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Neeraja Purandare, Mallika Somayajulu, Maik Hüttemann, Lawrence I Grossman, Siddhesh Aras
Coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and CHCHD2 (MNRR1) are homologous proteins with 58% sequence identity and belong to the twin CX9C 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])...
March 14, 2018: Journal of Biological Chemistry
Elisa Rubino, Ming Zhang, Tiziana Mongini, Silvia Boschi, Liliana Vercelli, Alessandro Vacca, Flora Govone, Annalisa Gai, Maria Teresa Giordana, Mark Grinberg, Ekaterina Rogaeva, Innocenzo Rainero
Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10...
February 14, 2018: Neurobiology of Aging
Xiang-Qian Che, Qian-Hua Zhao, Yue Huang, Xia Li, Ru-Jing Ren, Sheng-Di Chen, Qi-Hao Guo, Gang Wang
As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c...
2018: Journal of Alzheimer's Disease: JAD
Isabella R Straub, Alexander Janer, Woranontee Weraarpachai, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva, Eric A Shoubridge
CHCHD10 and its paralogue CHCHD2 belong to a family of twin CX9C motif proteins, most of which localize to the intermembrane space of mitochondria. Dominant mutations in CHCHD10 cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), and mutations in CHCHD2 have been associated with Parkinson's disease, but the function of these proteins remains unknown. Here we show that the p.R15L CHCHD10 variant in ALS patient fibroblasts destabilizes the protein, leading to a defect in the assembly of complex I, impaired cellular respiration, mitochondrial hyperfusion, an increase in the steady-state level of CHCHD2, and a severe proliferation defect on galactose, a substrate that forces cells to synthesize virtually all of their ATP aerobically...
November 7, 2017: Human Molecular Genetics
Eldad Zacksenhaus, Mariusz Shrestha, Jeff C Liu, Ioulia Vorobieva, Philip E D Chung, YoungJun Ju, Uri Nir, Zhe Jiang
A switch from catabolic to anabolic metabolism, a major hallmark of cancer, enables rapid cell duplication, and is driven by multiple oncogenic alterations, including PIK3CA mutation, MYC amplification, and TP53 loss. However, tumor growth requires active mitochondrial function and oxidative phosphorylation (OXPHOS). Recently, loss of the retinoblastoma (RB1) tumor suppressor in breast cancer was shown to induce mitochondrial protein translation (MPT) and OXPHOS. Here, we discuss how increased OXPHOS can enhance anabolic metabolism and cell proliferation, as well as cancer stemness and metastasis...
November 2017: Trends in Cancer
S R Burstein, F Valsecchi, H Kawamata, M Bourens, R Zeng, A Zuberi, T A Milner, S M Cloonan, C Lutz, A Barrientos, G Manfredi
Mutations in coiled-coil-helix-coiled-coil-helix-domain containing 10 (CHCHD10), a mitochondrial twin CX9C protein whose function is still unknown, cause myopathy, motor neuron disease, frontotemporal dementia, and Parkinson's disease. Here, we investigate CHCHD10 topology and its protein interactome, as well as the effects of CHCHD10 depletion or expression of disease-associated mutations in wild-type cells. We find that CHCHD10 associates with membranes in the mitochondrial intermembrane space, where it interacts with a closely related protein, CHCHD2...
January 1, 2018: Human Molecular Genetics
Andreas Puschmann
PURPOSE OF REVIEW: This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes. RECENT FINDINGS: Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted...
September 2017: Current Neurology and Neuroscience Reports
Xianyin Lai, Christopher B Umbricht, Kurt Fisher, Justin Bishop, Qiuying Shi, Shaoxiong Chen
Distinguishing follicular carcinoma from follicular adenoma, based on cytomorphological features, has always been challenging to cytopathologists. Identification of biomarkers for improving diagnostic accuracy is important for clinical management. Meanwhile, it is critical to identify therapeutic target candidates for treatment of follicular carcinoma. Currently, no reliable diagnostic protein biomarkers and therapeutic targets are available. To explore novel protein biomarker and therapeutic target candidates, a liquid chromatography-tandem mass spectrometry approach was applied to analyze control, follicular adenoma, and follicular carcinoma using formalin-fixed, paraffin-embedded tissue samples...
July 12, 2017: Journal of Proteomics
Jong-Min Kim
No abstract text is available yet for this article.
August 2017: Human Mutation
Lawrence I Grossman, Neeraja Purandare, Rooshan Arshad, Stephanie Gladyck, Mallika Somayajulu, Maik Hüttemann, Siddhesh Aras
The central role of energy metabolism in cellular activities is becoming widely recognized. However, there are many gaps in our knowledge of the mechanisms by which mitochondria evaluate their status and call upon the nucleus to make adjustments. Recently, a protein family consisting of twin CX9C proteins has been shown to play a role in human pathophysiology. We focus here on two family members, the isoforms CHCHD2 (renamed MNRR1) and CHCHD10. The better studied isoform, MNRR1, has the unusual property of functioning in both the mitochondria and the nucleus and of having a different function in each...
2017: Oxidative Medicine and Cellular Longevity
Hongrui Meng, Chikara Yamashita, Kahori Shiba-Fukushima, Tsuyoshi Inoshita, Manabu Funayama, Shigeto Sato, Tomohisa Hatta, Tohru Natsume, Masataka Umitsu, Junichi Takagi, Yuzuru Imai, Nobutaka Hattori
Mutations in CHCHD2 have been identified in some Parkinson's disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants...
June 7, 2017: Nature Communications
Murni Tio, Rujing Wen, Yih Lin Lim, Zul Haikhel Bin Zukifli, Shaoping Xie, Patrick Ho, Zhidong Zhou, Tong-Wey Koh, Yi Zhao, Eng-King Tan
Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction that could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress, and impairment in synaptic transmission...
