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Year : 2015  |  Volume : 11  |  Issue : 3  |  Page : 535-544

Role of mitochondrial DNA mutations in brain tumors: A mini-review

Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

Date of Web Publication9-Oct-2015

Correspondence Address:
Abdul Aziz Mohamed Yusoff
Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.161925

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 > Abstract 

Brain tumor is molecularly a heterogeneous group of diseases, and genetic factors seem to play a crucial role in its genesis. Even though multiple alterations in the nuclear-encoded genes such as tumor suppressor and oncogenes are believed to play a key role in brain tumorigenesis, the involvement of the mitochondrial genome to this event remains controversial to date. Mitochondrial DNA (mtDNA) has been suspected to be associated with the carcinogenesis because of its high sensitivity to mutations and inefficient repair mechanisms in comparison to nuclear DNA. Thus, defects in mtDNA could also lead to the development of brain tumor. By virtue of their clonal nature and high copy number, mtDNA mutations may provide a new effective molecular biomarker for the cancer detection. It has been suggested that establishing mtDNA defective pattern might be useful in cancer diagnostics and detection, the prognosis of cancer outcome, and/or the response to certain treatments. This mini-review gives a brief overview on the several aspects of mtDNA, with a particular focus on its role in tumorigenesis and progression of brain tumor. Understanding the role of mitochondria and brain tumor development could potentially translate into therapeutic strategies for patients with these tumors.

Keywords: Brain tumor, mitochondrial DNA, mutation

How to cite this article:
Mohamed Yusoff AA. Role of mitochondrial DNA mutations in brain tumors: A mini-review. J Can Res Ther 2015;11:535-44

How to cite this URL:
Mohamed Yusoff AA. Role of mitochondrial DNA mutations in brain tumors: A mini-review. J Can Res Ther [serial online] 2015 [cited 2022 Aug 16];11:535-44. Available from: https://www.cancerjournal.net/text.asp?2015/11/3/535/161925

 > Introduction Top

Brain tumors are estimated to represent 85-90% of all primary central nervous system (CNS) tumors. [1] Worldwide incidence of the disease is over 240,000 cases each year. [2] In developed countries, most studies reveal that the number of people who develop brain tumors and die from them has increased. They are the second leading cause of cancer death in young adult men aged 20-39 and the fifth in young adult women. The exact cause of brain tumors is unknown, but there are many possible risk factors that have been proven or are believed to contribute to the development of brain tumors for instances, genetic conditions, and environmental factors.

Currently, a combination of surgery, radiation, and chemotherapy is commonly used for the treatment of brain tumor. However, the distinct type of brain tumor is often difficult to diagnose and confirm at the initial stage. In addition, prognosis remains poor for high tumor recurrence and tumor progression. Therefore, further research is urgently needed to understand the molecular mechanisms underlying the tumorigenesis of brain tumor. The new research should crucially be targeted on developing more efficient therapeutic strategies against brain tumor.

So far, researches on genesis and development of tumor are intensively focused and studied on alteration of the gene in nucleus, and brain tumors is the one where most were reported arise as the result of progressive nuclear genetic alterations. Multiple genetic events have been identified in brain tumor cells involving some well-known susceptibility genes such as tumor suppressor and oncogenes that are encoded by the nuclear DNA (nDNA). For instance, the p53 tumor suppressor gene is frequently mutated and often detected, altered, or lost early in brain tumor mainly in astrocytic tumors formation. [3],[4],[5] Similarly, mutations or loss of phosphatase and tensin homolog, p16, retinoblastoma, and amplification of epidermal growth factor receptor, MDM2, cyclin-dependent kinase 4, cyclin-dependent kinase 6 are also involved in the pathogenesis of brain tumor. [6],[7]

Although, it is well-established that multiple alterations in the nuclear-encoded genes are associated with tumor development; it is reasonable to consider and postulate that there is another factor or genome yet to be investigated. The involvement of the mitochondrial genome in tumorigenesis and cancer progression remains controversial to date. Mitochondrial abnormalities that associated with mitochondrial DNA (mtDNA) alterations have been widely reported to be involved in the development of brain tumors. [8],[9],[10],[11],[12] Hence, it may be a new target for brain tumors therapy. The aims of this mini-review are to provide the readers with a brief overview of mitochondrial genetics and biology as well as to summarize the data on mtDNA mutations previously reported in brain tumors.

