Disease models of Leigh syndrome: From yeast to organoids

Abstract

Leigh syndrome (LS) is a severe mitochondrial disease that results from mutations in the nuclear or mitochondrial DNA that impairs cellular respiration and ATP production. Mutations in more than 100 genes have been demonstrated to cause LS. The disease most commonly affects brain development and function, resulting in cognitive and motor impairment. The underlying pathogenesis is challenging to ascertain due to the diverse range of symptoms exhibited by affected individuals and the variability in prognosis. To understand the disease mechanisms of different LS-causing mutations and to find a suitable treatment, several different model systems have been developed over the last 30 years. This review summarizes the established disease models of LS and their key findings. Smaller organisms such as yeast have been used to study the biochemical properties of causative mutations. Drosophila melanogaster, Danio rerio, and Caenorhabditis elegans have been used to dissect the pathophysiology of the neurological and motor symptoms of LS. Mammalian models, including the widely used Ndufs4 knockout mouse model of complex I deficiency, have been used to study the developmental, cognitive, and motor functions associated with the disease. Finally, cellular models of LS range from immortalized cell lines and trans-mitochondrial cybrids to more recent model systems such as patient-derived induced pluripotent stem cells (iPSCs). In particular, iPSCs now allow studying the effects of LS mutations in specialized human cells, including neurons, cardiomyocytes, and even three-dimensional organoids. These latter models open the possibility of developing high-throughput drug screens and personalized treatments based on defined disease characteristics captured in the context of a defined cell type. By analyzing all these different model systems, this review aims to provide an overview of past and present means to elucidate the complex pathology of LS. We conclude that each approach is valid for answering specific research questions regarding LS, and that their complementary use could be instrumental in finding treatment solutions for this severe and currently untreatable disease.

Keywords: Leigh syndrome; animal models; disease modeling; mitochondrial diseases; organoids; phenotyping; pluripotent stem cells.

FIGURE 1

Models of Leigh syndrome. Leigh syndrome disease models (first column) with modeled respiratory chain (RC) defects in cyan (second column) and not modeled RC defects in white. The pictograms in the second column show the mitochondrial oxidative phosphorylation machinery. The third column shows the correlation of the model phenotype with the observed phenotype in patients based on the Human Phenotype Orthology (HPO; ORPHA:506). Phenotypes were separated in symptoms of the cardiovascular and respiratory system (anatomical heart symbol), nervous system (brain symbol), musculature (muscle symbol), metabolism (mitochondrion symbol), immunology (antibody symbol), growth (separating cells symbol), eye, ear, skin, hair, nails (face symbol), and cellular phenotype (apoptotic cell symbol). Cyan symbols indicate overall matching phenotypes, light gray symbols indicate not matching or not evaluated phenotypes. Created with BioRender.com.