April 21, 2017: Human Mutation
Qi-Lin Xin, Cheng-Lin Deng, Xi Chen, Jun Wang, Shao-Bo Wang, Wei Wang, Fei Deng, Bo Zhang, Gengfu Xiao, Lei-Ke Zhang
Zika virus (ZIKV) is an emerging arbovirus belonging to the genus Flavivirus of the family Flaviviridae During replication processes, flavivirus manipulates host cell systems to facilitate its replication, while the host cells activate antiviral responses. Identification of host proteins involved in the flavivirus replication process may lead to the discovery of antiviral targets. The mosquitoes Aedes aegypti and Aedes albopictus are epidemiologically important vectors for ZIKV, and effective restrictions of ZIKV replication in mosquitoes will be vital in controlling the spread of virus...
June 15, 2017: Journal of Virology
Elisa Rubino, Livia Brusa, Ming Zhang, Silvia Boschi, Flora Govone, Alessandro Vacca, Annalisa Gai, Lorenzo Pinessi, Leonardo Lopiano, Ekaterina Rogaeva, Innocenzo Rainero
In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinson's disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10...
May 2017: Neurobiology of Aging
Siddhesh Aras, Hassan Arrabi, Neeraja Purandare, Maik Hüttemann, John Kamholz, Stephan Züchner, Lawrence I Grossman
We previously showed that MNRR1 (Mitochondrial Nuclear Retrograde Regulator 1, also CHCHD2) functions in two subcellular compartments, displaying a different function in each. In the mitochondria it is a stress regulator of respiration that binds to cytochrome c oxidase (COX) whereas in the nucleus it is a transactivator of COX4I2 and other hypoxia-stimulated genes. We now show that binding of MNRR1 to COX is promoted by phosphorylation at tyrosine-99 and that this interaction stimulates respiration. We show that phosphorylation of MNRR1 takes place in mitochondria and is mediated by Abl2 kinase (ARG)...
February 2017: Biochimica et Biophysica Acta
Chao Gao, Yi-Meng Chen, Qian Sun, Ya-Chao He, Pei Huang, Tian Wang, Dun-Hui Li, Liang Liang, Jun Liu, Qin Xiao, Sheng-Di Chen
CHCHD2 is the latest identified Parkinson's disease (PD)-causing gene, and previous studies have reported the same CHCHD2 variant (182C>T, Thr61Ile) in both PD and essential tremor (ET) patients. Whether CHCHD2 gene mutations are involved in both of these diseases remains unclear. We sequenced CHCHD2 gene in 171 familial ET patients, 133 autosomal dominant Parkinson's disease patients, and 211 normal controls. No pathogenic mutations were found, suggesting that CHCHD2 gene may not play a major role in our familial Chinese Han ET and PD patients...
January 2017: Neurobiology of Aging
Lili Zhu, Aurora Gomez-Duran, Gabriele Saretzki, Shibo Jin, Katarzyna Tilgner, Dario Melguizo-Sanchis, Georgios Anyfantis, Jumana Al-Aama, Ludovic Vallier, Patrick Chinnery, Majlinda Lako, Lyle Armstrong
Human induced pluripotent stem cell (hiPSC) utility is limited by variations in the ability of these cells to undergo lineage-specific differentiation. We have undertaken a transcriptional comparison of human embryonic stem cell (hESC) lines and hiPSC lines and have shown that hiPSCs are inferior in their ability to undergo neuroectodermal differentiation. Among the differentially expressed candidates between hESCs and hiPSCs, we identified a mitochondrial protein, CHCHD2, whose expression seems to correlate with neuroectodermal differentiation potential of pluripotent stem cells...
October 24, 2016: Journal of Cell Biology
Hongwei Wu, Xingjiao Lu, Zhidong Cen, Fei Xie, Xiaosheng Zheng, You Chen, Wei Luo
Recently, Funayama et al. identified CHCHD2 as a novel causative gene of Parkinson disease (PD). However, the relationship between CHCHD2 and essential tremor (ET) patients was still unknown. Genetic analysis of CHCHD2 gene was conducted in 60 probands of ET families with autosomal dominant inheritance and 90 healthy controls in Chinese population. No pathogenic CHCHD2 mutation was found in ET patients. However, we identified one rare variant, c.5C>T, a reported risk variant for sporadic PD in Japanese populations, and examined the frequency of three common variants...
November 10, 2016: Neuroscience Letters
Zhi-Dong Zhou, Wuan-Ting Saw, Eng-King Tan
The coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing proteins are evolutionarily conserved nucleus-encoded small mitochondrial proteins with important functions. So far, nine members have been identified in this protein family. All CHCHD proteins have at least one functional coiled-coil-helix-coiled-coil-helix (CHCH) domain, which is stabilized by two pairs of disulfide bonds between two helices. CHCHD proteins have various important pathophysiological roles in mitochondria and other key cellular processes...
September 2017: Molecular Neurobiology
Nan-Nan Li, Ling Wang, Eng-King Tan, Lan Cheng, Xiao-Yi Sun, Zhong-Jiao Lu, Jun-Ying Li, Jin-Hong Zhang, Rong Peng
Recently, mutations in the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) gene have been identified in Japanese families with autosomal dominant Parkinson's disease (PD) and two single nucleotide variants (rs10043 and Pro2Leu) increased risk of sporadic PD. The role of CHCHD2 in PD susceptibility in other Asian populations still remains to be clarified. In a large Chinese cohort from mainland China (31 familial PD patients, 1,027 sporadic PD patients, and 1,095 health controls), we examined the association of rs10043 and Pro2Leu variants in CHCHD2 with PD...
December 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
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