84 research outputs found
Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature
Reduction in the levels of CoQ biosynthetic proteins is related to an increase in lifespan without evidence of hepatic mitohormesis
Mitohormesis is an adaptive response induced by a mild mitochondrial stress that promotes longevity
and metabolic health in different organisms. This mechanism has been proposed as the cause of the
increase in the survival in Coq7+/â (Mclk1+/â) mice, which show hepatic reduction of COQ7, early
mitochondrial dysfunction and increased oxidative stress. Our study shows that the lack of COQ9 in
Coq9Q95X mice triggers the reduction of COQ7, COQ6 and COQ5, which results in an increase in life
expectancy. However, our results reveal that the hepatic CoQ levels are not decreased and, therefore,
neither mitochondrial dysfunction or increased oxidative stress are observed in liver of Coq9Q95X mice.
These data point out the tissue specific differences in CoQ biosynthesis. Moreover, our results suggest
that the effect of reduced levels of COQ7 on the increased survival in Coq9Q95X mice may be due to
mitochondrial mechanisms in non-liver tissues or to other unknown mechanisms.This work was supported by grants from Ministerio de
EconomĂa Competitividad, Spain, and the ERDF (Grant Number SAF2015-65786-R), from the ConsejeriÌa de
EconomiÌa, InnovacioÌn, Ciencia y Empleo, Junta de AndaluciÌa (grant number P10-CTS-6133) and from the
University of Granada (grant reference âUNETEâ, UCE-PP2017-06). AHG is a âFPU fellowâ from the Ministerio
de EducacioÌn Cultura y Deporte, Spain. MLS was a predoctoral fellow from the ConsejeriÌa de EconomiÌa,
InnovacioÌn, Ciencia y Empleo, Junta de AndaluciÌa. LCL was supported by the âRamoÌn y Cajalâ National
Programme, Ministerio de EconomiÌa y Competitividad, Spain (RYC-2011-07643)
Chronic kidney disease and coenzyme Q10 supplementation
Among the potential causes of chronic kidney disease (CKD), mitochondrial respiratory chain (MRC) dysfunction, oxidative stress and inflammation have been implicated as contributor factors to the pathogenesis of this disorder. It is thought that CoQ10 supplementation may offer some therapeutic potential in the treatment of patients with CKD, since CoQ10 has a key role in normal MRC function, as well as having antioxidant and anti-inflammatory action. This article will outline the current knowledge on the use of CoQ10 in the treatment of CK
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