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FEBS Letters Apr 2021Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different... (Review)
Review
Mitochondrial disorders are monogenic disorders characterized by a defect in oxidative phosphorylation and caused by pathogenic variants in one of over 340 different genes. The implementation of whole-exome sequencing has led to a revolution in their diagnosis, duplicated the number of associated disease genes, and significantly increased the diagnosed fraction. However, the genetic etiology of a substantial fraction of patients exhibiting mitochondrial disorders remains unknown, highlighting limitations in variant detection and interpretation, which calls for improved computational and DNA sequencing methods, as well as the addition of OMICS tools. More intriguingly, this also suggests that some pathogenic variants lie outside of the protein-coding genes and that the mechanisms beyond the Mendelian inheritance and the mtDNA are of relevance. This review covers the current status of the genetic basis of mitochondrial diseases, discusses current challenges and perspectives, and explores the contribution of factors beyond the protein-coding regions and monogenic inheritance in the expansion of the genetic spectrum of disease.
Topics: DNA, Mitochondrial; Humans; Mitochondrial Diseases; Exome Sequencing
PubMed: 33655490
DOI: 10.1002/1873-3468.14068 -
FEBS Letters Apr 2021The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction... (Review)
Review
The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co-ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.
Topics: Animals; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Neoplasm Proteins; Neoplasms; Neurodegenerative Diseases; Protein Transport
PubMed: 33314127
DOI: 10.1002/1873-3468.14022 -
Current Neurology and Neuroscience... May 2021We aim to summarize the sleep disorders reported in patients affected by primary mitochondrial dysfunctions and describe the association with their clinical and... (Review)
Review
PURPOSE OF REVIEW
We aim to summarize the sleep disorders reported in patients affected by primary mitochondrial dysfunctions and describe the association with their clinical and molecular characteristics.
RECENT FINDINGS
Sleep complaints are prevalent in mitochondrial disorders. Sleep-disordered breathing is the main sleep disorder reported in mitochondrial diseases. OSA and CSA are, respectively, more frequently associated with patients characterized by the prevalent involvement of the skeletal muscle and the predominant involvement of the central nervous system. Other sleep disorders, such as restless legs syndrome, have been rarely described. Sleep disorders are frequently associated with primary mitochondrial disorders, and the clinical phenotypes affect the type of sleep disturbance associated with the mitochondrial dysfunction. A polysomnographic study should be performed in every subject with this neurogenetic disorder both at diagnosis and during follow-up for the numerous adverse clinical outcomes associated with sleep disorders and the frailty of mitochondrial patients.
Topics: Humans; Mitochondrial Diseases; Polysomnography; Restless Legs Syndrome; Sleep Apnea Syndromes; Sleep Wake Disorders
PubMed: 33948737
DOI: 10.1007/s11910-021-01121-2 -
Archives of Disease in Childhood Nov 2017Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of... (Review)
Review
Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of cell apoptosis and numerous biochemical catabolic and synthetic pathways that are critical for cellular health. Primary mitochondrial disorders are a group of greater than 200 single gene defects arising from two genomes (nuclear and mitochondrial) leading to mitochondrial dysfunction, and are associated with extremely heterogeneous phenotypes. Neuromuscular features predominate, but often with multisystem involvement. Clinical suspicion of a mitochondrial disorder should prompt multipronged investigation with biochemical and molecular genetic studies. Recent wide-scale adoption of next-generation sequencing approaches has led to a rapid increase in the number of disease genes. The advances in unravelling the genetic landscape of mitochondrial diseases have not yet been matched by progress in developing effective therapies, and the mainstay of care remains supportive therapies in a multidisciplinary team setting.
