Field Of Mitochondrial Medicine Research Articles

Mitochondria Have Made a Long Evolutionary Path from Ancient Bacteria Immigrants within Eukaryotic Cells to Essential Cellular Hosts and Key Players in Human Health and Disease.

Mitochondria have made a long evolutionary path from ancient bacteria immigrants within the eukaryotic cell to become key players for the cell, assuming crucial multitasking skills critical for human health and disease. Traditionally identified as the powerhouses of eukaryotic cells due to their central role in energy metabolism, these chemiosmotic machines that synthesize ATP are known as the only maternally inherited organelles with their own genome, where mutations can cause diseases, opening up the field of mitochondrial medicine. More recently, the omics era has highlighted mitochondria as biosynthetic and signaling organelles influencing the behaviors of cells and organisms, making mitochondria the most studied organelles in the biomedical sciences. In this review, we will especially focus on certain 'novelties' in mitochondrial biology "left in the shadows" because, although they have been discovered for some time, they are still not taken with due consideration. We will focus on certain particularities of these organelles, for example, those relating to their metabolism and energy efficiency. In particular, some of their functions that reflect the type of cell in which they reside will be critically discussed, for example, the role of some carriers that are strictly functional to the typical metabolism of the cell or to the tissue specialization. Furthermore, some diseases in whose pathogenesis, surprisingly, mitochondria are involved will be mentioned.

Mitochondrial disease in children.

Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.

Mitochondrial diseases: advances and issues.

Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders.

Nutrition and nutritional signaling as therapy targets for mitochondrial disorders

Mitochondrial disorders are degenerative diseases known to be responsible for a number of heterogenous clinical presentations with multi-systemic dysfunctions that often involves the nervous, endocrine, renal and cardiac system. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these conditions. Despite significant progress made in the field of mitochondrial medicine during the last two decades, defining the specific biochemical defects and underlying molecular mechanisms, the avaliable information about effective treatment approaches is limited. The goal of nutritional treatment of mitochondrial dysfunction in various neurological syndromes are based primarily in improving theefficiency of the processes of oxidative phosphorylation at the system level. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of new therapeutic agents, such as antioxidants, radical scavangers and cofactors. A literature review of the use of these supplements in mitochondrial disorders is presented.

Mitochondrial disorders: challenges in diagnosis & treatment.

Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.

Mitochondrial disease: current understanding and future directions.

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

The pathogenicity scoring system for mitochondrial tRNA mutations revisited

Confirming the pathogenicity of mitochondrial tRNA point mutations is one of the classical challenges in the field of mitochondrial medicine. In addition to genetic and functional studies, the evaluation of a genetic change using a pathogenicity scoring system is extremely useful to discriminate between disease-causing mutations from neutral polymorphisms. The pathogenicity scoring system is very robust for confirming pathogenicity, especially of mutations that show impaired activity in functional studies. However, mutations giving normal results using the same functional approaches are disregarded, and this compromises the power of the system to rule out pathogenicity. We propose to include a new criterion in the pathogenicity scoring systems regarding mutations which fail to show any mitochondrial defect in functional studies. To evaluate this proposal we characterized two mutations, m.8296A>G and m.8347A>G, in the mitochondrial tRNALys gene (MT-TK) using trans-mitochondrial cybrid analysis. m.8347A>G mutation severely impairs oxidative phosphorylation, suggesting that it is highly pathogenic. By contrast, the behavior of cybrids homoplasmic for the m.8296A>G mutation is similar to cybrids containing wild-type mitochondrial DNA (mtDNA). The results indicate that including not only positive but also negative outcomes of functional studies in the scoring system is critical for facilitating the diagnosis of this complex group of diseases.

The optic nerve: a "mito-window" on mitochondrial neurodegeneration.

