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.
Highlights
Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce
Various ATP synthase disorders resulting from defects in the structure or assembly of this enzyme complex have been described, including neuropathy, ataxia and retinitis pigmentosa (NARP), a fatal encephalopathy known as Leigh syndrome, and hypertrophic cardiomyopathy[5,6,7]
NaPT markedly improved the respiratory growth of fmc1D yeast in a dose-dependent manner (Fig. 1a). This compound was effective in a cybrid cell line derived from NARP patients carrying the atp6T8993G mutation, a mutation implicated in maternally inherited Leigh’s syndrome[7,18]
Summary
Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Loss of Fmc[1] directly and severely impairs ATP synthase assembly, while secondarily impairing the respiratory chain biogenesis and activity as well as mitochondrial membrane potential[9] These secondary consequences on the respiratory chain are frequently observed in the context of reduced ATP synthase activity[10,11,12,13], and are believed to reflect a regulatory mechanism that maintains a balanced production of ATP synthase and respiratory chain complexes[7,12,14]. TIM17+/– deletion sensitivity (z-score) modification, is sufficient to rescue several phenotypes associated with ATP synthase deficiency Modulating this pathway is effective in cells derived from ATP synthase-disorder patients, demonstrating the conservation of these therapeutic effects. Our study provides the first indication that mitochondrial protein sorting is a promising therapeutic target for the treatment of ATP synthase disorders
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