2. Academic Validation
  3. NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish

NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish

  • Cell Death Discov. 2025 Mar 1;11(1):82. doi: 10.1038/s41420-025-02369-0.
Yen-Lin Chen # 1,  Brian Hon-Yin Chung # 2,  Masakazu Mimaki 3,  Shumpei Uchino 3 4,  Yin-Hsiu Chien 5 6,  Christopher Chun-Yun Mak 2,  Steven Shinn-Forng Peng 7,  Wei-Chen Wang 1,  Yu-Li Lin 8,  Wuh-Liang Hwu 5 6,  Shyh-Jye Lee 9 10 11,  Ni-Chung Lee 12 13
Affiliations

Affiliations

  • 1 Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan.
  • 2 Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • 3 Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173-8605, Japan.
  • 4 Department of Pediatrics, The University of Tokyo, Tokyo, 113-8655, Japan.
  • 5 Department of Medical Genetics, National Taiwan University Hospital, Taipei, 10041, Taiwan.
  • 6 Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 10041, Taiwan.
  • 7 Department of Radiology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 10002, Taiwan.
  • 8 Department of Medical Research, National Taiwan University Hospital, Taipei, 10041, Taiwan.
  • 9 Department of Life Science, National Taiwan University, Taipei, 10617, Taiwan. jefflee@ntu.edu.tw.
  • 10 Center for Biotechnology, National Taiwan University, Taipei, 10617, Taiwan. jefflee@ntu.edu.tw.
  • 11 Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 10617, Taiwan. jefflee@ntu.edu.tw.
  • 12 Department of Medical Genetics, National Taiwan University Hospital, Taipei, 10041, Taiwan. ncleentu@ntu.edu.tw.
  • 13 Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 10041, Taiwan. ncleentu@ntu.edu.tw.
  • # Contributed equally.
PMID: 40025060 DOI: 10.1038/s41420-025-02369-0
Abstract

Complex I of the mitochondrial electron transfer chain is one of the largest membrane protein assemblies ever discovered. A patient carrying a homozygous NDUFB7 intronic mutation died within two months after birth due to cardiorespiratory defects, preventing further study. Here, we report another patient with compound heterozygous mutations in NDUFB7 who suffers from pons abnormality, lactic acidosis, prematurity, prenatal and postnatal growth deficiency, incomplete closure of the abdominal wall (ventral hernia), and a poorly functioning gastrointestinal tract (pseudo-obstruction). We demonstrated that the patient's skin fibroblasts are deficient in Complex I assembly and reduced supercomplex formation. This report further broadens the spectrum of mitochondrial disorders. The patient has had several surgeries. After receiving treatment with Coenzyme Q10 and vitamin B complex, she has remained stable up to this point. To further explore the functionality of NDUFB7 in vivo, we knocked down Ndufb7 in zebrafish embryos. This resulted in brain ventricle and neuronal defects, elevated lactic acid levels, and reduced oxygen consumption, indicating defective mitochondrial respiration. These phenotypes can be specifically rescued by ectopic expression of ndufb7. More importantly, Mitoquinone mesylate (MitoQ), a common remedy for mitochondrial disorders, can ameliorate these conditions. These results suggest a role for NDUFB7 in mitochondrial activity and the suitability of the zebrafish model for further drug screening and the development of therapeutic strategies for this rare disease.

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