Discovery of EMRE in fungi resolves the true evolutionary history of the mitochondrial calcium uniporter
Bibliographic record
Abstract
Abstract Mitochondrial calcium (mt-Ca 2+ ) uptake is central for the regulation of numerous cellular processes in eukaryotes 1 . This occurs through a highly selective Ca 2+ uniporter located at the inner mitochondrial membrane and driven by the membrane potential 2–4 . While the physiological role of the uniporter was extensively studied for decades, its genetic identity was only recently determined, with MCU 5,6 , MICU1 7 and EMRE 8 constituting pore-forming and regulatory subunits. Preliminary evolutionary analyses suggested an ancient eukaryotic origin of mt-Ca 2+ uptake, but also pinpointed inconsistent phylogenetic distributions of MCU, MICU1, and EMRE within fungi, where homologs of MCU were present in the absence of the supposedly essential regulators, MICU1 and EMRE 9,10 . Here, we perform the most comprehensive phylogenomic analysis of the mt-Ca 2+ uptake system and trace its evolution across 1,156 fully-sequenced eukaryotes. In contrast to earlier assumptions 9–11 we find compelling evidence that previously identified animal and fungal MCUs, the targets of several structural and functional efforts 11–16 , represent two distinct paralogous subfamilies originating from an ancestral duplication. We further uncover a complete “animal-like” uniporter complex within chytrid fungi, including bona-fide orthologs of MCU, MICU1, and EMRE. This first identification of EMRE outside Holozoa (animals and their unicellular relatives) and its strong coevolution with “animal-like” MICU1 and MCU indicates that these three components formed the core of the ancestral opisthokont uniporter. We confirm this finding experimentally, by showing that chytrid EMRE orthologs in combination with either human or “animal-like” MCUs, but not with “fungal-specific” MCUs, can reconstitute mt-Ca 2+ uptake in vivo in the yeast Saccharomyces cerevisiae . Hence, we here solve a purported evolutionary paradox: the presence of MCU homologs in fungal species devoid of other uniporter components and with no detectable mt-Ca 2+ uptake. Altogether, our study clarifies the evolution of the mt-Ca 2+ uniporter and identifies new important targets for comparative structural and functional studies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".