Scholarlink

<p>Ataxia telangiectasia (AT) is a rare multisystem disorder caused by the loss of functional ATM protein, leading to immunodeficiency, cancer predisposition, neurodegeneration, diabetes, heart failure, and premature aging. Although ATM’s role as a sensor of DNA double-strand breaks (DSBs) is well established, the mechanisms underlying the diverse AT phenotypes remain incompletely understood, with evidence suggesting they extend beyond DSB sensing. Here, we uncover widespread glycogen accumulation as a key feature of AT cells and tissues, driven by dysregulated glucose metabolism and impaired mitochondrial respiration assessed with a multidimensional approach including metabolomics, flux analysis, histopathology, bioenergetic measurements, and electron tomography. These metabolic defects contribute to reduced cellular viability and premature senescence observed in AT patient-derived cells. Strikingly, inactivation of FNIP2, which controls mitochondrial respiration, partially rescues these defects in AT cellular models. We show that FNIP2 interacts with the SERCA2b calcium channel, and its inactivation enhances cytoplasmic calcium availability, stimulating mitochondrial respiration and increasing glucose consumption. This metabolic reprogramming prevents glycogen accumulation and improves survival in AT primary cells. Our findings provide novel insights into AT pathophysiology and indicate the FNIP2-SERCA2b axis as a novel potential target for mitigating the systemic effects of AT and improving outcomes in this complex disease.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting the FNIP2-SERCA2b axis improves metabolic and mitochondrial defects in Ataxia Telangiectasia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月2日

查看全文
  • Maria Vinciguerra,
  • Catiana El Kharef,
  • Christopher Bruhn,
  • Lucia Falbo,
  • Chiara Milanese,
  • Matteo Audano,
  • Galina V. Beznoussenko,
  • Alexander A. Mironov,
  • Domenico Delia,
  • Marco Foiani,
  • Pier Giorgio Mastroberardino,
  • Nico Mitro,
  • Vincenzo Costanzo

摘要

Ataxia telangiectasia (AT) is a rare multisystem disorder caused by the loss of functional ATM protein, leading to immunodeficiency, cancer predisposition, neurodegeneration, diabetes, heart failure, and premature aging. Although ATM’s role as a sensor of DNA double-strand breaks (DSBs) is well established, the mechanisms underlying the diverse AT phenotypes remain incompletely understood, with evidence suggesting they extend beyond DSB sensing. Here, we uncover widespread glycogen accumulation as a key feature of AT cells and tissues, driven by dysregulated glucose metabolism and impaired mitochondrial respiration assessed with a multidimensional approach including metabolomics, flux analysis, histopathology, bioenergetic measurements, and electron tomography. These metabolic defects contribute to reduced cellular viability and premature senescence observed in AT patient-derived cells. Strikingly, inactivation of FNIP2, which controls mitochondrial respiration, partially rescues these defects in AT cellular models. We show that FNIP2 interacts with the SERCA2b calcium channel, and its inactivation enhances cytoplasmic calcium availability, stimulating mitochondrial respiration and increasing glucose consumption. This metabolic reprogramming prevents glycogen accumulation and improves survival in AT primary cells. Our findings provide novel insights into AT pathophysiology and indicate the FNIP2-SERCA2b axis as a novel potential target for mitigating the systemic effects of AT and improving outcomes in this complex disease.