Mitochondrial disorders: aetiologies, models systems, and candidate therapies G. Jane Farrar, Naomi Chadderton, Paul F. Kenna, and Sophia Millington-Ward Smurfit Institute of Genetics, School of Genetics & Microbiology, Trinity College Dublin, Dublin 2, Ireland It has become evident that many human disorders are characterised by mitochondrial dysfunction either at a primary level, due to mutations in genes whose encoded products are involved in oxidative phosphorylation, or at a secondary level, due to the accumulation of mitochon- drial DNA (mtDNA) mutations. This has prompted keen interest in the development of cell and animal models and in exploring innovative therapeutic strategies to modulate the mitochondrial deficiencies observed in these diseases. Key advances in these areas are outlined in this review, with a focus on Leber hereditary optic neuropathy (LHON). This exciting field is set to grow exponentially and yield many candidate therapies to treat this class of disease. Mitochondrial dysfunction in human disorders The mitochondrion, an intracellular organelle believed to have originated from an aerobic bacterium some 1.5 billion years ago [1], provides an essential supply of cellular energy in the form of ATP generated via oxidative phos- phorylation (OXPHOS) with hundreds of mitochondria populating the cytoplasmic compartment [2] (Figure 1). Given the essential role of these organelles in cellular bioenergetics, it is not surprising that mitochondrial dys- function is a hallmark of many heritable and acquired disorders. The advent of genetic linkage and next-genera- tion sequencing (NGS) technologies has led to significant insights into the role of mitochondrial mutations in driving disease processes [3,4]. Mitochondrial disorders can be subdivided into three classes: (i) primary mitochondrial disorders caused by mutations in mitochondrial genes; (ii) disorders with mutations in nuclear genes involved in mitochondrial function; and (iii) secondary disorders that arise from the accumulation of mitochondrial damage over time frequently involving neurodegenerative pathologies [5–8]. Tissues such as retina, brain, and muscle, which have enormous energy requirements, are particularly vul- nerable to variations in mitochondrial function. Approxi- mately 50% of mitochondrial disorders have an ocular phenotype [9]. In addition to dominant optic atrophy (DOA) [10] and LHON (Box 1 [11]), mitochondrial dysfunc- tion has been linked to multifactorial diseases, including age-related macular degeneration (AMD) [7,12] and dia- betic retinopathies [12], as well as complex disorders in- volving multiple tissues, including the eye, such as neuropathy, ataxia and retinitis pigmentosa (NARP) and Kearns–Sayre syndrome (KSS) [13,14]. The significant mitochondrial dysfunction characteris- tic of many disorders has galvanised interest in the devel- opment of methodologies to simulate mitochondrial disorders in animal models and to deliver gene and small molecule-based drugs to the mitochondria. Studies in ani- mal models will be essential in the development of thera- pies for these diverse and frequently devastating clinical conditions. Here, we review recent work highlighting the role of mitochondrial dysfunction in disease and the prog- ress made towards understanding and treating these dis- eases, with a particular focus on LHON, a genetically well- characterised primary mitochondrial disorder. Molecular characteristics of mitochondrial dysfunction Screens for pathogenic mtDNA mutations initially focused on genes encoding components of OXPHOS, such as those implicated in complex I deficiency disorders [15], together with nuclear genes whose products participate in OXPHOS. Additionally, pathogenic mutations have been found in genes whose products facilitate translation and assembly of OXPHOS complexes, in genes implicated in the fission and fusion of these dynamic organelles, and in mtDNA maintenance [16]. Mutations can operate through quantita- tive effects on mtDNA numbers or qualitative effects on mtDNA function. Mutations in the nuclear-encoded mito- chondrial-specific DNA polymerase g (POLG) involved in mtDNA replication and maintenance [17] have been impli- cated in diverse neurodegenerative conditions, including mitochondrial recessive ataxic syndrome (MIRAS) and late-onset chronic progressive ophthalmoplegia [18]. Fac- tors that modulate mitochondrial RNA (mtRNA) metabo- lism by influencing mtRNA production, processing, stability, and polyadenylation have also been implicated. Mutations in mitochondrial amino acyl-tRNA synthetases (mt-aaRSs), key players in the translational machinery that link amino acids to their cognate mitochondrial tRNAs, are involved in several disorders [19]. Mutations in specific mitochondrial tRNAs have been reported [20,21]; for exam- ple, position 3243 in the mitochondrial tRNA LEU(UUR) underlies 80% of mitochondrial encephalopathy lactic aci- dosis and stroke-like episodes (MELAS) [21]. Review 0168-9525/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tig.2013.05.005 Corresponding author: Farrar, G.J. (gjfarrar@tcd.ie). Keywords: mitochondrial disease; gene therapy; Leber hereditary optic neuropathy. 488 Trends in Genetics August 2013, Vol. 29, No. 8