Mitochondrial disease: current understanding and future directions.

Abstract

Mitochondrial disease was chosen as the topic for the 13th Neurobiology of Disease in Children Symposium, held on October 31, 2013, in Austin, Texas. Program codirectors Drs Bruce Cohen and William Copeland prepared an engaging agenda that included individual presentations as well as a panel discussion from leaders working to advance the field of mitochondrial medicine. The symposium covered a variety of topics such as clinical features, recent advances in understanding the pathogenesis of mitochondrial disease, and new investigations of characteristic symptoms of the broad class of mitochondrial dysfunction. This was followed by a session on controversial topics and unanswered questions. The symposium concluded with a panel discussion led by scientific leaders in the field of mitochondrial medicine. Dr Eric Schon initiated the symposium, giving an overview of mitochondrial biology, including the genetic and molecular components that contribute to the vast array of clinical representations associated with mitochondrial disease. After the introduction, Dr Bruce Cohen presented common issues involved with properly classifying various mitochondrial diseases, in addition to providing potential diagnostic tools for clinicians to properly diagnose disease. Dr Patrick Chinnery discussed the genetic theory of heteroplasmy in which individual patients contain varying levels of mutated copies of genes, creating a wide spectrum of disease severity. Dr Chinnery went on to detail a study conducted with his group that analyzed more than 100 primary oocytes after surgical hysterectomy. The group assessed the level and distribution of mutated genetic information within the evaluated oocytes. To conclude the first session, Dr Robert Naviaux described the etiology of primary and secondary polymerase gamma disorders. Dr Naviaux defined how changes in biological pathways related to polymerase gamma can increase the mutation load in individual patients. Depending on the genetic loci where the replication error occurs, mutated polymerase gamma can produce various mitochondrial syndromes. The next session of the symposium focused on progress in understanding the molecular mechanisms behind various mitochondrial dysfunctions. Dr William Copeland detailed his work in understanding the basic function involved in polymerase gamma, and how variation from the enzymatic machinery can promote disease pathology. Dr Copeland reviewed various accessory proteins and subunits, such as polymerase gamma exonuclease and twinkle helicase, which ensure proper replication of the mitochondrial genome. Dr Copeland also elaborated on the contributions of the gene POLG2, responsible for producing the p55 subunit, to the fidelity of mitochondrial genome replication. Dr Richard Youle shared interesting findings about the association of mitochondrial dysfunction and disease pathology in Parkinson patients, as a model for understanding pediatric disorders. Dr Youle described disease progression in Parkinson patients caused by an inhibition of the mitochondrial quality control pathway, which leads to cellular accumulation of damaged or inefficient mitochondria. Dr Vamsi Mootha concluded the session with his presentation on a computational biology approach to mitochondrial research. Dr Mootha specifically detailed the effects genetic sequencing methods such as mito exome sequencing have had on the advancement of mitochondrial research. The third session of the symposium focused on translational and clinical advances in mitochondrial disease research. Dr Michio Hirano gave an overview of current gene and enzyme replacement therapies that target the nuclear DNA defect associated with mitochondrial disease symptoms. This discussion focused on current advances in these treatment options within animal models, which shift heteroplasmy under a threshold level to alleviate the effects of disease progression. Dr Mark Tarnopolsky introduced contemporary studies on exercise therapies for treating moderate pediatric myopathies. In addition, he described a therapeutic agent called myokines, which can be given to patients with mitochondrial disease via muscular injection to mimic the beneficial effects of physical exercise. Dr Gregory Enns discussed the results of various clinical trials involving patients with mitochondrial disease who were treated with EPI-743, also