Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease

Castellani, Christina A; Longchamps, Ryan J.; Sun, Jing; Güallar, Eliseo; Arking, Dan E.

doi:10.1016/j.mito.2020.06.004

Cited by 214 publications

(176 citation statements)

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“…Differences of heteroplasmy levels among tissues (blood <20%, tumors 1-95%) observed in this study could be biased by contamination by a different proportion of germline mtDNA during sequencing (69) or that the unregistered singletons germline variants showing <2% of heteroplasmy load arose during the genomic sequencing process (70). Our current strategy does not allow us to identify whether the heteroplasmy comes from the enrichment of mutated mitochondria or from mtDNA copy numbers (mtDNA-CN) variations.…”

Section: High Heteroplasmy Levels Of Germline Variants In Tumors and mentioning

confidence: 74%

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

et al. 2020

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Studies have suggested a potential role of somatic mitochondrial mutations in cancer development. To analyze the landscape of somatic mitochondrial mutation in breast cancer and to determine whether mitochondrial DNA (mtDNA) mutational burden is correlated with overall survival (OS), we sequenced whole mtDNA from 92 matchedpaired primary breast tumors and peripheral blood. A total of 324 germline variants and 173 somatic mutations were found in the tumors. The most common germline allele was 663G (12S), showing lower heteroplasmy levels in peripheral blood lymphocytes than in their matched tumors, even reaching homoplasmic status in several cases. The heteroplasmy load was higher in tumors than in their paired normal tissues. Somatic mtDNA mutations were found in 73.9% of breast tumors; 59% of these mutations were located in the coding region (66.7% non-synonymous and 33.3% synonymous). Although the CO1 gene presented the highest number of mutations, tRNA genes (T, C, and W), rRNA 12S, and CO1 and ATP6 exhibited the highest mutation rates. No specific mtDNA mutational profile was associated with molecular subtypes of breast cancer, and we found no correlation between mtDNA mutational burden and OS. Future investigations will provide insight into the molecular mechanisms through which mtDNA mutations and heteroplasmy shifting contribute to breast cancer development.

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Section: High Heteroplasmy Levels Of Germline Variants In Tumors and mentioning

confidence: 74%

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

et al. 2020

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“…Due to the importance of mitochondria in metabolism and energy production, mitochondrial dysfunction plays a role in the etiology of many human diseases [4]. mtDNA-CN has been shown to be a proxy for mitochondrial function, and is consequently an attractive biomarker due to its ease of measurement [5,6]. Indeed, low levels of mtDNA-CN in peripheral blood have been associated with an increased risk for a number of chronic aging-related diseases including frailty, kidney disease, cardiovascular disease, heart failure, and overall mortality [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

Yang

Castellani

Longchamps

et al. 2020

Preprint

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Mitochondrial DNA copy number (mtDNA-CN) can be used as a proxy for mitochondrial function and is associated with a number of aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect risk for diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated the relationships between mtDNA-CN measured in whole blood and gene expression from whole blood as well as 47 additional tissues. We evaluated associations between blood-derived mtDNA-CN and gene expression in whole blood for 418 individuals, correcting for known confounders and surrogate variables derived from RNA-sequencing. Using a permutation-derived cutoff (p<2.70e-6), mtDNA-CN was significantly associated with expression for 721 genes in whole blood, including nuclear genes that are required for mitochondrial DNA replication. Significantly enriched pathways included splicing (p=1.03e-8) and ubiquitin-mediated proteolysis (p=2.4e-10). Genes with target sequences for the mitochondrial transcription factor NRF1 were also enriched (p=1.76e-35). In non-blood tissues, there were more significantly associated genes than expected in 30 out of 47 tested tissues, suggesting that global gene expression in those tissues is correlated with mtDNA-CN. Pathways that were associated in multiple tissues included RNA-binding, catalysis, and neurodegenerative disease. We evaluated the association between mtDNA-CN and incident neurodegenerative disease in an independent dataset, the UK Biobank, using a Cox proportional-hazards model. Higher mtDNA-CN was significantly associated with lower risk for incident neurodegenerative disease (HR=0.73, 95% CI= 0.66;0.90). The observation that mtDNA-CN measured in whole blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Key pathways in maintaining cellular homeostasis, including splicing, RNA binding, and catalytic genes were significantly associated with mtDNA-CN, reinforcing the importance of mitochondria in aging-related disease. As a specific example, genes involved in neurodegenerative disease were significantly enriched in multiple tissues. This finding, validated in a large independent cohort study showing an inverse association between mtDNA-CN and neurodegenerative disease, solidifies the link between blood-derived mtDNA-CN, altered gene expression in both blood and non-blood tissues, and aging-related disease.

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“…Increased mtDNA copy number is a compensatory response to mild oxidative stress (25,26) and is an established biomarker of mitochondrial function (46). Mitochondrial DNA copy number of NADH dehydrogenase 1 (ND1) relative to Beta-2-microglobulin (B2M) was significantly elevated in the ASD group compared to the control group (p = 0.002) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While we were unable to measure gene expression because of the low integrity of RNA extracted from the tissue source (buccal swabs) used in our study, previous studies have shown that differential methylation alters the expression of these genes (20,42,43,53). We investigated whether mitochondrial DNA copy number, a marker of mitochondrial function (46), was altered in our cohort. Changes in mtDNA copy number have been reported in ASD, with both increases (54–56) and decreases (57,58) observed in ASD.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

Bam

Buchanan

Mahony

et al. 2021

Preprint

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BackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children.ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1α that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1α promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 × 10−6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter. There was a positive correlation between methylation at PGC-1α at CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1α at CpG#4 promoter and mtDNA copy number in controls (Spearman’s r = −0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1α methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1α at CpG#4 (Spearman’s r = −0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1α CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology.ConclusionsThese data show an association between PGC-1α promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

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Thinking outside the nucleus: Mitochondrial DNA copy number in health and disease

Cited by 214 publications

References 100 publications

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

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