Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

Abstract

SUMMARYMitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

Mitochondria and the dynamic control of stem cell homeostasis

“…This is the case for both mouse embryonic NPCs and adult NPCs, which activate the OXPHOS program already during the initial stages of neurogenesis . NPCs derived from human PSCs also display a tubular mitochondrial network and OXPHOS‐dependent metabolism when they are generated and cultured using leukemia inhibitory factor (LIF) , itself capable of activating mitochondrial respiration .…”

Personalized medicine in a dish: the growing possibility of neuropsychiatric disease drug discovery tailored to patient genetic variants using stem cells

“…Over the course of neuronal differentiation from hiPSCs, mitochondria shift toward a neuronal-like oxidative metabolism. hiPSC-derived NPCs derived from three patients with homoplasmic mitochondrial mutations in MT-ATP6 not only retained the mutant genotype, but also exhibited disease relevant phenotypes such as decreased ATP production, abnormally high mitochondrial membrane potential, and altered calcium homeostasis (31). Moreover, as a proof-of-concept, they successfully screened 130 drugs on NPCs derived from one of these patients, identifying ten compounds that significantly reduced mitochondrial membrane potential (31).…”

“…Variation between mitochondrial populations in donor cells, disease cells and hiPSC-derived populations remains a similar concern for mitochondrial disorders. Although it is clear that a homoplasmic mitochondrial population can be accurately maintained and modeled using hiPSC-based models (31), the extent to which that is true for heteroplasmic mitochondrial disorders is unknown.…”

A step forward in disease modelling for mitochondrial diseases

“…Recently, the group of Alessandro Prigione published an excellent paper, of great interest in this field of science, presenting a novel approach to mitochondrial disease modelling and drug discovery using multipotent neural progenitor cell (NPC) and neurons, derived from PSC (11).…”