Defects in the mitochondrial genome (mtDNA) are a significant cause of clinically important neurological disease. Despite this recognition and the small size of the mitochondrial genome, the underlying disease mechanisms remain uncertain. Thus, though diagnosis is possible, it is difficult for clinicians to offer more than limited help to patients. This project aims to elucidate the connection between a mtDNA mutation and the resulting neurological disorder by undertaking, for the first time, a thorough examination of the proximal defects occurring within the neurons themselves. This will be done by creating transmitochondrial cybrids in human, adult-derived embryonal carcinoma cells (not embryonic stem cells) and thereby establishing a model system of mitochondrial disorders in human-derived, cultured neurons. The cellular defects of the neurons will be characterized by analyzing the development, neurotransmitter expression, electrophysiology, cell death sensitivity, and bioenergetics of the neurons. Hopefully, the knowledge of the specific defects at the cellular level will allow better targeting for therapy of disorders of the mitochondrial respiratory chain.
