Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis
Bibliographic record
Abstract
Adrenal and gonadal mitochondrial metabolic activity requires electrons from cofactors, cholesterol, and a substrate for rapid steroid synthesis, an essential requirement for mammalian survival.Substrate activity depends on its environment, which is regulated by chaperones and mitochondrial translocases.Cytochrome P450 side-chain cleavage enzyme (SCC or CYP11A1) catalyzes cholesterol to pregnenolone conversion, although its mechanism of action is not well understood.We find that SCC is directly imported into the mitochondrial matrix, where its N-terminal sequence is cleaved sequentially, after which it becomes activated following the second cleavage, which is dependent on the folding of the protein.Following integration of the SCC C terminus into the TIM23 complex, amino acids 141 to 146 interact with the intermembrane-exposed Tim50 protein, forming a large complex.The absence of Tim50 or its mutation reduced enzymatic activity.For the first time, we report that a protein activated at the matrix remains mostly unfolded and is transported back to the IMS to integrate with the TIM23 translocase complex and align with the Tim50 protein.Amino acid changes that suppress the association of Tim50 with SCC ablate metabolic activity.Thus, the TIM23 complex is the central regulator of metabolism guided by Tim50.KEYWORDS mitochondria, pregnenolone, progesterone, protein import, protein folding C ellular metabolism is closely regulated and compartmentalized within distinct subcellular organelles, where mitochondria and the endoplasmic reticulum (ER) play crucial roles in metabolism, as organelle structure and function are dynamically regulated by the intracellular environment.Cells can also respond to stress in a way specific to individual organelles.Specifically, the ER stress response or the unfolded protein response (UPR) is activated in response to mild or short-term stress triggers, inducing the expression of genes involved in the maintenance of ER or mitochondrial function (1).Impaired stress response arises from defects in the adrenal gland, resulting in altered metabolism possibly due to suborganelle disruption (1).The dynamic and complex membranous structures allow the formation of contact sites with other organelles and structures, where contact with mitochondria forms mitochondrionassociated membranes (MAM) that physically interact with the ER for mitochondrial metabolic action (2).The molecular basis of mitochondrial redistribution depends on protein-folding steps in the cytoplasm, as the rapid burst of directed movements is interrupted by pauses in variable motion depending on the cytoplasmic environment (3).The final destination of a protein in the cell is determined by specific sequence elements within
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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 | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.003 |
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".