Mitochondrial DNA copy number changes, heteroplasmy, and mutations in plasma-derived exosomes and brain tissue of glioblastoma patients

Soltész, Beáta; Pös, Ondrej; Wlachovska, Zuzana; Budiš, Jaroslav; Hekel, Rastislav; Striešková, Lucia; Liptak, Jana Bozenka; Krampl, Werner; Styk, Jakub; Németh, Nikolett; Keserű, Judit Sz; Jenei, Adrienn; Buglyó, Gergely; Klekner, Álmos; Nagy, Bálint; Szemes, Tomáš

doi:10.1016/j.mcp.2022.101875

Cited by 6 publications

(6 citation statements)

References 36 publications

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“…The researchers observed reduced mtDNA content in both exosomes and brain tissues of tumor samples compared to the control group, suggesting that exosome analysis could serve as an alternative method for evaluating mtDNA copy numbers and highlighting the potential of mtDNA copy number as a biomarker for glioblastoma development. 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.…”

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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“…DNAs, especially the mitochondrial‐derived DNA (mtDNA), have also been found to be abundant in exosomes. Researchers have extracted and identified mtDNA in glioblastoma circulating EVs, [ 114 ] which can reflect the genome‐wide methylation for molecular classification of brain tumors. [ 115 ] Moreover, researchers also found that exosome‐derived embryonic stemness genes (such as the Nanog gene) could be used as diagnostic markers for glioma to elucidate the mechanisms of aggressive tumor growth.…”

Section: Advantages Of Bnvs For Brain Disease Diagnosis and Therapymentioning

confidence: 99%

“…No cell contents Detection lncRNA beta-amyloid cleaving enzyme 1-antisense (BACE1-AS); [ 141] lncRNA POU domain class 3 transcription factor 3 (POU3F3) [ 130] Mostly [ 114] methylated DNA; [ 115] Nanog DNA [ 116] complementary DNA (cDNA), genomic DNA [ 117] Not reported Not reported No cell contents Metabolites Treatment IDH1; 2-HG [ 121] Not reported Not reported Not reported No cell contents Detection Metabolic patterns analysis [ 122] Not reported Not reported Not reported No cell contents compared with healthy mice. For example, the downregulation of miRNA 148a-5p and upregulation of miR-27a-5p has been detected and confirmed by quantitative reverse transcription polymerase chain reaction.…”

Section: Not Reported Not Reportedmentioning

confidence: 99%

The Landscape of Biomimetic Nanovesicles in Brain Diseases

You,

Liang,

et al. 2023

Advanced Materials

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Brain diseases, such as brain tumors, neurodegenerative diseases, cerebrovascular diseases and brain injuries, are caused by various pathophysiological changes such as excessive or impaired angiogenesis, neuroinflammation, immune activation or suppression, neurodegenerative disorders, and neurovirulent protein deposition, which poses a serious health threat. Brain disorders are often difficult to treat due to the presence of the blood‐brain barrier (BBB), which hinders the delivery of drugs to the brain. Biomimetic nanovesicles (BNVs), including endogenous extracellular vesicles (EVs) derived from various cells and artificial nanovesicles (ANVs), possess the ability to penetrate the BBB and thus can be utilized for drug delivery to the brain. BNVs, especially endogenous EVs, are widely distributed in body fluids and usually carry various disease‐related signal molecules such as proteins, RNA and DNA, and may therefore also be analyzed to understand the etiology and pathogenesis of brain diseases. This review will cover the exhaustive classification and characterization of BNVs and pathophysiological roles involved in various brain diseases, and emphatically focus on nanotechnology‐integrated BNVs for brain disease theranostics, including various diagnosis strategies and precise therapeutic regulations (e.g., immunity regulation, disordered protein clearance, anti‐neuroinflammation, neuro‐regeneration, angiogenesis and the gut‐brain axis regulation). We also discuss and outline the remaining challenges and future perspectives regarding the nanotechnology‐integrated BNVs for the diagnosis and treatment of brain diseases.This article is protected by copyright. All rights reserved

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“…The genome of glioblastoma cells stays heavily methylated. Many studies have shown that the mtDNA copy number is lower in glioma cells than in healthy cells (24)(25)(26)(27). Low mtDNA copy number appears to lead glioma cells to rely on glycolysis to produce ATP instead of oxidative phosphorylation, promoting cell proliferation (28).…”

Section: Dna Methylation Of Mitochondrial Dnamentioning

confidence: 99%

Mitoepigenetics and gliomas: epigenetic alterations to mitochondrial DNA and nuclear DNA alter mtDNA expression and contribute to glioma pathogenicity

2023

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Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.

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Mitochondrial DNA copy number changes, heteroplasmy, and mutations in plasma-derived exosomes and brain tissue of glioblastoma patients

Cited by 6 publications

References 36 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

The Landscape of Biomimetic Nanovesicles in Brain Diseases

Mitoepigenetics and gliomas: epigenetic alterations to mitochondrial DNA and nuclear DNA alter mtDNA expression and contribute to glioma pathogenicity

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