Abstract 274: Mitochondrial Translation Machinery Defects Causes Cardiomyopathy and i <i>n vivo</i> Functional Screening of Therapeutic Targets
Bibliographic record
Abstract
More than 95% of ATP consumed in the heart is derived from oxidative phosphorylation (OxPhos) in the mitochondria. Besides over a thousand proteins encoded by nuclear DNA, mitochondrial gene expression machinery generates 13 proteins for the OxPhos system that employs mitochondrial ribosomal proteins for translation. Mitochondrial ribosome protein S5 (MRPS5) encoded by MRPs gene family, is located at the mammalian mitochondrial ribosome 28S subunit and its importance has not been explored in the heart. Western blotting showed that MRPS5 expression was decreased in TAC-induced hypertrophic mouse hearts ( in vivo ), and in phenylephrine or isoproterenol-stimulated cardiomyocytes ( in vitro ). In the failing hearts of patients, Mrps5-mediated mt-CO1 was markedly decreased as well. To determine the functional role of MRPS5 in the heart, we generated an inducible cardiac-specific knockout mouse and showed that Mrps5-deficient mice developed time-dependent cardiac hypertrophy, fibrosis and heart failure. Mitochondria in the Mrps5-deficient adult cardiomyocytes exhibited membrane swelling and cristae collapsed together with decreased oxygen consumption and ATP production. Mitochondrial calcium homeostasis was also disrupted. Combined analysis of transcriptomics and metabolomics spatiotemporally identified 20 potential target genes associated with Mrps5 deficiency-mediated cardiac pathological processes. Through in vivo functional screening via adeno-associated virus (AAV) mediated gene delivery, we further narrowed down and confirmed that Kruppel-like factor 15 (Klf15) remarkably rescued cardiac phenotype in the Mrps5-deficient mice with maintained mitochondrial homeostasis, suppressed cardiac hypertrophy and fibrosis, as well as preserved cardiac function. Further RNA-sequencing and biochemical analysis mechanistically revealed that genes involved in glycolysis/ gluconeogenesis, PPAR signaling pathway and biosynthesis of amino acids, markedly altered when exploited AAV-Klf15 gene therapy in Mrps5-deficient mice heart. Our results demonstrates Mrps5 is essential for mitochondrial homeostasis and cardiac function and uncovers Klf15 as a potential therapeutic target for treating cardiac mitochondrial diseases.
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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) | 0.000 | 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) | 0.004 | 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".