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Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation.

ABSTRACT: Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities. Importantly, Mic60 deficiency decreased TFAM binding and mitochondrial RNA polymerase (POLRMT) recruitment to the mtDNA promoters. In addition, through mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays, we found that Mic60 interacted with mtDNA and was involved in the architecture of mtDNA D-loop region. Taken together, our findings reveal a previously unrecognized important role of Mic60 in mtDNA transcription.

SUBMITTER: Yang RF

PROVIDER: S-EPMC4303897 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation.

Yang Rui-Feng RF Sun Li-Hong LH Zhang Ran R Zhang Yuan Y Luo Yu-Xuan YX Luo Yu-Xuan YX Zheng Wei W Zhang Zhu-Qin ZQ Chen Hou-Zao HZ Liu De-Pei DP

Scientific reports 20150123

Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcri ...[more]

PMID: 25612828

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Project description:BackgroundA critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or, instead, are structural changes that are part of a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects. In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. However, whether this change in chromatin structure is causally involved in the development of structural defects remains unknown.ResultsDeep-sequencing analysis of the cortex transcriptome reveals that the emergence of alcohol-induced structural defects correlates with disruptions in the genetic pathways controlling oxidative phosphorylation and mitochondrial function. The majority of the affected pathways are downstream targets of the mammalian target of rapamycin complex 2 (mTORC2), indicating that this stress-responsive complex plays a role in propagating the epigenetic memory of alcohol exposure through gestation. Importantly, transcriptional disruptions of the pathways regulating oxidative homeostasis correlate with the emergence of increased H3K9me2 across genic, repetitive, and non-transcribed regions of the genome. However, although associated with gene silencing, none of the candidate genes displaying increased H3K9me2 become transcriptionally repressed, nor do they exhibit increased markers of canonical heterochromatin. Similar to studies in C. elegans, disruptions in oxidative homeostasis induce the chromatin looping factor SATB2, but in mammals, this protein does not appear to drive increased H3K9me2 or altered patterns of gene expression.ConclusionsOur studies demonstrate that changes in H3K9me2 associate with alcohol-induced congenital defects, but that this epigenetic change does not correlate with transcriptional suppression. We speculate that the mobilization of SATB2 and increased enrichment of H3K9me2 may be components of a nuclear stress response that preserve chromatin integrity and interactions under prolonged oxidative stress. Further, we postulate that while this response may stabilize chromatin structure, it compromises the nuclear plasticity required for normal differentiation.

Project description:Purpose: A critical question emerging in the field of developmental toxicology is whether alterations in chromatin structure induced by toxicant exposure control patterns of gene expression or instead are structural changes that arise due to a nuclear stress response. Previously, we used a mouse model to conduct a three-way comparison between control offspring, alcohol-exposed but phenotypically normal animals, and alcohol-exposed offspring exhibiting craniofacial and central nervous system structural defects.In the cerebral cortex of animals exhibiting alcohol-induced dysgenesis, we identified a dramatic increase in the enrichment of dimethylated histone H3, lysine 9 (H3K9me2) within the regulatory regions of key developmental factors driving histogenesis in the brain. Whether this change in chromatin structure is causally involved in the development of structural defects remains unknown. Methods: We isolated total RNA from the GD17 cortex using the RNeasy Plus Mini Kit (catalog # 74134, Qiagen) according to the manufacturer's instructions. Before RNASeq library preparation, we randomized samples and generated sequencing libraries using the TruSeq RNA Sample Preparation kit (catalog # RS-122-2001, Illumina). We sequenced pooled samples using an Illumina HiSeq 2500 at Whitehead Genomic Services (Cambridge, MA). The sequencing data were demultiplexed, aligned using STAR with default parameters (Dobin et al., 2013), and referenced against the Mus musculus genome (UCSC version mm10). Results: To identify transcriptional differences distinguishing affected fetuses from unaffected offspring, we returned to our previously published, early gestational binge model of maternal alcohol exposure (Veazey et al., 2015). Here, dams were intraperitoneally administered injections of either vehicle or alcohol on gestational-day seven. On gestational-day 17 (GD17), stage-matched control and alcohol- exposed fetuses were dissected and scored for both ocular and craniofacial congenital defects. After determining the sex of each fetus using PCR analysis targeting the Y-chromosome, we found that the majority of affected samples (13/17; 76%) were female. We then isolated RNA from the GD17 fetal cortex of three (n=3) control, EtOH-exposed unaffected, and EtOH-exposed affected offspring and conducted deep-sequencing analysis of the cortex transcriptome. Our sequencing analyses identified a small number (88) of differentially expressed transcripts between the control and unaffected samples. In contrast, comparisons between control and affected, as well as unaffected and affected, identified 876 (412 downregulated, 522 upregulated) and 2281 (1432 downregulated, 1041 upregulated) differentially expressed genes, respectively Conclusions: Alterations in the genetic pathways regulating oxidative phosphorylation and mitochondrial dysfunction distinguish alcohol-exposed affected vs. unaffected offspring.

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Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation.

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Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation.

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