Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

• Published in: The Journal of clinical investigation 2021-03, Vol.131 (6), p.1-12
• Main Authors: Stenton, Sarah L, Sheremet, Natalia L, Catarino, Claudia B, Andreeva, Natalia A, Assouline, Zahra, Barboni, Piero, Barel, Ortal, Berutti, Riccardo, Bychkov, Igor, Caporali, Leonardo, Capristo, Mariantonietta, Carbonelli, Michele, Cascavilla, Maria L, Charbel Issa, Peter, Freisinger, Peter, Gerber, Sylvie, Ghezzi, Daniele, Graf, Elisabeth, Heidler, Juliana, Hempel, Maja, Heon, Elise, Itkis, Yulya S, Javasky, Elisheva, Kaplan, Josseline, Kopajtich, Robert, Kornblum, Cornelia, Kovacs-Nagy, Reka, Krylova, Tatiana D, Kunz, Wolfram S, La Morgia, Chiara, Lamperti, Costanza, Ludwig, Christina, Malacarne, Pedro F, Maresca, Alessandra, Mayr, Johannes A, Meisterknecht, Jana, Nevinitsyna, Tatiana A, Palombo, Flavia, Pode-Shakked, Ben, Shmelkova, Maria S, Strom, Tim M, Tagliavini, Francesca, Tzadok, Michal, van der Ven, Amelie T, Vignal-Clermont, Catherine, Wagner, Matias, Zakharova, Ekaterina Y, Zhorzholadze, Nino V, Rozet, Jean-Michel, Carelli, Valerio, Tsygankova, Polina G, Klopstock, Thomas, Wittig, Ilka, Prokisch, Holger
• Format: Article
• Language: English
• Subjects: Biomedical research; Causes of; Cell lines; Deoxyribonucleic acid; DNA; Electron transport chain; Family medical history; Females; Genetic aspects; Health aspects; Leber's optic atrophy; Males; Mitochondrial DNA; Mutation; NADH dehydrogenase; NADH-ubiquinone oxidoreductase; Optic atrophy; Optic neuropathy; Physiological aspects; Point mutation; Protein turnover; Proteins; Reactive oxygen species
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI138267

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.