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Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay

Journal of Human Genetics volume 65, pages 231–240 (2020)Cite this article

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Abstract

TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Here, we identified two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] from a patient with severe anemia, lactic acidosis, and developmental delay. Patient-derived immortalized lymphocytes showed decreased TOM70 expression, oligomerized TOM70 complex, and TOM 20/22/40 complex compared with expression in control lymphocytes. Functional analysis revealed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects, with complex IV being primarily affected. As a result, patient-derived cells grew slower in galactose medium and generated less ATP and more extracellular lactic acid than did control cells. In vitro cell model compensatory experiments confirmed the pathogenicity of TOMM70 variants since only wild-type TOM70, but not mutant TOM70, could restore the complex IV defect and TOM70 expression in TOM70 knockdown U2OS cells. Altogether, we report the first case of mitochondrial disease-causing mutations in TOMM70 and demonstrate that TOM70 is essential for multi-OXPHOS assembly. Mutational screening of TOMM70 should be employed to identify mitochondrial disease-causing gene mutations in the future.

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Acknowledgements

This work has been made possible by the National Natural Science Foundation of China (key program, 81830071; emergency program, 81741061); Zhejiang Provincial Natural Science Foundation of China (LY19H040004); the Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A).

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  1. These authors contributed equally: Xiujuan Wei, Miaomiao Du, Jie Xie

Authors and Affiliations

  1. Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Xiujuan Wei, Miaomiao Du, Jie Xie, Ting Luo, Yan Zhou, Kun Zhang, Jin Li, Deyu Chen, Pu Xu, Manli Jia, Huaibin Zhou, Hezhi Fang & Jianxin Lyu

  2. Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310053, Zhejiang, China

    Jianxin Lyu

  3. Department of Pediatrics, Peking University First Hospital, 100034, Beijing, China

    Yanling Yang

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Contributions

JL and YY planned the project and designed the experiments. YY collected samples. XW, MD, JX, TL, KZ, YZ, JL, DC, PX, MJ and HF performed the biochemical experiments. HF and XW wrote the manuscript.

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Correspondence to Hezhi Fang, Jianxin Lyu or Yanling Yang.

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Wei, X., Du, M., Xie, J. et al. Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay. J Hum Genet 65, 231–240 (2020). https://doi.org/10.1038/s10038-019-0714-1

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