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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 -
Cellular and Molecular Life Sciences :... Nov 2021Mitochondria-the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat-are highly dynamic, double-membraned organelles that... (Review)
Review
Mitochondria-the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat-are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding-and potentially reversing-the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health.
Topics: Amino Acid Metabolism, Inborn Errors; Animals; Energy Metabolism; Homeostasis; Humans; Mitochondria; Mitochondrial Diseases; Mitophagy; Organelles; Signal Transduction
PubMed: 34524466
DOI: 10.1007/s00018-021-03934-3 -
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 -
Orphanet Journal of Rare Diseases Oct 2023Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic...
BACKGROUND
Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group.
RESULTS
The overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%).
CONCLUSION
The wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.
Topics: Humans; Mutation; Mitochondrial Diseases; DNA, Mitochondrial; Mitochondria; Genotype
PubMed: 37784170
DOI: 10.1186/s13023-023-02921-0 -
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 -
Handbook of Clinical Neurology 2023This chapter provides a overview of this volume of the Handbook of Clinical Neurology, placing recent advances in our understanding of mitochondrial disorders in a... (Review)
Review
This chapter provides a overview of this volume of the Handbook of Clinical Neurology, placing recent advances in our understanding of mitochondrial disorders in a historical context, and speculates about the future.
Topics: Humans; Mitochondria; DNA, Mitochondrial; Mutation; Mitochondrial Diseases; Neurology
PubMed: 36813319
DOI: 10.1016/B978-0-12-821751-1.00001-4 -
Endocrinology Jan 2021Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of... (Review)
Review
Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Because of the central role of mitochondria in energy production, heme biosynthesis, calcium buffering, steroidogenesis, and apoptosis signaling within cells, understanding the molecular mechanisms behind mitochondrial dysregulation and its potential implications in disease is critical. This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Evidence is presented from studies in different human populations, and rodents with genetic manipulations of pathways known to affect mitochondrial function.
Topics: Animals; Humans; Infertility; Mitochondrial Diseases; Obesity
PubMed: 32945868
DOI: 10.1210/endocr/bqaa158 -
Handbook of Clinical Neurology 2023Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous... (Review)
Review
Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous chapters of this book, classical mitochondrial phenotypes and syndromes are extensively described. However, these well-known clinical pictures are more the exception rather than the rule in mitochondrial medicine. In fact, more complex, unspecified, incomplete, and/or overlap clinical entities may be even more frequent, with multisystem appearance or progression. In this chapter, we describe some complex neurological presentations, as well as the multisystem manifestations of mitochondrial diseases, ranging from the brain to the other organs.
Topics: Humans; DNA, Mitochondrial; Mitochondrial Diseases; Brain; Mitochondria; Syndrome; Mutation
PubMed: 36813308
DOI: 10.1016/B978-0-12-821751-1.00003-8 -
Signal Transduction and Targeted Therapy May 2024Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly,... (Review)
Review
Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.
Topics: Humans; Mitochondria; Mitochondrial Diseases; DNA, Mitochondrial; MicroRNAs; Neoplasms; Neurodegenerative Diseases; Cardiovascular Diseases; Animals
PubMed: 38744846
DOI: 10.1038/s41392-024-01839-8 -
Endocrine Reviews May 2022Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine...
Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes mellitus being predominant but also include hypogonadism, hypoadrenalism, and hypoparathyroidism. There have been major developments in mitochondrial disease over the past decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow-up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow-up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next-generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important because it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial because important reproductive options have been developed that will prevent the transmission of mitochondrial disease because of mitochondrial DNA variants to the next generation.
Topics: Diabetes Mellitus; Genetic Testing; Humans; Mitochondria; Mitochondrial Diseases; Phenotype
PubMed: 35552684
DOI: 10.1210/endrev/bnab036