1,721,028 research outputs found
Towards a therapy for mitochondrial disease: an update
Full text linkPreclinical work aimed at developing new therapies for mitochondrial diseases has recently given new hopes and opened unexpected perspectives for the patients affected by these pathologies. In contrast, only minor progresses have been achieved so far in the translation into the clinics. Many challenges are still ahead, including the need for a better characterization of the pharmacological effects of the different
approaches and the design of appropriate clinical trials with robust outcome measures for this extremely heterogeneous, rare, and complex group of disorders. In this review, we will discuss the most important achievements and the major challenges in this very dynamic research field
Historical perspective on mitochondrial medicine
No full textIn this review, we trace the origins and follow the development of mitochondrial medicine from the premolecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water. © 2010 Wiley-Liss, Inc
Metabolic disorders of fetal life: Glycogenoses and mitochondrial defects of the mitochondrial respiratory chain
No full textTwo major groups of inborn errors of energy metabolism are reviewed -glycogenoses and defects of the mitochondrial respiratory chain - to see how often these disorders present in fetal life or neonatally. After some general considerations on energy metabolism in the pre- and postnatal development of the human infant, different glycogen storage diseases and mitochondrial encephalomyopathies are surveyed. General conclusions are that: (i) disorders of glycogen metabolism are more likely to cause 'fetal disease' than defects of the respiratory chain; (ii) mitochondrial encephalomyopathies, especially those due to defects of the nuclear genome, are frequent causes of neonatal or infantile diseases, typically Leigh syndrome, but usually do not cause fetal distress; (iii) notable exceptions include mutations in the complex III assembly gene BCS1L resulting in the GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death), and defects of mitochondrial protein synthesis, which are the 'new frontier' in mitochondrial translational research. © 2011
CoQ 10 deficiencies and MNGIE: Two treatable mitochondrial disorders
No full textBackground: Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q 10 (CoQ 10 or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Scope of review: Here, we describe clinical and molecular features of CoQ 10 deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ 10 deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ 10 biosynthesis, often improve with CoQ 10 supplementation. In vitro and in vivo studies of CoQ 10 deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ 10 deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE. Major conclusions: CoQ 10 deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules. General significance: Studies of CoQ 10 deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010. © 2012 Elsevier B.V
mtDNA maintenance: disease and therapy
No full textMitochondrial maintenance disorders present as a spectrum ranging from severe infantile multisystemic syndrome to childhood or adult tissue-specific diseases. Hallmark is the variable association of qualitative (point mutations, multiple deletions) or quantitative (copy number reduction) molecular genetic defect of mitochondrial DNA (mtDNA), biochemical dysfunction with multiple OXPHOS defects and morphological alterations of the mitochondrial network.
Therapies for mitochondrial disorders, targeting pathogenic mechanism with “general” or “disease tailored” action, have been successfully experimented in in vitro and in vivo studies. Preclinical evidence of efficacy and safety has led for some of them to the translation into clinical trials. Those are specifically available for treatment in mtDNA maintenance disorders, bringing the hope to find a definitive cure in the immediate future.
In this chapter, we will present an overview of the clinical syndrome in the mtDNA replication pathway and will elucidate the potential application of pharmacological approaches with general action to mtDNA maintenance disorders by analyzing compounds increasing mitochondrial biogenesis or modulating mTOR pathway. In addition, we will explore supplementation of nucleosides, clearance of toxic metabolites and enzyme replacement therapies in enzymatic deficiencies and gene therapy approaches in the same pathway
From the Structural and (Dys)Function of ATP Synthase to Deficiency in Age-Related Diseases
Full text linkThe ATP synthase is a mitochondrial inner membrane complex whose function is essential for cell bioenergy, being responsible for the conversion of ADP into ATP and playing a role in mitochondrial cristae morphology organization. The enzyme is composed of 18 protein subunits, 16 nuclear DNA (nDNA) encoded and two mitochondrial DNA (mtDNA) encoded, organized in two domains, FO and F1. Pathogenetic variants in genes encoding structural subunits or assembly factors are responsible for fatal human diseases. Emerging evidence also underlines the role of ATP-synthase in neurodegenerative diseases as Parkinson’s, Alzheimer’s, and motor neuron diseases such as Amyotrophic Lateral Sclerosis. Post-translational modification, epigenetic modulation of ATP gene expression and protein level, and the mechanism of mitochondrial transition pore have been deemed responsible for neuronal cell death in vivo and in vitro models for neurodegenerative diseases. In this review, we will explore ATP synthase assembly and function in physiological and pathological conditions by referring to the recent cryo-EM studies and by exploring human disease models
Metabolic myopathies
No full textWe consider recent developments in disorders affecting three areas of metabolism: glycogen, fatty acids, and the mitochondrial respiratory chain. Among the glycogenoses, new attention has been directed to defects of glycogen synthesis resulting in absence rather than excess of muscle glycogen ("aglycogenosis"). These include defects of glycogen synthetase and defects of glycogenin, the primer of glycogen synthesis. Considerable progress also has been made in our understanding of alterations of glycogen metabolism that result in polyglucosan storage. Among the disorders of lipid metabolism, mutations in the genes encoding two triglyceride lipases acting hand in hand cause severe generalized lipid storage myopathy, one associated with ichthyosis (Chanarin-Dorfman syndrome), the other dominated by juvenile-onset weakness. For the mitochondrial myopathies, we discuss the importance of homoplasmic mitochondrial DNA mutations and review the rapid progress made in our understanding of the coenzyme Q10 deficiencies, which are often treatable. © Springer Science+Business Media, LLC 2010
Mitochondrial metabolism in neural stem cells and implications for neurodevelopmental and neurodegenerative diseases
Full text linkAbstract Mitochondria are cytoplasmic organelles having a fundamental role in the regulation of neural stem cell (NSC) fate during neural development and maintenance. During embryonic and adult neurogenesis, NSCs undergo a metabolic switch from glycolytic to oxidative phosphorylation with a rise in mitochondrial DNA (mtDNA) content, changes in mitochondria shape and size, and a physiological augmentation of mitochondrial reactive oxygen species which together drive NSCs to proliferate and differentiate. Genetic and epigenetic modifications of proteins involved in cellular differentiation (Mechanistic Target of Rapamycin), proliferation (Wingless-type), and hypoxia (Mitogen-activated protein kinase)–and all connected by the common key regulatory factor Hypoxia Inducible Factor-1A–are deemed to be responsible for the metabolic shift and, consequently, NSC fate in physiological and pathological conditions. Both primary mitochondrial dysfunction due to mutations in nuclear DNA or mtDNA or secondary mitochondrial dysfunction in oxidative phosphorylation (OXPHOS) metabolism, mitochondrial dynamics, and organelle interplay pathways can contribute to the development of neurodevelopmental or progressive neurodegenerative disorders. This review analyses the physiology and pathology of neural development starting from the available in vitro and in vivo models and highlights the current knowledge concerning key mitochondrial pathways involved in this process
Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy
No full textAbstract
Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (&lt;10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11–59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A&gt;G in Europe and c.518T&gt;G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype–phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan–Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.</jats:p
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