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TRalpha Deficiency Drives Sarcopenia by Disrupting Perimitochondrial Targeting of Pink1 mRNA and Mitophagy

ABSTRACT: Skeletal muscle-specific ablation of thyroid hormone receptor alpha (TRalpha) in young mice is sufficient to recapitulate key phenotypic hallmarks of age-related sarcopenia—including myofiber atrophy, exercise intolerance, and mitochondrial quality control failure—establishing receptor decline as a cell-autonomous driver of sarcopenia pathogenesis rather than a passive biomarker. The underlying mechanism reveals how systemic endocrine signals culminate in organelle-specific quality control defects: TRalpha transcriptionally drives the RNA-binding protein CLUH, which facilitates the perimitochondrial enrichment of Pink1 mRNA for localized synthesis of the mitophagy-initiating kinase. Consequently, TRalpha loss disrupts perimitochondrial Pink1 mRNA localization, impairing local PINK1 abundance and mitophagic priming, leading to accumulation of damaged mitochondria. Restoring CLUH expression rescues Pink1 mRNA spatial localization, mitophagy flux, and cellular senescence markers in both TRalpha-deficient myofibers and naturally aged muscle cells. These findings identify spatial transcriptome organization as an underappreciated regulatory layer in muscle wasting and provide a genetically defined framework linking endocrine decline to organelle-level post-transcriptional regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE318551 | GEO | 2026/02/05

REPOSITORIES: GEO

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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

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TRalpha Deficiency Drives Sarcopenia by Disrupting Perimitochondrial Targeting of Pink1 mRNA and Mitophagy

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