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Cell Apr 2020Mitochondrial diseases are clinically heterogeneous disorders caused by a wide spectrum of mutations in genes encoded by either the nuclear or the mitochondrial genome.... (Review)
Review
Mitochondrial diseases are clinically heterogeneous disorders caused by a wide spectrum of mutations in genes encoded by either the nuclear or the mitochondrial genome. Treatments for mitochondrial diseases are currently focused on symptomatic management rather than improving the biochemical defect caused by a particular mutation. This review focuses on the latest advances in the development of treatments for mitochondrial disease, both small molecules and gene therapies, as well as methods to prevent transmission of mitochondrial disease through the germline.
Topics: Animals; DNA, Mitochondrial; Genetic Therapy; Genome, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mutation; NAD; Reactive Oxygen Species
PubMed: 32220313
DOI: 10.1016/j.cell.2020.02.051 -
Journal of Neurology Jan 2016Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement... (Review)
Review
Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the mitochondrial and nuclear genome make mitochondrial disease particularly challenging for the clinician. In this review article we cover mitochondrial genetics and common neurological presentations associated with adult mitochondrial disease. In addition, specific and supportive treatments are discussed.
Topics: Humans; Mitochondrial Diseases
PubMed: 26315846
DOI: 10.1007/s00415-015-7884-3 -
Journal of Internal Medicine Jun 2020Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but... (Review)
Review
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 30 years, 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.
Topics: Child; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype
PubMed: 32176382
DOI: 10.1111/joim.13054 -
International Journal of Molecular... Jan 2021Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy... (Review)
Review
Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.
Topics: Animals; DNA, Mitochondrial; Energy Metabolism; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Models, Molecular; Mutation; Protein Conformation
PubMed: 33435522
DOI: 10.3390/ijms22020586 -
Genetics in Medicine : Official Journal... Sep 2015The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This... (Review)
Review
PURPOSE
The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients.
METHODS
The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.
RESULTS
Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.
CONCLUSION
The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.
Topics: Consensus; Delphi Technique; Evidence-Based Medicine; Humans; Mitochondrial Diseases; Treatment Outcome
PubMed: 25503498
DOI: 10.1038/gim.2014.177 -
Mitochondrion Nov 2019Mitochondrial dynamics shape the mitochondrial network and contribute to mitochondrial function and quality control. Mitochondrial fusion and division are integrated... (Review)
Review
Mitochondrial dynamics shape the mitochondrial network and contribute to mitochondrial function and quality control. Mitochondrial fusion and division are integrated into diverse cellular functions and respond to changes in cell physiology. Imbalanced mitochondrial dynamics are associated with a range of diseases that are broadly characterized by impaired mitochondrial function and increased cell death. In various disease models, modulating mitochondrial fusion and division with either small molecules or genetic approaches has improved function. Although additional mechanistic understanding of mitochondrial fusion and division will be critical to inform further therapeutic approaches, mitochondrial dynamics represent a powerful therapeutic target in a wide range of human diseases.
Topics: Animals; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Dynamics
PubMed: 31228566
DOI: 10.1016/j.mito.2019.06.002 -
International Journal of Molecular... Oct 2022Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect... (Review)
Review
Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.
Topics: Humans; Neurologists; Mitochondrial Diseases; DNA, Mitochondrial; Epilepsy; Mitochondria; Mutation
PubMed: 36362003
DOI: 10.3390/ijms232113216 -
Lancet (London, England) Jun 2018Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear... (Review)
Review
Mitochondria are dynamic bioenergetic organelles whose maintenance requires around 1500 proteins from two genomes. Mutations in either the mitochondrial or nuclear genome can disrupt a plethora of cellular metabolic and homoeostatic functions. Mitochondrial diseases represent one of the most common and severe groups of inherited genetic disorders, characterised by clinical, biochemical, and genetic heterogeneity, diagnostic odysseys, and absence of disease-modifying curative therapies. This Review aims to discuss recent advances in mitochondrial biology and medicine arising from widespread use of high-throughput omics technologies, and also includes a broad discussion of emerging therapies for mitochondrial disease. New insights into both bioenergetic and biosynthetic mitochondrial functionalities have expedited the genetic diagnosis of primary mitochondrial disorders, and identified novel mitochondrial pathomechanisms and new targets for therapeutic intervention. As we enter this new era of mitochondrial medicine, underpinned by global unbiased approaches and multifaceted investigation of mitochondrial function, omics technologies will continue to shed light on unresolved mitochondrial questions, paving the way for improved outcomes for patients with mitochondrial diseases.
Topics: Genetic Therapy; Genomics; Humans; Metabolomics; Mitochondria; Mitochondrial Diseases; Mutation; Proteomics
PubMed: 29903433
DOI: 10.1016/S0140-6736(18)30727-X -
FEBS Letters Apr 2021Mitochondrial disorders are among the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system... (Review)
Review
Mitochondrial disorders are among the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase [also called complex V (cV)]. The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by cV to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here, we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.
Topics: Adenosine Triphosphate; Animals; DNA, Mitochondrial; Electron Transport; Electron Transport Chain Complex Proteins; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 33159691
DOI: 10.1002/1873-3468.13995 -
Texas Heart Institute Journal 2013Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of... (Review)
Review
Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory chain, in the absence of concomitant coronary artery disease, hypertension, valvular disease, or congenital heart disease. The typical cardiac manifestations of mitochondrial disease--hypertrophic and dilated cardiomyopathy, arrhythmias, left ventricular myocardial noncompaction, and heart failure--can worsen acutely during a metabolic crisis. The optimal management of mitochondrial disease necessitates the involvement of a multidisciplinary team, careful evaluations of patients, and the anticipation of iatrogenic and noniatrogenic complications. In this review, we describe the complex pathophysiology of mitochondrial disease and its clinical features. We focus on current practice in the diagnosis and treatment of patients with mitochondrial cardiomyopathy, including optimal therapeutic management and long-term monitoring. We hope that this information will serve as a guide for practicing cardiologists who treat patients thus affected.
Topics: Animals; Cardiomyopathies; DNA, Mitochondrial; Energy Metabolism; Genetic Predisposition to Disease; Humans; Mitochondria, Heart; Mitochondrial Diseases; Phenotype; Predictive Value of Tests; Risk Factors; Treatment Outcome
PubMed: 24082366
DOI: No ID Found