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<p>Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD<sup>+</sup> salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD<sup>+</sup> transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low <i>SLC25A51</i> expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of <i>Nampt</i>, <i>Nmnat1</i>, <i>Nmnat3</i>, <i>Slc25a51</i>, <i>Nadk2</i> and <i>Aldh18a1</i>, genes involved in NAD<sup>+</sup> salvage and transport, induced aortic aneurysm, with <i>Slc25a51</i> deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.</p>

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Mitochondrial NAD+ deficiency in vascular smooth muscle impairs collagen III turnover to trigger thoracic and abdominal aortic aneurysm

  • 期刊论文

  • 发表日期：

    2025年1月22日

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  • Jingjing Zhang,
  • Yuyi Tang,
  • Shan Zhang,
  • Zhuxin Xie,
  • Wenrui Ma,
  • Shaowen Liu,
  • Yixuan Fang,
  • Shufen Zheng,
  • Ce Huang,
  • Guoquan Yan,
  • Mieradilijiang Abudupataer,
  • Yue Xin,
  • Jingqiao Zhu,
  • Wenjing Han,
  • Weizhong Wang,
  • Fenglin Shen,
  • Hao Lai,
  • Yang Liu,
  • Dan Ye,
  • Fa-Xing Yu,
  • Yanhui Xu,
  • Cuiping Pan,
  • Chunsheng Wang,
  • Kai Zhu,
  • Weijia Zhang

摘要

Thoracic and abdominal aortic aneurysm poses a substantial mortality risk in adults, yet many of its underlying factors remain unidentified. Here, we identify mitochondrial nicotinamide adenine dinucleotide (NAD)⁺ deficiency as a causal factor for the development of aortic aneurysm. Multiomics analysis of 150 surgical aortic specimens indicated impaired NAD+ salvage and mitochondrial transport in human thoracic aortic aneurysm, with expression of the NAD+ transporter SLC25A51 inversely correlating with disease severity and postoperative progression. Genome-wide gene-based association analysis further linked low SLC25A51 expression to risk of aortic aneurysm and dissection. In mouse models, smooth muscle-specific knockout of Nampt, Nmnat1, Nmnat3, Slc25a51, Nadk2 and Aldh18a1, genes involved in NAD+ salvage and transport, induced aortic aneurysm, with Slc25a51 deletion producing the most severe effects. Using these models, we suggest a mechanism that may explain the disease pathogenesis: the production of type III procollagen during aortic medial matrix turnover imposes a high demand for proline, an essential amino acid component of collagen. Deficiency in the mitochondrial NAD⁺ pool, regulated by NAD⁺ salvage and transport, hinders proline biosynthesis in mitochondria, contributing to thoracic and abdominal aortic aneurysm.