Identification and small molecule rescue of mitochondrial dysfunction phenotype which converges across Leigh Syndrome and Huntington’s Disease patient fibroblasts

Mitochondrial dysfunction is implicated in a variety of complex neurological disorders. Primary mitochondrial diseases are caused directly by mutations in genes encoding mitochondrial proteins, leading to mitochondrial dysfunction and disease. Mitochondrial dysfunction is also a key contributor to pathogenesis in multiple neurodegenerative diseases. Rescue of mitochondrial function is therefore an attractive therapeutic target in both groups of diseases. In this study, we used primary fibroblasts derived from patients with the primary mitochondrial disease Leigh syndrome (LS) and the neurodegenerative disease Huntington’s disease (HD) to investigate mitochondrial phenotypes in these patients. We used these to identify modifiable measures of mitochondrial phenotype using a high content imaging screen. Despite having distinct underlying disease causes, different mitochondrial phenotypes in LS and HD patient derived cells converged on an imbalance between functional and dysfunctional mitochondria. Through multi-parameter screening of the mitochondrial phenotype we identified the AMPK activator A769662 as a small molecule able to rescue this imbalance in both LS and HD patient derived fibroblasts via different pathways. Our findings indicate that high throughput screening for mitochondrial phenotypes could identify novel therapeutic agents to rescue mitochondrial dysfunction in complex neurological disorders.