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

Müller, Kathrin; Andersen, Peter M.; Hübers, Annemarie; Marroquin, Nicolai; Volk, Alexander E; Danzer, Karin M; Meitinger, Thomas; Ludolph, Albert C.; Strom, Tim M.; Weishaupt, Jochen H.

doi:10.1093/brain/awu227

Cited by 103 publications

(101 citation statements)

References 6 publications

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“…Moreover, the two living mutation carriers have ongoing disease durations of 43 and 412 years. These findings agree with the previous observation that CHCHD10 mutations are associated with slow progression and long disease duration (6-17 years) (Muller et al, 2014). In the current study, carriers developed ALS in their 40s or 50s (43, 54 and 58 years of age), similar to the reported range of 50-60 years in other CHCHD10 mutation carriers Chaussenot et al, 2014).…”

supporting

confidence: 93%

“…Affected family members were presented with a complex phenotype that included symptoms of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), cerebellar ataxia, Parkinson's disease and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range, including ALS/FTLD (p.S59L and p.P34S) Chaussenot et al, 2014), ALS (p.R15L and p.G66V) (Johnson et al, 2014;Muller et al, 2014), myopathy (p.R15S and p.G58R) (Ajroud-Driss et al, 2015) and lateonset spinal motor neuronopathy (p.G66V) (Penttila et al, 2015). All of them affect exon 2 (a mutational hotspot of CHCHD10).…”

mentioning

confidence: 99%

“…We identified a known CHCHD10 pathogenic p.R15L mutation (Johnson et al, 2014;Muller et al, 2014) in a patient with sporadic ALS (Patient 8807) (Fig. 1A), who developed symptoms involving his upper limb at 54 years of age and remains alive 12 years later.…”

mentioning

confidence: 99%

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Mutation analysis ofCHCHD10in different neurodegenerative diseases

Zhang

Zinman³

et al. 2015

Brain

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confidence: 93%

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confidence: 99%

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Mutation analysis ofCHCHD10in different neurodegenerative diseases

Zhang

Zinman³

et al. 2015

Brain

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“…142 Similarly, in mammals, the abundance of CHCHD4 (or that of its partner ALR) correlated 143 with respiratory chain activity and the oxidation kinetics of subunits CMC1, COA4 (also 144 called CMC3) and COX19 [39]. In human cells, the expression levels of CHCHD4 (or that of 145 its binding partner AIF) and the CIV complex copper chaperone COX17 correlate [36,40].…”

Section: Biogenesis Of Respiratory Chain Complexes 137mentioning

confidence: 98%

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

Modjtahedi

Tokatlidis

Dessen

et al. 2016

Trends in Biochemical Sciences

110

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Members of the coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein family that carry (CX 9 C) type motifs are imported into the mitochondrion with the help of the disulfide relay-dependent MIA import pathway. These evolutionary-conserved proteins are emerging as new cellular factors that control mitochondrial respiration, redox regulation, lipid homeostasis or membrane ultrastructure and dynamics. Here, we discuss recent insights on the activity of known (CX 9 C) motif-carrying proteins in mammals and review current data implicating the MIA40/CHCHD4 import machinery in the regulation of their mitochondrial import. Recent findings and the identification of disease-associated mutations in specific (CX 9 C) motif-carrying proteins have highlighted members of this family of proteins as potential therapeutic targets in a variety of human disorders.

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“…CHCHD10, although highly expressed in heart and skeletal muscle (7), was discovered to be mutated in a proportion of individuals suffering from several neurodegenerative diseases (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The clinical effects of these mutations have been well described (18).…”

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confidence: 99%

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

Purandare

Somayajulu

Hüttemann

et al. 2018

Journal of Biological Chemistry

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Coiled-coil-helix-coiled-coil-helix domaincontaining 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX 9 C family of proteins that mediate cellular stress responses. Despite the identification of several neurodegeneration-associated mutations in the CHCHD10 gene, few studies have assessed its physiological role. Here, we investigated CHCHD10's function as a regulator of oxidative phosphorylation in the mitochondria and the nucleus. We show that CHCHD10 co-purifies with cytochrome c oxidase (COX) and up-regulates COX activity by serving as a scaffolding protein required for MNRR1 phosphorylation, mediated by ARG (ABL proto-oncogene 2, non-receptor tyrosine kinase [ABL2]). The CHCHD10 gene was maximally transcribed in cultured cells at 8% oxygen, unlike MNRR1, which was maximally expressed at 4%, suggesting a fine-tuned oxygen-sensing system that adapts to the varying oxygen concentrations in the human body under physiological conditions. We show that nuclear CHCHD10 protein down-regulates the expression of genes harboring the oxygenresponsive element (ORE) in their promoters by interacting with and augmenting the activity of the largely uncharacterized transcriptional repressor CXXC finger protein 5 (CXXC5). We further show that two genetic CHCHD10 disease variants, G66V and P80L, in the mitochondria exhibit faulty interactions with MNRR1 and COX, reducing respiration and increasing reactive oxygen species (ROS), and in the nucleus abrogating transcriptional repression of ORE-containing genes. Our results reveal that CHCHD10 positively regulates mitochondrial respiration and contributes to transcriptional repression of ORE-containing genes in the nucleus, and that genetic CHCHD10 variants are impaired in these activities.CHCHD10 is a member of the twin CX 9 C family of proteins. This family, of which a number of members have displayed roles in disease (1), consists of proteins that contain two pairs of cysteine residues separated by 9 amino acids. These 4 cysteines form 2 disulfide bonds that stabilize the prototypical Coiled-coil Helix Coiled-coil Helix Domain (CHCHD) that traps CHCHD10 and other twin CX 9 C family members in the mitochondrial intermembrane space (IMS). Other members of this family include CHCHD4 (also called Mia40), necessary for import and proper folding of twin CX 9 C proteins in the IMS (2), and CHCHD3, which acts with CHCHD6 to stabilize mitochondrial cristae (3, 4). Another recently characterized member of this family is MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1; also called CHCHD2), a protein that is upregulated under hypoxic stress, and maximally so at 4% oxygen. 2Besides residing in the mitochondria, MNRR1 is also present in the nucleus. Mitochondrial MNRR1 interacts with cytochrome c oxidase (COX) and is required for optimal enzyme function. A stable knockdown of MNRR1 resembles a mitochondrial disease phenotype with decreased oxygen consumption, decreased cellular growth and mitochondrial membrane potential,...

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

Cited by 103 publications

References 6 publications

Mutation analysis ofCHCHD10in different neurodegenerative diseases

Mutation analysis ofCHCHD10in different neurodegenerative diseases

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): Partners in mitochondrial and nuclear function and dysfunction

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