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


Book Volume: 5

Article Number: 5585

DOI: 10.1038/ncomms6585


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

How to cite


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.


Aiyar, Raeka S., et al. "Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders." Nature Communications 5 (2014).

BibTeX: Download