Abstract
Background
Mitochondrial respiratory chain (RC) dysfunction constitutes the biochemical defect underlining a group of heterogenous clinical presentations known as mitochondrial disorders. NDUFA3 is an accessory subunit of Complex I (CI) and has recently been associated with Leigh Syndrome. However, the genetic evidence is limited and no functional analysis is available on the molecular mechanism.
Methods
We investigated the clinical features of the second family with biallelic NDUFA3 variants. The patient’s cells and HEK293T cells with NDUFA3 knock down (KD) were assessed to study the RC dysfunction. A zebrafish model with the morpholino targeting on ndufa3 were generated to study the phenotypes caused by ndufa3 disruption.
Results
The affected boy demonstrated global developmental delay, neurosensory hearing impairment, strabismus, muscle weakness, and hypertonia. He harbored a paternal exonic deletion NC_000019.9:g.54608143_54614387delinsCG and a maternally-inherited missense variant NM_004542.4:c.173G>A; p.(Arg58His). In patient’s cells and HEK293T cells with NDUFA3 KD, reduced levels of NDUFA3 and CI and Complex IV (CIV) were observed, which further impaired endogenous respiration and ATP generation. Re-expression of the wild-type but not the mutant NDUFA3 restored the CI and CIV levels in NDUFA3 deficient cells. Zebrafish with ndufa3 disruption demonstrated ndufa3 KD affected locomotor development.
Conclusions
Our findings confirm the association between NDUFA3 molecular defects and Leigh syndrome spectrum.
Impact
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NDUFA3 deficiency causes a mitochondrial respiration complex deficiency disorder.
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A family with biallelic NDUFA3 variants demonstrates phenotype resembling mitochondrial respiration complex defects.
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NDUFA3 defects reduce the amount of respiration complex I and IV; impair endogenous respiration and ATP generation.
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Zebrafish with ndufa3 knock down manifests delayed locomotor development.
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With this reported patient, the relationship between the gene and disease can be upgraded from “limited” to “moderate”.
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Data availability
The clinical and genetical data were submitted to LOVD (www.lovd.nl/NDUFA3) under the individual accession number 00382950.
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Acknowledgements
We thank the patient’s family for their participation in the study.
Funding
This work was funded by: the Precision Medical Research of National Key Research and Development Program (2022YFC2703400 to Y.Y.), National Natural Science Foundation of China (81830071 to J.L., and 82070914, 82271904 to Y.Y.), Natural Science Foundation of Shanghai (22ZR1451400 to Y.S., 23ZR1452700 to B.X.), National Natural Science Foundation of China-excellent young scientists fund (82222043 to H.F.) and “Pioneer” and “Leading Goose” Research and Development Program of Zhejiang Province (No. 2024C03152, to H.F.), Zhejiang Provincial Natural Science Foundation of China (No. LRG25H200001 to H.F.), Special Research Fund for Central Universities, Peking Union Medical College (No. ACA_202403 to H.F.).
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Yu Sun: Conceptualization, Formal analysis, Funding acquisition, Investigation, Writing-original draft, Writing-review and editing. Xiujuan Wei: Formal analysis, Investigation, Writing-original draft, Writing-review and editing. Bing Xiao: Funding acquisition, Investigation, Writing-original draft, Writing-review and editing. Yongfeng Luo: Investigation, Writing-review and editing. Ya Wang: Investigation, Writing-review and editing. Ripeng Liu: Investigation, Writing-review and editing. Yongkun Zhan: Investigation, Writing-review and editing. Xudong Cai: Investigation, Writing-review and editing. Xiantao Ye: Data curation, Investigation, Writing-review and editing. Shiyi Xu: Investigation, Writing-review and editing. Jianxin Lyu: Investigation, Writing-review and editing. Hezhi Fang: Conceptualization, Funding acquisition, Writing-original draft, Writing-review and editing. Yongguo Yu: Conceptualization, Funding acquisition, Resources, Writing-original draft, Writing-review and editing.
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Sun, Y., Wei, X., Xiao, B. et al. Identification of novel NDUFA3 variants in a patient with mitochondrial disorders. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04403-4
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DOI: https://doi.org/10.1038/s41390-025-04403-4
