High-confidence assessment of functional impact of human mitochondrial non-synonymous genome variations by APOGEE

Castellana, Stefano; Fusilli, Caterina; Mazzoccoli, Gianluigi; Biagini, Tommaso; Capocefalo, Daniele; Carella, Massimo; Vescovi, Angelo L.; Mazza, Tommaso

doi:10.1371/journal.pcbi.1005628

Cited by 57 publications

(50 citation statements)

References 41 publications

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“…Also, we include Table S32 of predictions from the bioinformatics platforms that have been shown to have the highest sensitivity and specificity for the mtDNA variants. 137 Our study also had some limitations. Rare mtDNA mutations are usually heteroplasmic point mutations and/or mtDNA lesions that typically result in a primary mitochondrial disease, which can manifest as a broad range of clinical outcomes.…”

Section: Strengths and Limitationsmentioning

confidence: 87%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

109

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Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

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Section: Strengths and Limitationsmentioning

confidence: 87%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

109

View full text Add to dashboard Cite

show abstract

“…To compare mutation profiles in the benign-cancer tissue pairs, variants where classified into three categories: benign variants only, shared variants (assumed as germline variants) and tumor variants only. The variants were subsequently annotated with the precomputed MutPred scores as provided by Pereira et al in Supplementary Table 3 of their article 19 and the pre-computed pathogenicity predictions provided by MitImpact 2 15,63 by downloading the data as tab-delimited file and merging in a relational database.…”

Section: Methodsmentioning

confidence: 99%

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

et al. 2020

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Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.

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“…The heteroplasmy were defined if a double peaks of two residues were verified at the same position in the electro-chromatograms. Pathogenic prediction were analyzed using PolyPhen2 ( http://genetics.bwh.harvard.edu/pph2/ ) [2] and MitImpact 2 [3] .…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Dataset of mitochondrial genome variants in oncocytic tumors

et al. 2018

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This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.

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High-confidence assessment of functional impact of human mitochondrial non-synonymous genome variations by APOGEE

Cited by 57 publications

References 41 publications

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Dataset of mitochondrial genome variants in oncocytic tumors

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