1,721,415 research outputs found
Mitochondrial DNA: Impacting Central and Peripheral Nervous Systems
No full textBecause of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA (mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy
Clinical syndromes associated with mtDNA mutations: Where we stand after 30 years
No full textThe landmark year 1988 can be considered as the birthdate of mitochondrial medicine, when the first pathogenic mutations affecting mtDNA were associated with human diseases. Three decades later, the field still expands and we are not ‘scraping the bottom of the barrel’ yet. Despite the tremendous progress in terms of molecular characterization and genotype/phenotype correlations, for the vast majority of cases we still lack a deep understanding of the pathogenesis, good models to study, and effective therapeutic options. However, recent technological advances including somatic cell reprogramming to induced pluripotent stem cells (iPSCs), organoid technology, and tailored endonucleases provide unprecedented opportunities to fill these gaps, casting hope to soon cure the major primary mitochondrial phenotypes reviewed here. This group of rare diseases represents a key model for tackling the pathogenic mechanisms involving mitochondrial biology relevant to much more common disorders that affect our currently ageing population, such as diabetes and metabolic syndrome, neurodegenerative and inflammatory disorders, and cancer
Dominant Optic Atrophy (DOA): Modeling the Kaleidoscopic Roles of OPA1 in Mitochondrial Homeostasis
Full text linkIn the year 2000, the discovery of OPA1 mutations as causative for dominant optic atrophy (DOA) was pivotal to rapidly expand the field of mitochondrial dynamics and describe the complex machinery governing this pathway, with a multitude of other genes and encoded proteins involved in neurodegenerative disorders of the optic nerve. OPA1 turned out to be a much more complex protein than initially envisaged, connecting multiple pathways beyond its strict role in mitochondrial fusion, such as sensing of OXPHOS needs and mitochondrial DNA maintenance. As a consequence, an increasing need to investigate OPA1 functions at multiple levels has imposed the development of multiple tools and models that are here reviewed. Translational mitochondrial medicine, with the ultimate objective of translating basic science necessary to understand pathogenic mechanisms into therapeutic strategies, requires disease modeling at multiple levels: from the simplest, like in yeast, to cell models, including the increasing use of reprogrammed stem cells (iPSCs) from patients, to animal models. In the present review, we thoroughly examine and provide the state of the art of all these approaches
Reply: Mitochondrial DNA copy number differentiates the Leber's hereditary optic neuropathy affected individuals from the unaffected mutation carriers
Full text link197th ENMC international workshop: Neuromuscular disorders of mitochondrial fusion and fission - OPA1 and MFN2 molecular mechanisms and therapeutic strategies. 26-28 April 2013, Naarden, The Netherlands
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International workshop: outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. Rome, Italy, 16-18 november 2016
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Lebers hereditary optic neuropathy: New quinone therapies change the paradigm
No full textLebers hereditary optic neuropathy is a maternally inherited disease of the optic nerve prevalent in young adult males that usually leads to permanent and severe blindness. Three primary mitochondrial DNA (mtDNA) mutations affecting the respiratory complex I account for approximately 95% of cases. The mtDNA mutations are necessary but not sufficient to cause blindness. The incomplete penetrance is probably due to complex combinations of nuclear modifying genes, age and gender issues and specific environmental risk factors. The optic nerve is particularly susceptible to mitochondrial dysfunction, particularly the intra-retinal unmyelinated axons. There has been a dearth of effective treatments for this devastating cause of visual loss. Recently, there has been much progress in understanding the natural history and pathogenic mechanisms of Lebers hereditary optic neuropathy. This has led to trials using quinones to overcome the complex I defect produced by the mtDNA mutations. Other therapies are also proposed, such as gene therapy. © 2012 Expert Reviews Ltd
Proteolytic Cleavage of Opa1 Stimulates Mitochondrial Inner Membrane Fusion and Couples Fusion to Oxidative Phosphorylation
Full text linkSummaryMitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism
Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology
Full text linkMelanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive RGCs that mediate many relevant non-image forming functions of the eye, including the pupillary light reflex, through the projections to the olivary pretectal nucleus. In particular, the post-illumination pupil response (PIPR), as evaluated by chromatic pupillometry, can be used as a reliable marker of mRGC function in vivo. In the last years, pupillometry has become a promising tool to assess mRGC dysfunction in various neurological and neuro-ophthalmological conditions. In this review we will present the most relevant findings of pupillometric studies in glaucoma, hereditary optic neuropathies, ischemic optic neuropathies, idiopathic intracranial hypertension, multiple sclerosis, Parkinson's disease, and mood disorders. The use of PIPR as a marker for mRGC function is also proposed for other neurodegenerative disorders in which circadian dysfunction is documented
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