Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders
Aiyar RS, Bohnert M, Duvezin-Caubet S, Voisset C, Gagneur J, Fritsch ES, Couplan E, Von Der Malsburg K, Funaya C, Soubigou F, Courtin F, Suresh S, Kucharczyk R, Evrard J, Antony C, St Onge RP, Blondel M, Di Rago JP, Van Der Laan M, Steinmetz LM (2014)
Publication Type: Journal article
Publication year: 2014
Journal
Book Volume: 5
Article Number: 5585
DOI: 10.1038/ncomms6585
Abstract
Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases.
Involved external institutions
European Molecular Biology Laboratory (EMBL)
Germany (DE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Institut national de physique nucléaire et de physique des particules (IN2P3)
France (FR)
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
France (FR)
Stanford University
United States (USA) (US)
Polska Akademia Nauk (PAN) / Polish Academy of Sciences
Poland (PL)
Germany (DE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Institut national de physique nucléaire et de physique des particules (IN2P3)
France (FR)
National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM)
France (FR)
Stanford University
United States (USA) (US)
Polska Akademia Nauk (PAN) / Polish Academy of Sciences
Poland (PL)
How to cite
APA:
Aiyar, R.S., Bohnert, M., Duvezin-Caubet, S., Voisset, C., Gagneur, J., Fritsch, E.S.,... Steinmetz, L.M. (2014). Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders. Nature Communications, 5. https://doi.org/10.1038/ncomms6585
MLA:
Aiyar, Raeka S., et al. "Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders." Nature Communications 5 (2014).
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