Sleep and circadian defects in a Drosophila model of mitochondrial encephalomyopathy

Mitochondrial encephalomyopathies (ME) are complex, incurable diseases characterized by severe bioenergetic distress that can affect the function of all major organ systems but is especially taxing to neuromuscular tissues. Animal models of MEs are rare, but the Drosophila ATP6(1) mutant is a stable, well-characterized genetic line that accurately models progressive human mitochondrial diseases such as Maternally-Inherited Leigh Syndrome (MILS), Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP), and Familial Bilateral Striatal Necrosis (FBSN). While it is established that this model exhibits important hallmarks of ME, including excess cellular and mitochondrial reactive oxygen species, shortened lifespan, muscle degeneration, and stress-induced seizures, it is unknown whether it exhibits defects in sleep or circadian function. This is a clinically relevant question, as many neurological and neurodegenerative diseases are characterized by such disturbances, which can exacerbate other symptoms and worsen quality of life. Since Drosophila is highly amenable to sleep and circadian studies, we asked whether we could detect disease phenotypes in the circadian behaviors of ATP6(1). Indeed, we found that day-time and night-time activity and sleep are altered through disease progression, and that circadian patterns are disrupted at both the behavioral and neuronal levels. These results establish ATP6(1) as an important model of sleep and circadian disruption in ME that can be studied mechanistically at the molecular, cellular, and behavioral level to uncover underlying pathophysiology and test novel therapies.