Journal Article

DZNE-2026-00494

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Bi-allelic variants in NDUFA5 cause a mitochondriopathy with complex I deficiency.

Tan, N. B. ; Gautschi, M. ; Raum, M. ; Hock, D. H. ; Kopajtich, R. ; Wang, J. ; Qian, X. ; Sharma, T. ; Green, T. E. ; Nuoffer, J.-M. ; Bell, K. M. ; Pospieszny, K. ; Stait, T. ; Pike, C. ; Cao, M. ; White, S. M. ; Thorburn, D. R. ; Brunet, T. ; Wagner, M. ; Müller-Felber, W. ; Zeng, L. H.Extern* ; Klopstock, T.DZNE* ; Schaller, A. ; Liu, J. ; Stroud, D. A. ; Prokisch, H.

2026
Cell Press New York, NY [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ajhg.2026.03.003

Abstract: NDUFA5 encodes a structural subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) located in the peripheral arm of the enzyme complex. Complex I is the largest enzyme of the mitochondrial respiratory chain and is essential for oxidative phosphorylation. There are many well-characterized conditions associated with nuclear-encoded mitochondrial complex I dysfunction, including Leigh syndrome, leukoencephalopathy, lethal infantile mitochondrial disease, hypertrophic cardiomyopathy, and exercise intolerance. The vast majority of these nuclear-encoded mitochondrial complex I deficiencies are autosomal-recessive conditions. To date, variants in NDUFA5 have not been associated with mitochondriopathy in humans. We identified a cohort of four individuals from three unrelated families with bi-allelic variants in NDUFA5. All individuals present with variable multisystem disease in the setting of a mitochondrial complex I deficiency, biochemically proven via an array of respiratory chain enzymology, blue native PAGE, and mass-spectrometry-based proteomics in peripheral blood mononuclear cells, lymphoblastoid cell lines, fibroblasts, and skeletal muscle. Transcriptomics and RT-PCR demonstrated aberrant mRNA expression in all affected individuals. Finally, we generated zebrafish ndufa5 F0 mutants that exhibited defects of morphological development, locomotor deficits, and abnormal brain activity. Our data demonstrate that bi-allelic variants in NDUFA5 cause a mitochondrial complex I deficiency, characterized by a variable multisystem phenotype that encompasses severe congenital heart defects, hematological abnormalities, and neurological involvement consistent with Leigh syndrome.

Keyword(s): Humans (MeSH) ; Electron Transport Complex I: deficiency (MeSH) ; Electron Transport Complex I: genetics (MeSH) ; Animals (MeSH) ; Mitochondrial Diseases: genetics (MeSH) ; Mitochondrial Diseases: pathology (MeSH) ; Zebrafish: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; NADH Dehydrogenase: genetics (MeSH) ; Alleles (MeSH) ; Pedigree (MeSH) ; Mitochondria: genetics (MeSH) ; Mitochondria: pathology (MeSH) ; Mutation (MeSH) ; Muscle, Skeletal: pathology (MeSH) ; Muscle, Skeletal: metabolism (MeSH) ; Leigh Disease: genetics (MeSH) ; Child (MeSH) ; Child, Preschool (MeSH) ; CI deficiency ; NDUFA5 ; complex I deficiency ; mitochondrial disease ; mitochondriopathy ; Electron Transport Complex I ; NADH Dehydrogenase

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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