FASEB J. 2026 Sep 30;40(18):e72311. doi: 10.1096/fj.202602631R.
ABSTRACT
Hypertrophic cardiomyopathy (HCM) is frequently linked to sarcomeric gene mutations, yet many familial cases remain unexplained by known pathogenic genes. Transcriptional coactivator TAZ serves as the core effector of the Hippo signaling pathway that regulates cardiomyocyte proliferation and myocardial hypertrophy, and its PDZ-binding motif is critical for maintaining the normal function of TAZ. Deletion of this motif triggers TAZ dysfunction and subsequently induces HCM; however, the underlying molecular mechanism remains to be further elucidated. PDZ-binding motif-deleted TAZ (TAZ-ΔPDZ) was identified as the pathogenic mutation in HCM. Functional experiments revealed that TAZ-ΔPDZ exacerbated phenylephrine (PE)-induced cardiomyocyte hypertrophy, manifested as enlarged cardiomyocyte surface area, upregulated expression of hypertrophy marker proteins (ANP/BNP/β-MHC), and intracellular calcium overload. Mechanistically, TAZ-ΔPDZ blocked the transcriptional activation of mitofusin 2 (MFN2) by T-box transcription factor 5 (TBX5), thereby triggering calcium overload and aggravating myocardial hypertrophy. Further in vivo animal experiments verified that TBX5 overexpression reduced heart size, alleviated myocardial collagen deposition and inflammatory cell infiltration, and decreased intracellular calcium concentration to exert cardioprotective effects; however, TAZ-ΔPDZ markedly reversed such protective effects mediated by TBX5 overexpression. TAZ-ΔPDZ impairs TBX5 transcriptional function, reduces MFN2 expression, triggers cardiomyocyte calcium overload, and ultimately causes cardiac hypertrophy. This study is expected to provide novel insights for the prevention, control, and screening of pathogenic genes underlying hereditary HCM.
PMID:42771491 | DOI:10.1096/fj.202602631R