Topics: Genetic Testing; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Phenotype
PubMed: 28647693
DOI: 10.1136/archdischild-2016-311370 -
Pediatric Clinics of North America Feb 2017Mitochondrial disease (MD) occurs when alteration of mitochondrial respiratory chain complex function caused by genetic mutation produces a detectable disease state.... (Review)
Review
Mitochondrial disease (MD) occurs when alteration of mitochondrial respiratory chain complex function caused by genetic mutation produces a detectable disease state. These mutations may be found in either the nuclear or mitochondrial genomes, and may only be present in a subset of cells or body tissues. Thus, the phenotype of MD is extremely variable and the definitive diagnosis of MD is complex. This article provides a brief description of a strategy used in the diagnosis of MD, by integrating data from clinical, imaging, pathologic, molecular, and enzymatic assessments. Additional information on characteristic findings seen in classic MD syndromes is also provided.
Topics: Biomarkers; Child; Diagnosis, Differential; Genome, Human; Humans; Mitochondrial Diseases; Mutation; Phenotype; Rare Diseases; Syndrome
PubMed: 27894442
DOI: 10.1016/j.pcl.2016.08.011 -
Current Heart Failure Reports Feb 2023We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy. (Review)
Review
PURPOSE OF REVIEW
We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy.
RECENT FINDINGS
Mechanistic studies have shed light into the underpinnings of mitochondrial disorders, providing novel insights into mitochondrial physiology and identifying new therapeutic targets. Mitochondrial disorders are a group of rare genetic diseases that are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes that are essential to mitochondrial function. The clinical picture is extremely heterogeneous, the onset can occur at any age, and virtually, any organ or tissue can be involved. Since the heart relies primarily on mitochondrial oxidative metabolism to fuel contraction and relaxation, cardiac involvement is common in mitochondrial disorders and often represents a major determinant of their prognosis.
Topics: Humans; Heart Failure; Mitochondrial Diseases; DNA, Mitochondrial; Cardiomyopathies; Mutation
PubMed: 36802007
DOI: 10.1007/s11897-023-00592-3 -
Genes Oct 2021Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a... (Review)
Review
Mitochondrial disease originates from genetic changes that impact human bodily functions by disrupting the mitochondrial oxidative phosphorylation system. MitoCarta is a curated and published inventory that sheds light on the mitochondrial proteome, but the function of some mitochondrially-localised proteins remains poorly characterised. Consequently, various gene editing systems have been employed to uncover the involvement of these proteins in mitochondrial biology and disease. CRISPR/Cas9 is an efficient, versatile, and highly accurate genome editing tool that was first introduced over a decade ago and has since become an indispensable tool for targeted genetic manipulation in biological research. The broad spectrum of CRISPR/Cas9 applications serves as an attractive and tractable system to study genes and pathways that are essential for the regulation and maintenance of mitochondrial health. It has opened possibilities of generating reliable cell and animal models of human disease, and with further exploitation of the technology, large-scale genomic screenings have uncovered a wealth of fundamental mechanistic insights. In this review, we describe the applications of CRISPR/Cas9 system as a genome editing tool to uncover new insights into pathomechanisms of mitochondrial diseases and/or biological processes involved in mitochondrial function.
Topics: CRISPR-Cas Systems; Gene Editing; Humans; Mitochondria; Mitochondrial Diseases
PubMed: 34680998
DOI: 10.3390/genes12101604 -
Journal of Internal Medicine Jun 2020Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OXPHOS). OXPHOS deficiency can be the result of... (Review)
Review
Mitochondrial diseases are extremely heterogeneous genetic conditions characterized by faulty oxidative phosphorylation (OXPHOS). OXPHOS deficiency can be the result of mutation in mtDNA genes, encoding either proteins (13 subunits of the mitochondrial complexes I, III, IV and V) or the tRNA and rRNA components of the in situ mtDNA translation. The remaining mitochondrial disease genes are in the nucleus, encoding proteins with a huge variety of functions, from structural subunits of the mitochondrial complexes, to factors involved in their formation and regulation, components of the mtDNA replication and expression machinery, biosynthetic enzymes for the biosynthesis or incorporation of prosthetic groups, components of the mitochondrial quality control and proteostasis, enzymes involved in the clearance of toxic compounds, factors involved in the formation of the lipid milieu, etc. These different functions represent potential targets for 'general' therapeutic interventions, as they may be adapted to a number of different mitochondrial conditions. This is in contrast with 'tailored', personalized therapeutic approaches, such as gene therapy, cell therapy and organ replacement, that can be useful only for individual conditions. This review will present the most recent concepts emerged from preclinical work and the attempts to translate them into the clinics. The common notion that mitochondrial disorders have no cure is currently challenged by a massive effort of scientists and clinicians, and we do expect that thanks to this intensive investigation work and tangible results for the development of strategies amenable to the treatment of patients with these tremendously difficult conditions are not so far away.
