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Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions
Full text linkBackground: An increasing number of mitochondrial DNA (mtDNA) mutations, mainly in complex I genes, have
been associated with variably overlapping phenotypes of Leber’s hereditary optic neuropathy (LHON),
mitochondrial encephalomyopathy with stroke-like episodes (MELAS) and Leigh syndrome (LS). We here describe
the first case in which the m.4171C>A/MT-ND1 mutation, previously reported only in association with LHON, leads
also to a Leigh-like phenotype.
Case presentation: A 16-year-old male suffered subacute visual loss and recurrent vomiting and vertigo associated
with bilateral brainstem lesions affecting the vestibular nuclei. His mother and one sister also presented subacute
visual loss compatible with LHON. Sequencing of the entire mtDNA revealed the homoplasmic m.4171C>A/MT-ND1
mutation, previously associated with pure LHON, on a haplogroup H background. Three additional non-synonymous
homoplasmic transitions affecting ND2 (m.4705T>C/MT-ND2 and m.5263C>T/MT-ND2) and ND6 (m.14180T>C/MT-ND6)
subunits, well recognized as polymorphisms in other mtDNA haplogroups but never found on the haplogroup H
background, were also present.
Conclusion: This case widens the phenotypic expression of the rare m.4171C>A/MT-ND1 LHON mutation, which
may also lead to Leigh-like brainstem lesions, and indicates that the co-occurrence of other ND non-synonymous
variants, found outside of their usual mtDNA backgrounds, may have increased the pathogenic potential of the
primary LHON mutation
Molecular mechanisms behind inherited neurodegeneration of the optic nerve
Full text linkInherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphor-ylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mito-chondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neuro-degeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies
Mitochondrial retinopathies
Full text linkThe retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more com-plex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns–Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mito-chondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29
Dominance in mitochondrial disorders.
No full textDominant traits are rare in mitochondrial disorders but include important nosological entities such as alterations of organellar biogenesis and abnormalities in the structural integrity of the mitochondrial genome, determined by mutations in genes involved in its maintenance and propagation. Both haplo-insufficiency and 'gain-of-function' mechanisms underlie the pathogenesis of these disorders. Impairment in energy supply, abnormal mitochondrial trafficking, increased toxic damage by oxygen radicals, and mitochondrially driven apoptosis have been documented in different dominant syndromes. In addition, maternally inherited mutations of mitochondrial DNA can sometimes simulate dominant traits, mainly because of reduced penetrance and complex interaction with genetic and environmental factors. © SSIEM and Springer 2005
Mitochondrial disorders.
No full textPURPOSE OF REVIEW: Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration. RECENT FINDINGS: Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models. SUMMARY: The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'. © 2007 Lippincott Williams & Wilkins, Inc
Effects of genistein on Leber’s hereditary optic neuropathy (LHON) mitochondrial metabolism.
No full textLeber's hereditary optic neuropathy (LHON), a maternally inherited form of central vision loss, is caused by pathogenic point mutations in mitochondrial-encoded subunits of complex I, the first site of the mitochondrial respiratory chain. The most frequent LHON-associated mutations are the homoplasmic m. 11778 G>A in MTND4 gene, the m. 14484 T>C in MTND6 and the m.3460 G>A in ND1 gene [1-2].
One of the open problems in LHON is the variable penetrance: mtDNA mutations are necessary but not sufficient to induce the clinical phenotype. In fact, approximately 50% of males and only 10% of females harboring a primary mtDNA mutation develop the disease. Proposed modifiers include, secondary mtDNA mutations, mtDNA haplogroup, nuclear encoded genes, tobacco and alcohol consumption, and the exposure to toxic compounds [3-4].
By using the cell model of trans-mitochondrial cybrids we recently showed that estrogens ameliorate mitochondrial function, increase cell viability and prevent oxidative stress damage in LHON [5]. Thus, different exposure to estrogens between males and females may account for the still unexplained male prevalence.
Aim of the present study was to compare the anti-oxidative effects of estrogens and phytoestrogens (i.e genistein, one of the soy isoflavones) on LHON metabolism by using the cybrid cells model.
Cybrids were incubated in glucose-free, galactose supplemented medium, forcing the cells to rely mainly on the mitochondrial respiratory chain to produce ATP. Results show that, contrary to control cybrids, in each cell line harboring one of the three most frequent LHON pathogenic mutations, ROS increase, mitochondrial network is altered and there is an high percentage of cell death. Genistein (0.1 μM), similar to estrogens, prevents the alterations induced by galactose on cell growth, ROS production and mitochondrial network. Furthermore genistein activates ERK1 and ERK2 MAP kinases thus up-regulating Mn-SOD antioxidant enzyme. The effects of genistein are antagonised by ERs specific inhibitor (ICI 182780), demonstrating the involvement of estrogen-receptors as mechanism of protection of LHON cybrids from oxidative stress.
Our results open new therapeutic approaches for LHON.
1. Carelli V et al. (2004) - Prog Retin Eye Res, 23: 53–89.
2. Man PY et al. (2009) - J Med Genet, 46: 145–58.
3. Phasukkijwatana N et al. (2010) - Hum Genet 2010, 128: 39–49.
4. Kirkman MA et al. (2009) - Brain, 132: 2317–26.
5. Giordano C, Montopoli M et al. (2011) – Brain, 134:220-34
Factors in zero-order release of clonidine hydrochloride from monolithic polydimethylsiloxane matrices
No full textPathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction
No full textHere we define a category of human, maternally inherited disorders that are characterized by a homoplasmic mtDNA pathogenic mutation with variable penetrance and a stereotypical clinical expression, usually restricted to a single tissue. Examples of such disorders include Leber's hereditary optic neuropathy, mitochondrial non-syndromic sensorineural hearing loss, and a form of mitochondrial hypertrophic cardiomyopathy. The mtDNA mutation is necessary, but not sufficient to induce the pathology, and multiple lines of evidence suggest a two-locus genetic model involving a primary mitochondrial mutation and a nuclear modifier. The nuclear modifier does not induce any pathology per se, but it contributes to the pathogenic effect of the mitochondrial mutation. The nuclear modifier could be a common functional polymorphism in a tissue-specific protein, possibly with mitochondrial location
Nuclear genes in mitochondrial disorders
No full textNuclear genes encode hundreds of proteins involved in mitochondrial biogenesis and oxidative phosphorylation (OXPHOS). Nevertheless, the identification of nuclear genes responsible for OXPHOS-related disorders has proceeded at a much slower pace, compared with the discovery and characterization of mtDNA mutations. Reasons for such a gap include rarity of syndromes, genetic heterogeneity, and ignorance on this nuclear gene repertoire in humans. This scenario is changing rapidly, thanks to the discovery of several OXPHOS-related human genes, and to the identification in some of them of disease-associated mutations. In addition, new strategies - based on transcriptome and proteome analysis, and functional complementation assays - have been applied successfully to mitochondrial medicine
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