From passage to inhibition: Uncovering the structural and physiological inhibitory mechanisms of <scp>MCUb</scp> in mitochondrial calcium regulation
Bibliographic record
Abstract
Abstract Mitochondrial calcium (Ca 2+ ) regulation is critically implicated in the regulation of bioenergetics and cell fate. Ca 2+ , a universal signaling ion, passively diffuses into the mitochondrial intermembrane space (IMS) through voltage‐dependent anion channels (VDAC), where uptake into the matrix is tightly regulated across the inner mitochondrial membrane (IMM) by the mitochondrial Ca 2+ uniporter complex (mtCU). In recent years, immense progress has been made in identifying and characterizing distinct structural and physiological mechanisms of mtCU component function. One of the main regulatory components of the Ca 2+ selective mtCU channel is the mitochondrial Ca 2+ uniporter dominant‐negative beta subunit (MCUb). The structural mechanisms underlying the inhibitory effect(s) exerted by MCUb are poorly understood, despite high homology to the main mitochondrial Ca 2+ uniporter (MCU) channel‐forming subunits. In this review, we provide an overview of the structural differences between MCUb and MCU, believed to contribute to the inhibition of mitochondrial Ca 2+ uptake. We highlight the possible structural rationale for the absent interaction between MCUb and the mitochondrial Ca 2+ uptake 1 (MICU1) gatekeeping subunit and a potential widening of the pore upon integration of MCUb into the channel. We discuss physiological and pathophysiological information known about MCUb, underscoring implications in cardiac function and arrhythmia as a basis for future therapeutic discovery. Finally, we discuss potential post‐translational modifications on MCUb as another layer of important regulation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".