Nature cardiovascular research · 2026
PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.
СтатьяНазвание и аннотация: Перевод в очереди
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Lu Yao Wei, Liang Zhuomin, Dorr Kerry, Ruiz Samantha, Huang Xiaoran, Fangnibo Hanvi Denise, Juntilla Sheri M, Beutner Gisela, Lyu Shuhan, Guo Haipeng, Fernandes Tiago, Espinoza-Lewis Ramon A, Wang Tingting, Li Kathryn, Li Xue, Bir Singh Gurinder, Wang Yi, Deng Rui, Cowan Douglas, Mably John D, Pu William T, Huang Jessie, Porter George A, Conlon Frank, Chen Hong, Wang Da-Zhi
Аннотация
Mutations in the AARS2 gene are linked to infantile cardiomyopathy; however, the underlying molecular mechanism remains unknown. Here we report that PCBP1, a poly(rC) binding protein, interacts with the AARS2 transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of Pcbp1 in mice impairs normal splicing and causes premature termination of Aars2, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in Aars2 that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of Pcbp1 or Aars2 in the heart reduces oxidative phosphorylation, a hallmark of patients with AARS2 mutations. This reduction in mitochondrial-encoded proteome activates mitonuclear communication and the unfolded protein response pathway, thereby inducing a compensatory nuclear-encoded mitochondrial gene program. Our findings provide insights into the PCBP1-AARS2 regulatory axis in mitochondrial cardiomyopathy.