Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy

Floreani, Maura; Napoli, Eleonora; Martinuzzi, Andrea; Pantano, Giorgia; Riva, Valentina; Trevisan, Roberta; Bisetto, Elena; Valente, Lucia; Carelli, Valerio; Dabbeni-Sala, Federica

doi:10.1111/j.1742-4658.2004.04542.x

Cited by 97 publications

(88 citation statements)

References 48 publications

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“…Studies analyzing the impact of mutations in mtDNA-encoded genes on ROS production in different mitochondrial disease models (fibroblasts, transmitochondrial cybrids and neuronal NT2 cells) have frequently revealed increased ROS levels (Pitkanen and Robinson, 1996;Rana et al, 2000;Geromel et al, 2001;Wong et al, 2002;Beretta et al, 2004;Floreani et al, 2005;Gonzalo et al, 2005;Vives-Bauza et al, 2006). The deleterious effect of each mutation could be influenced by the genetic background of a specific patient, as the biosynthesis of the OXPHOS complexes implies the interaction between many different subunits and regulatory factors.…”

Section: Role Of the Mtdna Genetic Background On The Rc Dysfunction Amentioning

confidence: 99%

“…proposed as the main contributors to the pathogenesis of LHON (Wong et al, 2002;Floreani et al, 2005;Beretta et al, 2006;Sala et al, 2008). Our group analyzed the effect of the most common LHON mutations that lead to complex I deficiency on the assembly of the native mitochondrial RC complexes, and also checked whether distinct mitochondrial genetic backgrounds differentially affected this process (Pello et al, 2008).…”

Section: Role Of the Mtdna Genetic Background On The Rc Dysfunction Amentioning

confidence: 99%

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Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Section: Role Of the Mtdna Genetic Background On The Rc Dysfunction Amentioning

confidence: 99%

Section: Role Of the Mtdna Genetic Background On The Rc Dysfunction Amentioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

144

View full text Add to dashboard Cite

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“…Subsequent analysis of these cybrids (11) have revealed partial complex I and site I respiration defects, reduced ATP production, increased mitochondrial ROS production, sensitization of the mitochondrial permeability transition pore (mtPTP) with predilection to apoptosis, and oxidative stress-induced inhibition of the excitatory glutamate transporter 1 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

Mouse mtDNA mutant model of Leber hereditary optic neuropathy

Lin

Sharpley

Fan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.eber hereditary optic neuropathy (LHON), the first inherited mitochondrial (mt)DNA disease reported (1), is thought to be one of the most prevalent diseases caused by mtDNA missense mutations, having an estimated frequency of 15 in 100,000 (2). Most European LHON mutations occur in the mtDNA oxidative phosphorylation (OXPHOS) complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) genes, the three most common being the ND4 gene mutation at nucleotide G11778A causing an arginine 340 to histidine (R340H) substitution (1), the ND1 G3460A (A52T) mutation (3), and the ND6 T14484C (M64V) mutation (4). Milder LHON mutations are generally homoplasmic (pure mutant). In contrast, more severe mtDNA complex I ND gene mutations can cause basal ganglia degeneration presenting as dystonia or Leigh syndrome when homoplasmic but optic atrophy when heteroplasmic (mixed mutant and normal mtDNAs). Two examples of such mutations are ND6 G14459A (A72V) (5) and ND6 G14600A (P25L) (6).LHON generally presents in the second or third decade of life as acute or subacute onset of central vision loss, first in one eye and then in the other. The percentage of optic atrophy in patients varies markedly among pedigrees. Male patients are two to five times more likely to develop blindness than female patients (2), and maternal relatives who have not progressed to subacute optic atrophy can still show signs of visual impairment (7,8).In LHON, optic atrophy is associated with preferential loss of the central small-caliber optic nerve fibers of the papillomacular bundle, resulting in central scotoma but with sparing of the largercaliber peripheral fibers and retention of peripheral vision. The loss of the optic nerve fibers is attributed to the death of retinal ganglion cells (RGC) as a result of the high energy demand placed on the unmyelinated portion of the optic nerve fibers anterior to the lamina cribosa, an area associated with high mitochondrial density (2).Complex I is the largest and most intricate of the mitochondrial OXPHOS complexes. It is comprised of 45 subunits, 7 (ND1, -2, -3, -4, -4L, -5, and -6) of which are coded by the mtDNA (9). Complex I transfers electrons from NADH to ubiquinone, and the energy released from this redox reaction is coupled to pumping protons across the mitochondrial in...

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“…An enhanced ROS generation has been observed in inherited complex I deficiencies (Pitkanen and Robinson, 1996;Luo et al, 1997). It has been reported that transmitochondrial cytoplasmatic hybrids or cybrids (Vergani et al, 1995) carrying the three most common Leber's hereditary optic neuropathy pathogenic mutations in complex I subunit genes show a partial respiratory defect as well as a significant increase in ROS production (Floreani et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

et al. 2006

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Familial Non-Medullary Thyroid Carcinoma (fNMTC) represents 3 -7% of all thyroid tumours and is associated with some of the highest familial risks among all cancers, with an inheritance pattern compatible with an autosomal dominant model with reduced penetrance. We previously mapped a predisposing locus, TCO (Thyroid tumour with Cell Oxyphilia) on chromosome 19p13.2, for a particular form of thyroid tumour characterised by cells with an abnormal proliferation of mitochondria (oxyphilic or oncocytic cells). In the present work, we report the systematic screening of 14 candidate genes mapping to the region of linkage in affected TCO members, that led us to identify two novel variants respectively in exon 9 and exon 13 of TIMM44, a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumour development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO.

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Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy

Cited by 97 publications

References 48 publications

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Mouse mtDNA mutant model of Leber hereditary optic neuropathy

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

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