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Original research
MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction
  1. Kunqian Ji1,2,
  2. Yan Lin1,
  3. Xuebi Xu3,
  4. Wei Wang1,
  5. Dongdong Wang1,
  6. Chen Zhang4,
  7. Wei Li1,
  8. Yuying Zhao1,
  9. Chuanzhu Yan1,2,5
  1. 1Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong, China
  2. 2Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases of Shandong University, Jinan, China
  3. 3Department of Neurology, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang, China
  4. 4Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingda, China
  5. 5Brain Science Research Institute of Shandong University, Jinan, China
  1. Correspondence to Professor Chuanzhu Yan, Jinan, China; czyan{at}


Background Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have drawn much attention, among them, mutations in mitochondrial tRNA genes possessing prominent status. However, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear and there are very few effective therapies available to date.

Methods We performed muscle histochemistry, genetic analysis, molecular dynamic stimulation and measurement of oxygen consumption rate and respiratory chain complex activities to demonstrate the molecular pathomechanisms of m.5541C>T mutation. Moreover, we use cybrid cells to investigate the potential of taurine to rescue mitochondrial dysfunction caused by this mutation.

Results We found a pathogenic m.5541C>T mutation in the tRNATrp gene in a large MELAS family. This mutation first affected the maturation and stability of tRNATrp and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction. Surprisingly, we identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.

Conclusion The m.5541C>T mutation disturbed the translation machinery of mitochondrial tRNATrp and taurine supplementation may be a potential treatment for patients with m.5541C>T mutation. Further studies are needed to explore the full potential of taurine supplementation as therapy for patients with this mutation.

  • neuromuscular diseases
  • neurology
  • molecular medicine

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  • YZ and CY contributed equally.

  • Contributors KJ designed the study and statistical analyses, drafted and revised the manuscript. YL, XB, WW and DW were in charge of the genetic analysis, biochemical studies, and oxygen consumption analysis, respectively. WL and CZ were in charge of muscle histochemistry. YZ and CY revised the manuscript and are co-corresponding authors.

  • Funding This study was supported by the National Natural Science Foundation of China (nos. 81701237 and 81671235), People’s Benefit Project of Science and Technology in Qingdao (16-6-2-1-nsh) and the Taishan Scholars Programme of Shandong Province.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the medical Ethics Committee of Qilu Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplemental information.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.