Topics: Animals; Antioxidants; Genetic Therapy; Humans; Mitochondria; Mitochondrial Diseases; Nucleotides; Translational Research, Biomedical
PubMed: 32100338
DOI: 10.1111/joim.13046 -
Frontiers in Bioscience (Landmark... Mar 2017Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death.... (Review)
Review
Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death. Mitochondrial dysfunction, including impaired oxidative phosphorylation, preferentially affects heart function due to an imbalance of energy supply and demand. Recently, mitochondrial mutations and associated mitochondrial dysfunction were suggested as a causal factor of cardiac manifestations. Oxidative stress largely influences mtDNA stability due to oxidative modifications of mtDNA. Furthermore, the continuous replicative state of mtDNA and presence of minimal nucleoid structure render mitochondria vulnerable to oxidative damage and subsequent mutations, which impair mitochondrial functions. However, the occurrence of mtDNA heteroplasmy in the same mitochondrion or cell and presence of nuclear DNA-encoded mtDNA repair systems raise questions regarding whether oxidative stress-mediated mtDNA mutations are the major driving force in accumulation of mtDNA mutations. Here, we address the possible causes of mitochondrial DNA mutations and their involvement in cardiac manifestations. Current strategies for treatment related to mitochondrial mutations and/or dysfunction in cardiac manifestations are briefly discussed.
Topics: Animals; DNA Damage; DNA Repair; DNA, Mitochondrial; Heart Diseases; Humans; Mitochondria, Heart; Mitochondrial Diseases; Mutation; Oxidative Stress
PubMed: 28199200
DOI: 10.2741/4541 -
PloS One 2022Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not... (Review)
Review
BACKGROUND
Mitochondrial diseases are a large group of genetically heterogeneous and clinically diverse disorders. Diagnosis often takes many years for which treatment may not exist. Registries are often used to conduct research, establish natural disease progression, engage the patient community, and develop best disease management practices. In Canada, there are limited centralized registries for mitochondrial disease patients, presenting a challenge for patients and professionals.
OBJECTIVE
To support the creation of such a registry, a systematic scoping review was conducted to map the landscape of mitochondrial disease patient registries worldwide, with a focus on registry design and challenges. Furthermore, it addresses a knowledge gap by providing a narrative synthesis of published literature that describes these registries.
METHODS
Arksey and O'Malley's methodological framework was followed to systematically search English-language literature in PubMed and CINAHL describing the designs of mitochondrial disease patient registries, supplemented by a grey literature search. Data were extracted in Microsoft Excel. Stakeholder consultations were also performed with patient caregivers, advocates, and researchers to provide perspectives beyond those found in the literature. These data were thematically analyzed and were reported in accordance with the PRISMA-ScR reporting guidelines.
RESULTS
A total of 17 articles were identified describing 13 unique registries located in North America, Europe, Australia, and West Asia. These papers described the registries' designs, their strengths, and weaknesses, as well as their tangible outcomes such as facilitating recruitment for research and supporting epidemiological studies.
CONCLUSION
Based on our findings in this review, recommendations were formulated. These include establishing registry objectives, respecting patients and their roles in the registry, adopting international data standards, data evaluations, and considerations to privacy legislation, among others. These recommendations could be used to support designing a future Canadian mitochondrial disease patient registry, and to further research directly engaging these registries worldwide.
Topics: Humans; Canada; Registries; Research Personnel; Mitochondrial Diseases; Europe
PubMed: 36301904
DOI: 10.1371/journal.pone.0276883