A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes

Coumarin-DPPO a new bio-based phosphorus additive for poly(lactic acid): Processing and flame retardant application

This study addresses very important aspects of the sustainable development of new flame retardant materials: (i) the preparation of a novel flame retardant (FR) additive from bio-resource, (ii) its use as FR additive in poly(lactic acid) (PLA) based composites and, (iii) the in vitro toxicity assessment of the FR. The synthesis of this bio-based FR additive was achieved through a phospha-Michael addition of diphenylphosphine oxide (DPPO) and the naturally occurring compound coumarin, yielding 4-(diphenylphosphoryl)chroman-2-one (CU-DPPO). The flame-retarded CU-DPPO PLA composites were prepared either via conventional melt blending of commercially available PLA or through reactive extrusion (REX) of L-lactide. Characterization of the composites was performed through nuclear magnetic resonance (NMR), size exclusion chromatography (SEC) and thermogravimetric analysis (TGA). TGA analysis of the FR-PLA composites showed an increase in thermal stability, confirming the beneficial effect of the CU-DPPO additive. Direct insertion probe mass spectrometry (DIP-MS) analysis was used to gain insight on the mechanism of action of the FR additive, suggesting gas-phase activity. Rheological measurements exhibited the thermo-oxidative stabilizing effect in the modified PLA. The flame retardancy of the melt-blended PLA composites with CU-DPPO was investigated by limited oxygen index (LOI), cone calorimetry and vertical burning tests (UL 94 and BKZ-VB). Samples containing 10 wt.% of CU-DPPO showed improved fire performance with a limiting oxygen index (LOI) of 29%, passing Swiss vertical burning test (BKZ-VB) and obtaining a V-0 rating in the UL 94 test. Moreover, a preliminary toxicity assessment of the CU-DPPO, carried out using an established in vitro platform, showing no adverse effects on cell viability.ISSN:0141-3910ISSN:1873-232

Inactivation of Pif1 helicase causes a mitochondrial myopathy in mice

International audienceMutations in genes coding for mitochondrial helicases such as TWINKLE and DNA2 are involved in mitochondrial myopathies with mtDNA instability in both human and mouse. We show that inactivation of Pif1, a third member of the mitochondrial helicase family, causes a similar phenotype in mouse. pif1-/- animals develop a mitochondrial myopathy with respiratory chain deficiency. Pif1 inactivation is responsible for a deficiency to repair oxidative stress-induced mtDNA damage in mouse embryonic fibroblasts that is improved by complementation with mitochondrial isoform mPif1(67). These results open new perspectives for the exploration of patients with mtDNA instability disorders

CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis

International audienceCHCHD10-related diseases include mitochondrial DNA instability disorder, frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) clinical spectrum, late-onset spinal motor neuropathy (SMAJ), and Charcot-Marie-Tooth disease type 2 (CMT2). Here, we show that CHCHD10 resides with mitofilin, CHCHD3 and CHCHD6 within the "mitochondrial contact site and cristae organizing system" (MICOS) complex. CHCHD10 mutations lead to MICOS complex disassembly and loss of mitochondrial cristae with a decrease in nucleoid number and nucleoid disorganization. Repair of the mitochondrial genome after oxidative stress is impaired in CHCHD10 mutant fibroblasts and this likely explains the accumulation of deleted mtDNA molecules in patient muscle. CHCHD10 mutant fibroblasts are not defective in the delivery of mitochondria to lysosomes suggesting that impaired mitophagy does not contribute to mtDNA instability. Interestingly, the expression of CHCHD10 mutant alleles inhibits apoptosis by preventing cytochrome c release

Reply: CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis

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Reply: Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis

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Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease.

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Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation.

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Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?

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Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China.

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