Summary: Sequence-similarity transfer of uniporter activity from human MCU (Q8NE86). Reason: As for the IBA row, MCU is a channel rather than a carrier-type uniporter; replace with GO:0005262 calcium channel activity. Proposed replacements: calcium channel activity |
| GO:0036444 calcium import into the mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of calcium import into the mitochondrion, with fly MCU (FB:FBgn0042185) among the donors of PTN000335993. Reason: Core process of the uniporter pore; the target's own experimental data are among the descendant evidence for the node. Supporting Evidence: PMID:31042479 While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake |
| GO:0036444 calcium import into the mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of calcium import into the mitochondrion. Reason: Correct core process, supported by fly mutant data. Supporting Evidence: PMID:28726639 We generated Drosophila MCU loss-of-function mutants, which lacked mitochondrial calcium uptake in response to caffeine stimulation. |
| GO:0036444 calcium import into the mitochondrion | IMP PMID:27568554 Inhibiting the Mitochondrial Calcium Uniporter during Develo... | ACCEPT | Summary: Expression of a dominant-negative pore mutant reduces KCl-evoked mitochondrial calcium rise in mushroom body neurons. Reason: In vivo evidence that MCU mediates calcium entry into neuronal mitochondria. Supporting Evidence: PMID:27568554 In MCUD260Q,E263Q expressing brains, the response upon KCl stimulation was 46%±11% of the control |
| GO:0036444 calcium import into the mitochondrion | IMP PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: MCU null mitochondria lack fast calcium uptake. Reason: Core process, directly shown with a null allele. Supporting Evidence: PMID:31042479 Altogether, these data show that MCU1 is a null mutant incapable of fast Ca2+ uptake. |
| GO:0036444 calcium import into the mitochondrion | NAS PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: Author statement (NAS) that the uniporter mediates mitochondrial calcium uptake. Reason: Core process; duplicate of the IMP row from the same paper. Supporting Evidence: PMID:31042479 While loss of pore-forming MCU or EMRE abolishes fast mitochondrial Ca2+ uptake |
| GO:0051560 mitochondrial calcium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of mitochondrial calcium ion homeostasis (fly MCU FB:FBgn0042185 among donors). Reason: The uniporter is the main route of calcium entry into the matrix and so a principal determinant of mitochondrial calcium levels. Supporting Evidence: PMID:28726639 oxidative stress-induced increases in mitochondrial calcium, mitochondrial membrane potential depolarization, and cell death were prevented in these mutants |
| GO:0051560 mitochondrial calcium ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro (MCU family) mapping to mitochondrial calcium ion homeostasis. Reason: Consistent with MCU's role as the main mitochondrial calcium entry pathway. |
| GO:0051560 mitochondrial calcium ion homeostasis | IMP PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | ACCEPT | Summary: Reconstitution showing MCU-dependent mitochondrial calcium uptake requiring EMRE. Reason: Supports MCU control of matrix calcium; accepted with the other homeostasis rows. Supporting Evidence: PMID:27099988 metazoan MCU homologues from C. elegans and D. melanogaster require EMRE to transport Ca2+ |
| GO:0051560 mitochondrial calcium ion homeostasis | NAS PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: Author statement (NAS) linking the uniporter to mitochondrial calcium homeostasis. Reason: Consistent with the uniporter's role in matrix calcium uptake. Supporting Evidence: PMID:31042479 Mitochondrial Ca2+ uptake is an important mediator of metabolism and cell death. |
| GO:0072375 medium-term memory | IMP PMID:27568554 Inhibiting the Mitochondrial Calcium Uniporter during Develo... | KEEP AS NON CORE | Summary: MCU silencing in mushroom body neurons impairs intermediate-term memory. Reason: Robust phenotype (medium-term memory corresponds to intermediate-term memory) but a downstream, developmental consequence of uniporter function in mushroom body neurons. Supporting Evidence: PMID:27568554 Collectively, these results demonstrate that MCU expression and function are required in MBn to support ITM, but not learning. |
| GO:1990246 uniplex complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of uniplex complex membership (human MCU Q8NE86 and other donors). Reason: MCU is the pore subunit of the uniplex complex; fly MCU requires EMRE and is gated by MICU1, as in mammals. Uniplex complex is accepted for all fly uniporter subunits. Supporting Evidence: PMID:31042479 Co-expression of either MICU1-A or MICU1-B with MCU and EMRE prevented the MCU:EMRE phenotype (Figure 5B). |
| GO:1990246 uniplex complex | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of uniplex complex from human MCU (Q8NE86). Reason: Consistent with fly genetic and biochemical data on the MCU-EMRE-MICU uniporter. |
| GO:1990246 uniplex complex | NAS PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: Author statement (NAS) placing MCU in the uniporter complex. Reason: Core complex membership of the pore subunit. Supporting Evidence: PMID:31042479 This includes loss-of-function mutants for MCU, EMRE, MICU1, and MICU3 (Drosophila lack MCUb and MICU2) |
| GO:1990246 uniplex complex | TAS PMID:31042479 Comprehensive Genetic Characterization of Mitochondrial Ca(2... | ACCEPT | Summary: Traceable author statement placing MCU in the uniporter complex. Reason: Core complex membership; duplicate of the NAS row. Supporting Evidence: PMID:31042479 Here, we report a comprehensive genetic characterization of all known uniporter components conserved in Drosophila. |
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Download this section (compressed HTML)Q: Why does loss of MCU, which abolishes fast mitochondrial calcium uptake, have such mild organismal consequences in flies, and what slower calcium entry pathways compensate?
Experiment: Measure matrix calcium and bioenergetics in MCU null neurons under sustained stimulation to identify MCU-independent mitochondrial calcium entry routes.
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Download this section (compressed HTML)Mitochondrial calcium uniporter (MCU) encodes an inner mitochondrial membrane channel that transports calcium from the mitochondrial intermembrane space to the matrix. It is the main component of the mitochondrial calcium signaling pathway and functions in metabolism, cell death, and olfactory memory.
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