Prohibitins are required for the induction of mitochondrial quality control mechanisms and the integrated stress response in skeletal muscle cells
Bibliographic record
Abstract
Skeletal muscle health is dependent on the mitochondria that reside within it to maintain its function and metabolic flexibility. Chronic exercise has proven to be a potent intervention for the enhancement of the mitochondrial reticulum, indicating that training is a powerful strategy to improve muscle health. While our understanding of exercise-induced mitochondrial adaptations has been established, the key regulators underlying these processes remain underexplored. To investigate novel exercise-responsive mitochondrial regulators, a unique mitochondrial complex comprised of proteins Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2) were evaluated. Found within the inner mitochondrial membrane, PHBs have been implicated in several mitochondrial quality control (MQC) pathways, including biogenesis, mitophagy, and mitochondrial morphology, positioning them as critical regulators of mitochondrial function. Given the role of PHBs in various aspects of mitochondrial homeostasis, this would suggest that PHBs are required to mediate MQC pathways and permit exercise-induced mitochondrial adaptations. To examine this, PHB1 and PHB2 expression were targeted using short-interfering RNA within C2C12 myotubes and electrically stimulated for four days to induce contractile activity. Myotubes were then collected for protein measurements via western blotting techniques. Following a 56% reduction in both PHB1 and PHB2 protein, there was a marked decline in indicators of mitochondrial biogenesis, evident through a 38% reduction in mitochondrial transcription factor A (TFAM) and several mitochondrial-related proteins, including a 50% reduction in UQCRC2, a component of the electron transport chain. Mitochondrial fusion-related protein optic atrophy-1 (OPA-1) was significantly reduced, indicating that mitochondrial morphology is also affected with PHB silencing. These mitochondrial alterations were accompanied by the phosphorylation of eIF2α and upregulation of the transcription factor CHOP, which together are activated in response to cellular stress and dysfunction. Furthermore, a 3-fold increase in PINK1 protein was observed, indicating that the cellular stress observed may be mitochondrial-specific, as PINK1 is rapidly imported and degraded within healthy mitochondria. Contractile activity-induced mitochondrial adaptations were ablated with PHB knockdown, suggesting that PHBs may be required for the induction of MQC pathways by muscle contraction. These findings demonstrate that PHBs play a critical role in facilitating MQC, offering compelling new insight into the molecular mechanisms underpinning mitochondrial maintenance and adaptations observed in muscle with exercise. This work was supported by funds from the Natural Science and Engineering Research Council (NSERC). David A. Hood is the holder of a Canadian Research Chair in Cell Physiology. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.001 | 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".