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Nature Reviews. Genetics Apr 2022Mitochondria are subject to unique genetic control by both nuclear DNA and their own genome, mitochondrial DNA (mtDNA), of which each mitochondrion contains multiple... (Review)
Review
Mitochondria are subject to unique genetic control by both nuclear DNA and their own genome, mitochondrial DNA (mtDNA), of which each mitochondrion contains multiple copies. In humans, mutations in mtDNA can lead to devastating, heritable, multi-system diseases that display different tissue-specific presentation at any stage of life. Despite rapid advances in nuclear genome engineering, for years, mammalian mtDNA has remained resistant to genetic manipulation, hampering our ability to understand the mechanisms that underpin mitochondrial disease. Recent developments in the genetic modification of mammalian mtDNA raise the possibility of using genome editing technologies, such as programmable nucleases and base editors, for the treatment of hereditary mitochondrial disease.
Topics: Animals; DNA, Mitochondrial; Genome, Mitochondrial; Humans; Mammals; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 34857922
DOI: 10.1038/s41576-021-00432-x -
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 -
Journal of Inherited Metabolic Disease Jan 2024In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV)... (Review)
Review
In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator-like effector nucleases, zinc-finger nucleases, and meganucleases (mitoARCUS). rAAV-based approaches have been used successfully to deliver these nucleases in vivo in mice. Exciting developments in CRISPR-Cas9 gene editing technology have achieved in vivo gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR-free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.
Topics: Humans; Animals; Mice; CRISPR-Cas Systems; Gene Editing; Genetic Therapy; DNA, Mitochondrial; Endonucleases; Mitochondrial Diseases
PubMed: 38171948
DOI: 10.1002/jimd.12699 -
Nature Reviews. Drug Discovery Jun 2023
Topics: Humans; Mitochondrial Diseases; Mitochondria; Genetic Therapy
PubMed: 37106085
DOI: 10.1038/d41573-023-00067-z -
Handbook of Clinical Neurology 2023Mitochondrial diseases are a heterogeneous group of multisystem disorders caused by impaired mitochondrial function. These disorders occur at any age and involve any... (Review)
Review
Mitochondrial diseases are a heterogeneous group of multisystem disorders caused by impaired mitochondrial function. These disorders occur at any age and involve any tissue, typically affecting organs highly dependent on aerobic metabolism. Diagnosis and management are extremely difficult due to various underlying genetic defects and a wide range of clinical symptoms. Preventive care and active surveillance are strategies to try to reduce morbidity and mortality by timely treatment of organ-specific complications. More specific interventional therapies are in early phases of development and no effective treatment or cure currently exists. A variety of dietary supplements have been utilized based on biological logic. For several reasons, few randomized controlled trials have been completed to assess the efficacy of these supplements. The majority of the literature on supplement efficacy represents case reports, retrospective analyses and open-label studies. We briefly review selected supplements that have some degree of clinical research support. In mitochondrial diseases, potential triggers of metabolic decompensation or medications that are potentially toxic to mitochondrial function should be avoided. We shortly summarize current recommendations on safe medication in mitochondrial diseases. Finally, we focus on the frequent and debilitating symptoms of exercise intolerance and fatigue and their management including physical training strategies.
Topics: Humans; Retrospective Studies; Mitochondrial Diseases; Mitochondria; Fatigue; Exercise
PubMed: 36813313
DOI: 10.1016/B978-0-12-821751-1.00007-5 -
Heart Failure Reviews Mar 2021Maternally mitochondrial dysfunction includes a heterogeneous group of genetic disorders which leads to the impairment of the final common pathway of energy metabolism.... (Review)
Review
Maternally mitochondrial dysfunction includes a heterogeneous group of genetic disorders which leads to the impairment of the final common pathway of energy metabolism. Coronary heart disease and coronary venous disease are two important clinical manifestations of mitochondrial dysfunction due to abnormality in the setting of underlying pathways. Mitochondrial dysfunction can lead to cardiomyopathy, which is involved in the onset of acute cardiac and pulmonary failure. Mitochondrial diseases present other cardiac manifestations such as left ventricular noncompaction and cardiac conduction disease. Different clinical findings from mitochondrial dysfunction originate from different mtDNA mutations, and this variety of clinical symptoms poses a diagnostic challenge for cardiologists. Heart transplantation may be a good treatment, but it is not always possible, and other complications of the disease, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like syndrome, should be considered. To diagnose and treat most mitochondrial disorders, careful cardiac, neurological, and molecular studies are needed. In this study, we looked at molecular genetics of MIDs and cardiac manifestations in patients with mitochondrial dysfunction.
Topics: Cardiomyopathies; Heart Diseases; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Encephalomyopathies
PubMed: 32728985
DOI: 10.1007/s10741-020-10009-1 -
Open Biology Dec 2022Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary... (Review)
Review
Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.
Topics: Humans; Mitochondrial Diseases
PubMed: 36475414
DOI: 10.1098/rsob.220274 -
Handbook of Clinical Neurology 2023The mitochondrial disease group consists of different disorders with unprecedented variability of clinical manifestations and tissue-specific symptoms. Their... (Review)
Review
The mitochondrial disease group consists of different disorders with unprecedented variability of clinical manifestations and tissue-specific symptoms. Their tissue-specific stress responses vary depending on the patients' age and type of dysfunction. These responses include secretion of metabolically active signal molecules to systemic circulation. Such signals-metabolites or metabokines-can be also utilized as biomarkers. During the past 10 years, metabolite and metabokine biomarkers have been described for mitochondrial disease diagnosis and follow-up, to complement the conventional blood biomarkers lactate, pyruvate and alanine. These new tools include metabokines FGF21 and GDF15; cofactors (NAD-forms); sets of metabolites (multibiomarkers) and the full metabolome. FGF21 and GDF15 are messengers of mitochondrial integrated stress response that together outperform the conventional biomarkers in specificity and sensitivity for muscle-manifesting mitochondrial diseases. Metabolite or metabolomic imbalance (e.g., NAD+ deficiency) is a secondary consequence to the primary cause in some diseases, but relevant as a biomarker and a potential indicator of therapy targets. For therapy trials, the optimal biomarker set needs to be tailored to match the disease of interest. The new biomarkers have increased the value of blood samples in mitochondrial disease diagnosis and follow-up, enabling prioritization of patients to different diagnostic paths and having crucial roles in follow-up of therapy effect.
Topics: Humans; Mitochondrial Diseases; Mitochondria; Biomarkers; Pyruvic Acid
PubMed: 36813317
DOI: 10.1016/B978-0-12-821751-1.00006-3 -
Current Opinion in Endocrinology,... Feb 2024Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have... (Review)
Review
PURPOSE OF REVIEW
Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies.
RECENT FINDINGS
Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring.
SUMMARY
Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.
Topics: Humans; Female; Endocrine System Diseases; Diabetes Mellitus; Puberty, Precocious; Mitochondrial Diseases; Hyperthyroidism; Adrenal Insufficiency
PubMed: 38047549
DOI: 10.1097/MED.0000000000000848 -
International Journal of Molecular... Apr 2020The completion of the Special Issue dedicated to "mtDNA and mitochondrial stress signaling in human diseases" requests a final overall look to highlight the most...
The completion of the Special Issue dedicated to "mtDNA and mitochondrial stress signaling in human diseases" requests a final overall look to highlight the most valuable findings among the many presented data [...].
Topics: DNA, Mitochondrial; Disease Susceptibility; Humans; Mitochondria; Mitochondrial Diseases; Signal Transduction; Stress, Physiological
PubMed: 32283804
DOI: 10.3390/ijms21072617