Emerging Therapies for Mitochondrial Disorders

Helen Nightingale; Gerald Pfeffer; David Bargiela; Rita Horvath; Patrick F. Chinnery


Brain. 2016;139(6):1633-1648. 

In This Article

Abstract and Introduction


Mitochondrial disorders are a diverse group of debilitating conditions resulting from nuclear and mitochondrial DNA mutations that affect multiple organs, often including the central and peripheral nervous system. Despite major advances in our understanding of the molecular mechanisms, effective treatments have not been forthcoming. For over five decades patients have been treated with different vitamins, co-factors and nutritional supplements, but with no proven benefit. There is therefore a clear need for a new approach. Several new strategies have been proposed acting at the molecular or cellular level. Whilst many show promise in vitro, the clinical potential of some is questionable. Here we critically appraise the most promising preclinical developments, placing the greatest emphasis on diseases caused by mitochondrial DNA mutations. With new animal and cellular models, longitudinal deep phenotyping in large patient cohorts, and growing interest from the pharmaceutical industry, the field is poised to make a breakthrough.


Mitochondria are complex intracellular organelles that play a central role in cell homeostasis (Wallace, 1999). They are the principal source of intracellular energy, are intimately involved in both calcium and free radical metabolism, and they can trigger programmed cell death (apoptosis). Tissues and organs that critically dependent on these functions bear the brunt of the pathology in human mitochondrial diseases, which often affect the nervous system, muscle and endocrine organs (Pfeffer et al., 2012). Most mitochondrial disorders are progressive and often result in disability and premature death. Therefore, although they are rare diseases, with a minimum reported prevalence of 1 in 4300 (Schaefer et al., 2004), they have substantial impact on families and healthcare services.

Most mitochondrial disorders are ultimately thought to arise through a bioenergetic defect linked to a deficiency of ATP synthesis. ATP synthesis is the final step of respiration, which is carried out by five oxidative phosphorylation (OXPHOS) complexes situated on the inner mitochondrial membrane. Each complex has multiple protein subunits encoded by two distinct genomes: nuclear chromosomal DNA (nDNA), and the 16.5 kb mitochondrial genome (mtDNA).

Pathogenic mtDNA mutations often cause a subset of classical mitochondrial clinical syndromes (Chinnery and Hudson, 2013). However, an increased number of multisystem mitochondrial disorders are being described in the literature, many of which are yet to be fully characterized clinically and genetically. These include an emerging myriad of nuclear encoded mitochondrial disorders caused by mutations in some of the ~1500 nuclear genes thought to code for mitochondrial proteins (Chinnery and Hudson, 2013). In the past, the phenotypic and genetic diversity has made clinical diagnosis very challenging. However, with international diagnostic standards (Wolf and Smeitink, 2002), and the widespread availability of molecular genetic techniques, an accurate diagnosis is less challenging than before. Next generation sequencing is revolutionizing the diagnostic approach, with multi-gene panels, whole exome, and whole genome sequencing increasing the pace of diagnosis, and probably reducing the overall costs. As a consequence, more and more patients are being diagnosed with a mitochondrial disorder, placing even greater emphasis on developing treatments.

A recent systematic review identified over 1300 reports using a variety of approaches expected to bypass or enhance components of mitochondrial function. However, the vast majority of these reports are open-labelled case series with less than five subjects. Although ~30 randomized trials have been carried out to date, no treatment has shown a clear cut benefit on a clinically meaningful end-point (for reviews see Pfeffer et al., 2012; Kerr, 2013). It is therefore likely that components of the traditional 'mitochondrial cocktail' do not have a major therapeutic impact on most mitochondrial diseases. There is therefore a clear need for the field to 'think outside the box' when developing new treatments, harnessing the massive increase in our understanding of mitochondrial disease pathogenesis. After preclinical evaluation in cellular and animal models, new treatments showing promise should be studied in patients using a rigorous approach (Pfeffer et al., 2013). This review focuses on these new developments, with a particular emphasis on mtDNA diseases, which were previously thought to be intractable. Here we critically appraise each approach, and highlight areas where there is likely to be traction in the future. This is timely, because both small and large pharmaceutical companies are starting to see the potential market in developing treatments for these so-far untreatable disorders.