A Mutation in Para-Hydroxybenzoate-Polyprenyl Transferase (COQ2) Causes Primary Coenzyme Q10 Deficiency

Quinzii, Catarina M.; Naini, Ali; Salviati, Leonardo; Trevisson, Eva; Navas, Plácido; DiMauro, Salvatore; Hirano, Michio

doi:10.1086/500092

Cited by 322 publications

(288 citation statements)

References 33 publications

(37 reference statements)

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“…Activities of NADH: cytochrome c reductase (complexes I+III) and citrate synthase were determined spectrophotometrically in sonicated, permeabilized fibroblasts using previously described methods [16,18]. Results are expressed as units/citrate synthase (mean±SD).…”

Section: Mitochondrial Respiratory Chain Enzyme Activities and Coq Lementioning

confidence: 99%

“…The relationship between mtDNA mutations and cellular damage, as well as the activation of compensatory mechanisms to promote cell survival, are poorly understood. Treatments for mitochondrial diseases in general are largely inadequate [16]. As with many mitochondrial diseases, there is no cure for MERRF, and treatment is primarily symptomatic.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

et al. 2012

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Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A>G in the gene MT-TK, which encodes transfer RNA Lysine , affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease.

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Section: Mitochondrial Respiratory Chain Enzyme Activities and Coq Lementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

et al. 2012

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“…CoQ also limits the production of reactive oxygen species that can damage cellular processes. Human patients with CoQ deficiency exhibit diverse symptoms ranging in severity from infantile multiorgan disease (13,14) to discrete late onset cerebellar ataxia (15,16). Although the essential role of CoQ in mitochondrial energy production and cell survival are likely to account for these deficits, the molecular basis for this heterogeneity is unclear, as are the specific cellular pathologies arising from CoQ deficiency (17).…”

mentioning

confidence: 99%

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Earls

Hacker²,

Watson³

et al. 2010

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

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Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.cell death | disease | mitochondria | neurodegeneration | necrosis

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“…Although it was already described 30 years ago, molecular defects were identified only recently. Specifically, the first mutations in two genes encoding the initial two CoQ 10 biosynthetic enzymes (PDSS2 subunit of COQ1, and COQ2) were identified in infants or children with encephalomyopathy or Leigh syndrome and nephrotic syndrome [32,33]. Later, mutations in PDSS1 and others in COQ2 were indentified in infants or children with encephalomyopathy and/or nephrotic syndrome [34,35].…”

Section: Secondary Mitochondrial Disordersmentioning

confidence: 99%

Mitochondrial Disorders Therapy: The Utility of Melatonin~!2009-11-18~!2010-01-21~!2010-06-23~!

López¹,

Acuña-Castroviejo²,

Pino³

et al. 2010

TOBIOJ

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Mitochondria play a central role in the cell physiology. It is now recognized that, besides their classic function of energy metabolism, mitochondria are enrolled in multiple cell functions including energy distribution through the cell, energy/heat modulation, reactive oxygen species (ROS) regulation, calcium homeostasis, and apoptosis control. Recently, evidence is accumulating for a direct participation of mitochondria in stem cell proliferation and/or differentiation. All these functions suggest that mutations in either nuclear or mitochondrial DNA may induce serious cell impairments, and there is now evidence of more than 200 mtDNA mutations responsible for human pathologies. Moreover, mitochondria are, simultaneously, the main producer and target of ROS and, thus, multiple mitochondrial diseases are related to ROSinduced mitochondrial injuries. Among these, neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), inflammatory diseases such as sepsis, and aging itself, are caused or accompanied by ROS-induced mitochondrial dysfunctions. With regard to its action spectrum as an antioxidant, melatonin may be regarded as a firstchoice agent for preventing and/or reducing the excess of ROS, thereby maintaining mitochondrial homeostasis. Multiple in vitro and in vivo experiments have shown the protective role of melatonin on mitochondrial physiology, yielding a significant improvement in those diseases in which energy supply to the cell had been compromised. New lines of evidence suggest the participation of mitochondria in stem cell proliferation and differentiation, and preliminary data support the role of melatonin in these processes. This review accounts for the multiple functions of mitochondria and the mechanisms involved in the numerous beneficial effects of melatonin to maintain mitochondrial homeostasis.

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A Mutation in Para-Hydroxybenzoate-Polyprenyl Transferase (COQ2) Causes Primary Coenzyme Q10 Deficiency

Cited by 322 publications

References 33 publications

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

Recovery of MERRF Fibroblasts and Cybrids Pathophysiology by Coenzyme Q10

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Mitochondrial Disorders Therapy: The Utility of Melatonin~!2009-11-18~!2010-01-21~!2010-06-23~!

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