Mitochondrial disorders

Current Opinion in Neurology

Volumn 20, Issue 5, 2007, Pages 564-571

  Zeviani, Massimo ^a   Carelli, Valerio ^b  

^a DEPARTMENT OF NEUROSURGERY   (Italy)

^b UNIVERSITY OF BOLOGNA   (Italy)

Author keywords

Maternal inheritance; Mitochondrial disease; Mitochondrial DNA; Oxidative phosphorylation; Respiratory chain

Indexed keywords

MITOCHONDRIAL DNA; NUCLEOTIDE; UBIQUINONE;

APOPTOSIS; CELL DIVISION; CELL ORGANELLE; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENZYME DEFICIENCY; ENZYME SYNTHESIS; GENE EXPRESSION; GENETIC DISORDER; GENETIC HETEROGENEITY; GENETIC STABILITY; GENETIC TRAIT; HUMAN; HUNTINGTON CHOREA; METABOLISM; NERVE DEGENERATION; NONHUMAN; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOPHYSIOLOGY; REVIEW; RNA TRANSLATION; TISSUE SPECIFICITY;

DNA, MITOCHONDRIAL; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MITOCHONDRIA; MITOCHONDRIAL DISEASES; MUTATION; NEURODEGENERATIVE DISEASES; OXIDATIVE PHOSPHORYLATION; UBIQUINONE;

EID: 34648839889     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/WCO.0b013e3282ef58cd     Document Type: Review

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88. Davies VJ, Hollins AJ, Piechota MJ, et al. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet 2007; 16:1307-1318. Both OPA1 mouse models [87,88•] are based on mutations inducing haploin-sufficiency and both show how homozygosity is embryonically lethal, whereas heterozygous animals develop age-dependent optic neuropathy.
89. Chung KW, Kim SB, Park KD, et al. Early onset severe and late-onset mild Charcot- Marie-Tooth disease with mitofusin 2 (MFN2) mutations. Brain 2006; 129:2103-2118.
90. Verhoeven K, Claeys KG, Zuchner S, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain 2006; 129:2093-2102.
91. Zuchner S, De Jonghe P, Jordanova A, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol 2006; 59:276-281.
92. Carelli V, La Morgia C, Iommarini L, et al. Mitochondrial optic neuropathies: how two genomes may kill the same cell type? Biosci Rep 2007; 27:173-184. In a subset of MFN2 patients, optic atrophy is reported, with some hallmark features of mitochondrial optic neuropathies, grouping this disease with LHON, OPA1-related ADOA, complicated spastic paraparesis due to mutant paraplegin, and Friedreich ataxia.
93. Baloh RH, Schmidt RE, Pestronk A, Milbrandt J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 2007; 27:422-430. Mutant MFN2 expressed in cultured dorsal root ganglion neurons impairs axoplasmic transport, alters the mitochondrial shape and distribution and induces axonal degeneration without altering mitochondrial OXPHOS or ATP levels.
94. Loiseau D, Chevrollier A, Verny C, et al. Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease. Ann Neurol 2007; 61:315-323. In contrast with the previous study [93•], this paper reports that mutations in MFN2 are deleterious for fibroblast cell bioenergetics, by inducing mitochondrial uncoupling and reduction of mitochondrial membrane potential.
95. Waterham HR, Koster J, van Roermund CW, et al. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 2007; 356:1736-1741. The infant patient presented microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. Excessive tubulization of the mitochondrial meshwork was documented in her fibroblasts. DLP1 controls the fission of both mitochondria and peroxisomes; this is the first genetically documented defect common to both organelles.
96. Bender A, Krishnan KJ, Morris CM, et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 2006; 38:515-517. Using single cell microdissection, Bender et al. show that somatic mtDNA rearrangements accumulate in the dopaminergic neurons of Parkinson's disease patients, reaching levels (>50%) that are usually associated with OXPHOS failure. The latter was proven to occur by showing that neurons with high levels of deletions are also deficient in cytochrome c oxidase activity. The substantia nigra seems to be exquisitely prone to accumulate damaged mtDNA, since other areas of the brain, for instance the hippocampus, showed much lower levels of deletions in both Parkinson's disease patients and age-matched controls.
97. Ekstrand MI, Terzioglu M, Galter D, et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A 2007; 104:1325-1330.
98. Tan EK, Yew K, Chua E, et al. PINK1 mutations in sporadic early-onset Parkinson's disease. Mov Disord 2006; 21:789-793.
99. Ibanez P, Lesage S, Lohmann E, et al. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain 2006; 129:686-694.
100. Toft M, Myhre R, Pielsticker L, et al. PINK1 mutation heterozygosity and the risk of Parkinson's disease. J Neurol Neurosurg Psychiatry 2007; 78:82-84.
101. Djarmati A, Hedrich K, Svetel M, et al. Heterozygous PINK1 mutations: a susceptibility factor for Parkinson disease? Mov Disord 2006; 21:1526-1530.
102. Solans A, Zambrano A, Rodriguez M, Barrientos A. Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet 2006; 15:3063-3081.
103. Fukui H, Moraes CT. Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates. Hum Mol Genet 2007; 16:783-797. The papers by Solans et al. [102] and Fukui et al. [103•] both show that expression of mutant htt fragments containing pathological poly-glutamine expansions inhibit cell respiration by decreasing the activity of complexes II and III. These findings provide a link between the primary defect in Huntington's disease and OXPHOS impairment, possibly mediated by oxidative stress.
104. Weydt P, Pineda VV, Torrence AE, et al. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC1-alpha in Huntington's disease neurodegeneration. Cell Metab 2006; 4:349-362. PGC1-α is a master regulator of mitochondrial biogenesis and OXPHOS. Overexpression of PGC1-α in Huntington's disease striatal neurons was protective against complex II damage induced by 3-nitropropionic acid, a classical pharmacological model of Huntington's disease. PolyQ-expanded htt has been shown to alter transcription of a number of genes, including PGC1-α. In turn, transcriptional dysregulation of OXPHOS genes, induced by reduced PGC1-α expression, can contribute to the pathogenesis of Huntington's disease.
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