Loss of forebrain MTCH2 decreases mitochondria motility and calcium handling and impairs hippocampal-dependent cognitive functions

Ruggiero, Antonella; Aloni, Etay; Korkotian, Eduard; Zaltsman, Yehudit; Oni-Biton, Efrat; Kuperman, Yael; Tsoory, Michael; Shachnai, Liat; Levin-Zaidman, Smadar; Brenner, Ori; Segal, Menahem; Gross, Atan

doi:10.1038/srep44401

Cited by 41 publications

(36 citation statements)

References 54 publications

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“…Axonal transport analysis was carried by analysis of time-lapse images using imageJ or MATLAB, as in 67 , 68 . For transmission electron microscopy, motor neuron were prepared, following 69 and electron micrographs were captured with a FEI Tecnai SPIRIT transmission electron microscope (FEI, Eidhoven, Netherlands), operated at 120 kV and equipped with an EAGLE CCD Camera.…”

Section: Methodsmentioning

confidence: 99%

High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

Yardeni

Fine

Joshi

et al. 2018

Sci Rep

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microRNAs (miRNAs) are critical for neuronal function and their dysregulation is repeatedly observed in neurodegenerative diseases. Here, we implemented high content image analysis for investigating the impact of several miRNAs in mouse primary motor neurons. This survey directed our attention to the neuron-specific miR-124, which controls axonal morphology. By performing next generation sequencing analysis and molecular studies, we characterized novel roles for miR-124 in control of mitochondria localization and function. We further demonstrated that the intermediate filament Vimentin is a key target of miR-124 in this system. Our data establishes a new pathway for control of mitochondria function in motor neurons, revealing the value of a neuron-specific miRNA gene as a mechanism for the re-shaping of otherwise ubiquitously-expressed intermediate filament network, upstream of mitochondria activity and cellular metabolism.

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Section: Methodsmentioning

confidence: 99%

High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

Yardeni

Fine

Joshi

et al. 2018

Sci Rep

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“…It is not tremendously unexpected that MTCH2 has a direct impact on neurological function as the brain is one of the most metabolically active organs in the body. MTCH2 knockout mice exhibited deficits in both metabolic processes and hippocampal dependent spatial learning tasks [42,45,46]. There are known links between nutrition, specifically cholesterol consumption levels, in AD [47], which can also present health risks for cardiovascular function, another wellknown risk factor for AD.…”

Section: Mtch2 Chr11mentioning

confidence: 99%

Multi-Tissue Neocortical Transcriptome-Wide Association Study Implicates 8 Genes Across 6 Genomic Loci in Alzheimer’s Disease

Gockley

Montgomery

Poehlman

et al. 2020

Preprint

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AbstractBackgroundAlzheimer’s disease (AD), an incurable neurodegenerative disease, currently affecting 1.75% of the United States population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD-risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION Transcriptome Wide Association Study (TWAS) pipeline to ingest expression from multiple neocortical regions, provide a set of 6780 gene weights which are abstracatable across the neocortex, and leverage these to find 8 genes from six loci with associated AD risk validated through summary mendelian randomization (SMR) utilizing IGAP summary statistics.MethodA combined dataset of 2003 genotypes clustered to Central European (CEU) ancestry was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles across 6 Neo-cortical tissues (TCX=248, FP=50, IFG=41, STG=34, PHG=34, DLPFC=461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and provide support for cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues.ResultsCis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N=6775 (99.92%), Bonferroni: N=6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05); APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, KNOP1.ConclusionWe provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.

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“…We previously demonstrated that loss of MTCH2 results in embryonic lethality that is completed by E7.5 20 . Intriguingly, loss of MTCH2 also results in changes in mitochondria morphology 21 – 23 , suggesting that MTCH2 may play a role in regulating mitochondrial dynamics during embryogenesis. Here we show that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.…”

Section: Introductionmentioning

confidence: 99%

MTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells

et al. 2018

Self Cite

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The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2−/− ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2−/− and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.

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Loss of forebrain MTCH2 decreases mitochondria motility and calcium handling and impairs hippocampal-dependent cognitive functions

Cited by 41 publications

References 54 publications

High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria

Multi-Tissue Neocortical Transcriptome-Wide Association Study Implicates 8 Genes Across 6 Genomic Loci in Alzheimer’s Disease

MTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells

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