Induced pluripotent stem cell–based leber hereditary optic neuropathy model

Abstract Leber’s hereditary optic neuropathy (LHON) is the maternally inherited mitochondrial disease caused by homoplasmic mutations in the mitochondrial electron transport chain. The pathological mechanism of LHON is still unclear. The feature of incomplete penetrance indicates that complex factors are involved in the phenotypic expression of LHON. Therefore, the application of appropriate experimental models in the etiology of LHON requires further understanding. The traditional cell models of LHON were non-neuronal cells carrying mtDNA mutation, such as patient fibroblasts and cybrid cells, however, mutation is necessary but not sufficient to cause LHON. Ideal models of LHON should be capable of presenting incomplete penetrance that distinguishes healthy carrier cells from affected cells. In this chapter, we review the pathophysiology of LHON as it relates to old, new, and future models. We further compare the advantages and disadvantages of different models of LHON and clarify unanswered questions that might help to explore the new model in the future.