Insights regarding mitochondrial DNA copy number alterations in human cancer (Review)

Radzak, Siti Muslihah Abd; Khair, Siti Zulaikha Nashwa Mohd; Ahmad, Fadzil; Patar, Azim; Idris, Zamzuri; Yusoff, Abdul Aziz Mohamed

doi:10.3892/ijmm.2022.5160

Cited by 20 publications

(13 citation statements)

References 183 publications

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“… 20 Additionally, the evaluation of mtDNA content in multiple cancers has shown vast fluctuation, suggesting that mitochondrial copies are not particularly in stringent regulation. 21 , 22 Certainly, the amount of mtDNA copy number may vary depending on tissue types and is mostly present mostly in high-energy cells such as skeletal, cardiac muscles, and brain cells. 3 …”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study

Radzak,

Mohd Khair,

Idris

et al. 2024

The Eurasian Journal of Medicine

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Background: Investigating the role of mitochondrial DNA (mtDNA) alterations and their impact on brain tumor progression remains a significant focus in cancer research. The research aimed to explore the specific contributions of mtDNA copy number changes and their correlations with patient survival, large mtDNA deletions, and TFAM mutations in brain tumor patients. Methods: A total of 41 patients with confirmed brain tumors underwent DNA extraction from both tumor tissues and blood samples. The relative mtDNA copy number in comparison to the nuclear genome was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Long-range PCR assessed large-scale mtDNA deletions, and Sanger sequencing was applied to detect exon 4 TFAM mutations. Results: Analysis revealed significantly increased mtDNA copy numbers in brain tumor tissues (80.5%) compared to matched blood samples ( P < .001). Median delta Ct (∆Ct) values were 7.35 in cancerous tissues and 11.81 in blood ( P < .001), with median relative mtDNA content of 0.0123 and 0.0006, respectively ( P < .001). Patients with higher mtDNA copy numbers experienced longer overall survival periods ( P = .045) and notably favorable outcomes, particularly in high-grade tumor cases ( P = .016). Furthermore, a single-nucleotide deletion was identified in exon 4 of TFAM in a patient with glioblastoma IV, while no large-scale mtDNA deletions were found in brain tumor patients. Conclusion: Our study strongly supports the role of increased mtDNA copy numbers as a reliable predictor for improved survival and positive outcomes in high-grade brain tumor patients.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study

Radzak,

Mohd Khair,

Idris

et al. 2024

The Eurasian Journal of Medicine

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“…By comparing proliferative and senescent cells, we obtained evidence for an increase in mtDNA copy number in senescent cells. A decrease in mtDNA copy number, or mtDNA depletion, is seen in many cancers ( Abd Radzak et al, 2022 ). Vice versa, it has been speculated that the accumulation of mtDNA in senescent cells may be a key factor in suppressing tumorigenesis or inflammatory responses ( Miwa et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Woronzow,

Möhner,

Remane

et al. 2023

Front. Cell Dev. Biol.

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Cellular senescence is characterized by replication arrest in response to stress stimuli. Senescent cells accumulate in aging tissues and can trigger organ-specific and possibly systemic dysfunction. Although senescent cell populations are heterogeneous, a key feature is that they exhibit epigenetic changes. Epigenetic changes such as loss of repressive constitutive heterochromatin could lead to subsequent LINE-1 derepression, a phenomenon often described in the context of senescence or somatic evolution. LINE-1 elements decode the retroposition machinery and reverse transcription generates cDNA from autonomous and non-autonomous TEs that can potentially reintegrate into genomes and cause structural variants. Another feature of cellular senescence is mitochondrial dysfunction caused by mitochondrial damage. In combination with impaired mitophagy, which is characteristic of senescent cells, this could lead to cytosolic mtDNA accumulation and, as a genomic consequence, integrations of mtDNA into nuclear DNA (nDNA), resulting in mitochondrial pseudogenes called numts. Thus, both phenomena could cause structural variants in aging genomes that go beyond epigenetic changes. We therefore compared proliferating and senescent IMR-90 cells in terms of somatic de novo numts and integrations of a non-autonomous composite retrotransposons - the so-called SVA elements—that hijack the retropositional machinery of LINE-1. We applied a subtractive and kinetic enrichment technique using proliferating cell DNA as a driver and senescent genomes as a tester for the detection of nuclear flanks of de novo SVA integrations. Coupled with deep sequencing we obtained a genomic readout for SVA retrotransposition possibly linked to cellular senescence in the IMR-90 model. Furthermore, we compared the genomes of proliferative and senescent IMR-90 cells by deep sequencing or after enrichment of nuclear DNA using AluScan technology. A total of 1,695 de novo SVA integrations were detected in senescent IMR-90 cells, of which 333 were unique. Moreover, we identified a total of 81 de novo numts with perfect identity to both mtDNA and nuclear hg38 flanks. In summary, we present evidence for possible age-dependent structural genomic changes by paralogization that go beyond epigenetic modifications. We hypothesize, that the structural variants we observe potentially impact processes associated with replicative aging of IMR-90 cells.

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“…(2015) found that mtDNA_CN was positively correlated with mitochondrial mass and the respiratory capacity. Variation in mtDNA_CN has been associated with diverse pathologies, such as cardiomyopathy, diabetes and cancer (Kaaman et al ., 2007; Dillon et al ., 2012; Holmström et al ., 2012; Pirinen et al ., 2020; Abd Radzak et al ., 2022). This cellular trait is moderately heritable, with heritability estimates in humans of 0.33 to 0.65 (Xing et al ., 2008; López et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

Association between mitochondrial DNA copy number and production traits in pigs

Molinero,

Pena,

Estany

et al. 2024

Preprint

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Mitochondria are essential organelles in the regulation of cellular energetic metabolism. Mitochondrial DNA copy number (mtDNA_CN) can be used as a proxy for mitochondria number, size, and activity. The aims of our study are to evaluate the effect of mtDNA_CN and mitochondrial haploblocks on production traits in pigs, and to identify the genetic background of this cellular phenotype. We collected performance data of 234 pigs and extracted DNA from skeletal muscle. Whole-genome sequencing data was used to determine mtDNA_CN. We detected positive correlations of muscle mtDNA_CN with backfat thickness at 207 d (+0.14; p-value = 0.07), and negative correlations with carcase loin thickness (-0.14; p-value = 0.03). Pigs with less mtDNA_CN had greater loin thickness (+4.1 mm; p-value = 0.01) and lower backfat thickness (-1.1 mm; p-value = 0.08), which resulted in greater carcase lean percentage (+2.4%; p-value = 0.04) than pigs with high mtDNA_CN. These results support the hypothesis that a reduction of mitochondrial activity is associated with greater feed efficiency. Pork from pigs with less mtDNA_CN may also tend to have lower ultimate pH (correlation: +0.19; p-value < 0.01). We found no association of the most frequent mitochondrial haploblocks with mtDNA_CN or the production traits, but several genomic regions that harbour potential candidate genes with functions related to mitochondrial biogenesis and homeostasis were associated to mtDNA_CN. These regions provide new insights into the genetic background of this cellular phenotype but it is still uncertain if such associations translate into noticeable effects on the production traits.

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Insights regarding mitochondrial DNA copy number alterations in human cancer (Review)

Cited by 20 publications

References 183 publications

Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study

Mitochondrial Deoxyribonucleic Acid Copy Number Elevation As a Predictor for Extended Survival and Favorable Outcomes in High-Grade Brain Tumor Patients: A Malaysian Study

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts

Association between mitochondrial DNA copy number and production traits in pigs

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