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<p>Mutations in the <i>AARS2</i> 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 <i>AARS2</i> transcript to mediate its alternative splicing. Cardiomyocyte-specific deletion of <i>Pcbp1</i> in mice impairs normal splicing and causes premature termination of <i>Aars2</i>, leading to defects in heart development and postnatal lethality. Similarly, mice with a deletion in <i>Aars2</i> that mimics a disease-causing splicing lesion display heart developmental abnormalities, reminiscent of those in patients with infantile mitochondrial cardiomyopathy. Mechanistically, loss of <i>Pcbp1</i> or <i>Aars2</i> in the heart reduces oxidative phosphorylation, a hallmark of patients with <i>AARS2</i> 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.</p>

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PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Yao Wei Lu,
  • Zhuomin Liang,
  • Kerry Dorr,
  • Samantha Ruiz,
  • Xiaoran Huang,
  • Denise Fangnibo Hanvi,
  • Sheri M. Juntilla,
  • Gisela Beutner,
  • Shuhan Lyu,
  • Haipeng Guo,
  • Tiago Fernandes,
  • Ramon A. Espinoza-Lewis,
  • Tingting Wang,
  • Kathryn Li,
  • Xue Li,
  • Gurinder Bir Singh,
  • Yi Wang,
  • Rui Deng,
  • Douglas Cowan,
  • John D. Mably,
  • William T. Pu,
  • Jessie Huang,
  • George A. Porter Jr.,
  • Frank Conlon,
  • Hong Chen,
  • Da-Zhi Wang

摘要

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.