BioProject

Mitochondrial DNA (mtDNA) mutations predominantly cause neurological diseases. More...

Mitochondrial DNA (mtDNA) mutations predominantly cause neurological diseases. Searching for therapeutic strategies is hindered by the absence of viable neural model systems due to the challenges of engineering mtDNA. We demonstrate that neural progenitor cells (NPCs), rapidly obtained from human induced pluripotent stem cells (iPSCs), retain the parental mtDNA profile and exhibit mitochondrial maturation coupled with a metabolic switch away from glycolysis. Altered calcium homeostasis and mitochondrial hyperpolarization, both potential causes of neural impairment, were observed in iPSC-derived NPCs from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C). Phenotype-based high-content screenings (HCS) with FDA-approved compounds were then carried out, leading to the identification of possible innovative counteracting agents. We propose iPSC-derived NPCs, displaying mild proliferative properties and proper genotype/metabotype, as a bona fide model system for the establishment of personalized phenotypic drug discovery for untreatable mtDNA disorders affecting the nervous system. Overall design: In the first part of the work, Neural Induction (NI) NPCs were generated from PSCs (hESCs and iPSCs) and compared to NPCs derived using a rosette-based approach (rNPCs) and NPCs derived ex vivo from adult human brain (eNPCs). In the second part of the work, control fibroblasts, control PSCs, and control NI NPCs were compared to fibroblasts, iPSCs, and NI NPCs derived from three patients carrying a mutation in the mitochondrial gene MT-ATP6 (m.9185T>C). Less...