Abstract

Energy metabolism is essential for providing the energy necessary to ensure proper cellular function. Mutations in genes regulating this process lead to inherited metabolic disorders that can particularly affect tissues with high energy demands like the brain. The limited access to patient neural tissue and the difficulty to manipulate mitochondrial DNA complicates the development of transgenic animal models and cellular models, which are needed for treatment dis-covery. In this talk, I will summarize our efforts in using patient-derived and engineered induced pluripotent stem cells (iPSCs) to study mitochondrial neurological diseases. I will show examples of this approach in the context of Huntington´s disease (HD) and Leigh syndrome (LS), which is the most frequent and most severe mitochondrial disease affecting 1/40,000 newborns. We show that neuronal cultures and brain organoids derived from HD and LS-specific iPSCs can be used as model systems to investigate the neuropathological mechanisms and to carry out phenotypic compound screenings. Our data pave the way to the identification of disease-modifying therapies for currently incurable neurological and mitochondrial disorders.