Chapter 5 - Modeling mitochondrial encephalopathy due to MELAS/Leigh overlap syndrome using induced pluripotent stem cells

Abstract

Mitochondrial disease presents a variety of clinical manifestations such as encephalopathy, diabetes, and cardiomyopathy. Mitochondrial encephalopathy includes mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome (LS), and MELAS/Leigh overlap syndrome. Mitochondrial encephalopathy has been modeled to reveal pathogenesis, but this is also a challenging task. In this chapter, we discuss issues that must be considered for modeling mitochondrial encephalopathy using induced pluripotent stem cells (iPSCs). Based on the fact that iPSCs were established from the fibroblasts carrying a high proportion of random mitochondrial DNA (mtDNA) mutations, the mitochondrial function was not essential for reprogramming. Reprogramming efficiencies, however, differed from genotypes of mDNA mutations. Although the energy metabolism of iPSCs shifted from oxidative phosphorylation (OXPHOS) to anaerobic glycolysis, the metabolic signature of iPSCs was affected by a mutation of mtDNA, which encoded a subunit of OXPHOS enzymes. Emerging genome editing technologies were also successfully applied to mtDNA and may provide further evidence of the pathophysiological mechanisms in mitochondrial diseases in vitro. Furthermore we discuss the usefulness of neuronal three-dimensional differentiation models using iPSCs. This will allow us to elucidate the pathogenesis of encephalopathy in the context of vascular angiopathy in MELAS/Leigh overlap syndrome.