Enhanced mitochondrial buffering prevents Ca<sup>2+</sup> overload in naked mole‐rat brain
Bibliographic record
Abstract
Abstract Deleterious Ca 2+ accumulation is central to hypoxic cell death in the brain of most mammals. Conversely, hypoxia‐mediated increases in cytosolic Ca 2+ are retarded in hypoxia‐tolerant naked mole‐rat brain. We hypothesized that naked mole‐rat brain mitochondria have an enhanced capacity to buffer exogenous Ca 2+ and examined Ca 2+ handling in naked mole‐rat cortical tissue. We report that naked mole‐rat brain mitochondria buffer >2‐fold more exogenous Ca 2+ than mouse brain mitochondria, and that the half‐maximal inhibitory concentration (IC 50 ) at which Ca 2+ inhibits aerobic oxidative phosphorylation is >2‐fold higher in naked mole‐rat brain. The primary driving force of Ca 2+ uptake is the mitochondrial membrane potential (Δψ m ), and the IC 50 at which Ca 2+ decreases Δψ m is ∼4‐fold higher in naked mole‐rat than mouse brain. The ability of naked mole‐rat brain mitochondria to safely retain large volumes of Ca 2+ may be due to ultrastructural differences that support the uptake and physical storage of Ca 2+ in mitochondria. Specifically, and relative to mouse brain, naked mole‐rat brain mitochondria are larger and have higher crista density and increased physical interactions between adjacent mitochondrial membranes, all of which are associated with improved energetic homeostasis and Ca 2+ management. We propose that excessive Ca 2+ influx into naked mole‐rat brain is buffered by physical storage in large mitochondria, which would reduce deleterious Ca 2+ overload and may thus contribute to the hypoxia and ischaemia‐tolerance of naked mole‐rat brain. image Key points Unregulated Ca 2+ influx is a hallmark of hypoxic brain death; however, hypoxia‐mediated Ca 2+ influx into naked mole‐rat brain is markedly reduced relative to mice. This is important because naked mole‐rat brain is robustly tolerant against in vitro hypoxia, and because Ca 2+ is a key driver of hypoxic cell death in brain. We show that in hypoxic naked mole‐rat brain, oxidative capacity and mitochondrial membrane integrity are better preserved following exogenous Ca 2+ stress. This is due to mitochondrial buffering of exogenous Ca 2+ and is driven by a mitochondrial membrane potential‐dependant mechanism. The unique ultrastructure of naked mole‐rat brain mitochondria, as a large physical storage space, may support increased Ca 2+ buffering and thus hypoxia‐tolerance.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".