Retinal ganglion cells (RGCs) project their long axons, composing the optic nerve, to the brain, transmitting the visual information gathered by the retina, ultimately leading to formed vision in the visual cortex. The RGC cellular system, representing the anterior part of the visual pathway, is vulnerable to mitochondrial dysfunction and optic atrophy is a very frequent feature of mitochondrial and neurodegenerative diseases. The start of the molecular era of mitochondrial medicine, the year 1988, was marked by the identification of a maternally inherited form of optic atrophy, Leber's hereditary optic neuropathy, as the first disease due to mitochondrial DNA point mutations. The field of mitochondrial medicine has expanded enormously over the last two decades and many neurodegenerative diseases are now known to have a primary mitochondrial etiology or mitochondrial dysfunction plays a relevant role in their pathogenic mechanism. Recent technical advancements in neuro-ophthalmology, such as optical coherence tomography, prompted a still ongoing systematic re-investigation of retinal and optic nerve involvement in neurodegenerative disorders. In addition to inherited optic neuropathies, such as Leber's hereditary optic neuropathy and dominant optic atrophy, and in addition to the syndromic mitochondrial encephalomyopathies or mitochondrial neurodegenerative disorders such as some spinocerebellar ataxias or familial spastic paraparesis and other disorders, we draw attention to the involvement of the optic nerve in classic age-related neurodegenerative disorders such as Parkinson and Alzheimer disease. We here provide an overview of optic nerve pathology in these different clinical settings, and we review the possible mechanisms involved in the pathogenesis of optic atrophy. This may be a model of general value for the field of neurodegeneration. This article is part of a Special Issue entitled ‘Mitochondrial function and dysfunction in neurodegeneration’.

Professor Rolf Luft, 1914–2007

Rolf Luft came to appreciate at an early stage of his careerthat biomedicine, cell biology, cell physiology and geneticsarealldevelopingatatremendousrate,andthatitisthereforeof vital importance to retain a sharp focus and to addressone’schosen research questions in great depth. For this,a lotof hard work, talent and enthusiasm are definitely needed.This principle guided Rolf throughout his research careerand became the golden rule for all of his pupils.By applying his own standards Rolf was able to make aremarkable discovery, namely that disturbed function of acell organelle, the mitochondrion, could lead to disease. Helater remarked that he ‘was in the position to undertake thefirst studies of a cell organelle in humans in 1959–1962.They were performed following observations made at thebedside of a patient with striking symptoms never encoun-tered before. The clinical observations led first to an ideaabout the origin of the symptoms and second to studies ofthis particular organelle, the mitochondria’ [1]. This findingemerged from painstaking study of a 30-year-old womanwith profuse perspiration, extremely high energy intake andmyopathy [2]. He hypothesised that these abnormalitieswere due to a derangement of respiratory control in themitochondria. The concept of oxidative phosphorylationwas at that time based on studies of rat liver mitochondria,and he extended these techniques to mitochondria obtainedfrom biopsies of the patient’s gracilis muscles. The studiesshowed the features of ‘loosely-coupled’ respiration, i.e.deficient respiratory control with a partially maintainedability to synthesise ATP. This accounted for all the clinicalfeatures: abnormal heat production leading to increasedperspiration and the enormous energy intake needed tocompensate for the increased combustion. Electron micros-copy of the mitochondria revealed striking structuralabnormalities, with many mitochondria of highly variablesize located in the perinuclear zone of the muscle cells andvast paracrystalline inclusions. Despite the mystery that stillsurrounds the aetiology of Luft’s disease, the demonstrationof human pathology resulting from the biochemical andmorphological abnormalities in mitochondria had a majorimpact on the field of mitochondrial medicine and thecontinuing growth of the field from that time.Rolf Luft can no longer actively guide us in our dailywork. This giant in the fields of diabetes, endocrinologyand mitochondrial diseases died on 22 May 2007. Not onlywill we miss his stunning intellect, but also his generosityand humour. He was born in Stockholm on 29 June 1914.He came from a working-class Jewish family and moneywas scarce, but Rolf was a brilliant student and his studieswere funded by scholarships. He took his MD at the age of26, and 4 years later he submitted a doctoral thesis onCushing’s syndrome and the effects of cortisone. He wenton to play a leading role in establishing endocrinology as adiscipline in Sweden, and also in founding the SwedishEndocrine Society. His appointment to the KarolinskaInstitutet in 1961 represented the first chair of endocrinol-ogy in Europe.

Revolution in mitochondrial medicine

A revolution in chemical pathology occurred about 40 years ago with the discovery of a patient with mitochondrial dysfunction. The field of mitochondrial medicine has experienced explosive growth during the last decade. More than 50 mtDNA mutations and several nuclear gene mutations have been identified in affected patients. The recent development of animal models will continue the revolution in mitochondrial medicine by facilitating in depth studies of the molecular pathogenesis and development of novel drug and gene therapy strategies for mitochondrial dysfunction. As we enter the next millennium, we can expect mitochondrial medicine to remain a dynamic and rapidly developing field.