 > Genomics of mitochondrial dna Top

Mitochondria are cytoplasmic organelles with a variety of roles in energy metabolism and cellular homeostasis, including the generation of ATP via respiration and oxidative phosphorylation (OXPHOS), the production of reactive oxygen species (ROS), metabolic homeostasis, and the initiation and execution of apoptosis. [13],[14] Mitochondria have a genetic system of their own, separate from the nuclear one, with all the machinery necessary for its expression; that is, to replicate, transcribe, and translate the genetic information they contain. The mtDNA was discovered in 1963 [15] and the near-complete sequence for human mtDNA was available in 1981 [16] and was minimally revised in 1999. [17] Human mtDNA is mostly a double-stranded, closed circular molecule composed of 16,569 base pairs [Figure 1]. It contains only 37 genes: 13 of these genes encode proteins, and the remaining 24 are consisting of 22 tRNAs and 2 rRNAs that necessary for the synthesis of those 13 polypeptides. All 13 polypeptides are part of four of the five multi-enzymatic complexes in the OXPHOS system [Figure 2]. Each cell contains multiple copies of mitochondrial genes, giving rise to mitochondrial homoplasmy, when all mtDNA molecules within a cell are identical, or heteroplasmy where two or more forms of mtDNA coexist within a cell. [18]
Figure 1: The human mitochondrial genome. Human mitochondrial DNA is a 16,569 base pair circle of double-stranded DNA that encodes 13 essential respiratory chain subunits. ND1-ND6 and ND4L encode seven complex I (NADH-ubiquinone oxidoreductase) subunits, CYT b encodes one subunit of complex III (ubiquinol: cytochrome c oxidoreductase), COX I-COX III encode the three major catalytic subunits of complex IV, and ATPase6 and ATPase8 encode two subunits of complex V (ATP synthase). Also shown are the two ribosomal RNA (12S rRNA and 16S rRNA) genes and the 22 transfer RNA genes (blue spheres, depicted by single letter amino acid code abbreviation) required for mitochondrial protein synthesis. tRNAs are: F = Phenylalanine; V = Valine; L = Leucine; I = Isoleucine; Q = Glutamine; M = Methionine; W = Tryptophan; A = Alanine; N = Asparagine; C = Cysteine; Y = Tyrosine; S = Serine; D = Aspartic acid; K = Lysine; G = Glycine; R = Arginine; H = Histidine; E = Glutamic acid; T = Threonine; P = Proline. The genome is highly organized and shows the little redundancy of its coding sequence. The displacement loop or noncoding control region contains the promoters for transcription of the L (LSP) and H strands (HSP1 and HS2) and the origin of replication of the H strand (OH). The origin of light strand replication is shown as OL

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Figure 2: Structure of a mitochondrion and the human electron transport chain/oxidative phosphorylation system. (a) Schematic representation of mitochondrion structure. (b) The four complexes of the electron transport chain (I-IV) and the ATP synthase are schematized, and the electron/proton pathways along these complexes are indicated. As electrons flow along the electron transport chain, protons (H+) are pumped from the matrix into the intermembrane space through complexes I, III, and IV. Protons then flow back into the matrix through complex V, producing ATP. The number of mitochondrial DNA and nuclear DNA-coded subunits of each complex are also indicated

Click here to view

The mtDNA is highly sensitive to oxidative damage, and the rate of their mutation is much greater than nDNA. [19] This is due to the lack of protective histone protein and inefficient DNA repair mechanism. As mtDNA is in close proximity to the respiratory chain, it is also subjected to ROS produced as a byproduct of OXPHOS that can damage DNA. [20],[21],[22]

 > Warburg's Mitochondrial Dysfunction Theory in Cancer Cells Top

In 1956, the so-called "Warburg effect" phenomenon described by the German scientist, Warburg states that cancer cells prefer to utilize glycolysis rather than respiration to generate ATP, even in the presence of abundant oxygen. [23] He observed that cancer cells had a significant increase in glycolysis and lactate production in the presence of oxygen without an increase in OXPHOS. He further proposed that defects in energy metabolism, especially due to mitochondrial malfunction, are significant contributors to the initiation or progression of cancer. Dr. Warburg's discovery encouraged many scientists to realize the potential role of mitochondria in cancer cells. Since Warburg's proposal, alterations of mitochondria in the number, shape, and function have been reported in various cancers. [24] The conversion of ATP production from mitochondrial OXPHOS to glycolysis has been suggested to be the bioenergetic hallmark of cancer cells. [25]

 > Reactive oxygen spices and tumorigenesis Top

The mitochondrial respiratory chain is a major intracellular source or producer of ROS generation, as some of the electrons passing to molecular oxygen are instead leaked out of the chain. ROS produced in the mitochondria are hypothesized to function as signal transduction molecules modulating cell proliferation and expression of growth-related genes. [26],[27],[28],[29],[30] Overproduction of ROS will lead to various cellular components injury, such as damage to nDNA, proteins lipids as well as mitochondrial genome. [31],[32] Recent studies have demonstrated a role of ROS in promoting tumor development. [33]

It has been proposed that damage to mtDNA, if not repaired properly, it can form mutations in mtDNA that could initiate tumorigenesis and maintain cancer progression. [34],[35] Mutations in mtDNA may lead to a decreased efficiency of the OXPHOS system and increased leakage electrons as well as enhanced more mitochondrial and cellular ROS production. This situation may result in creating oxidative stress which will further accumulate more damage to mtDNA, because the location of mtDNA is in close proximity to the ROS-generating electron transport system. Thus, it is possible that persistent oxidative stress on cells may favor the neoplastic process through induction of mtDNA damage which leads to mutations. [36]

 > Mitochondria and cancer stem cells Top

Due to the prominent role of mitochondrial function in the alteration of oxidative stress, energy metabolism, and regulation of cell death in cancer cells, scientists have believed that they are also responsible in the regulation of cancer stem cells (CSCs) activity. [37] Although the origins of CSCs are not well-established, abundant evidence supports the hypothesis that CSCs arises from the accumulation of genetic alterations. Progressive genetic alterations will drive the transformation of normal stem cells (SCs) into CSCs, leading to cancer development.

Mitochondria in SCs have found to be important for maintaining stemness and differentiation. However, it remains uncertain whether mitochondrial properties of CSC are similar from those of SC.

Ye et al. reported on a comparison of mitochondrial features between lung CSC and nonlung CSC. They found that lung CSC isolated from the A549 lung cancer cell line showed a lower quantity of mtDNA, lower oxygen consumption rate, and have reduced ATP and ROS levels compared with nonlung CSC. [38]

In another study in leukemia CSC, Lagadinou's group showed that acute myeloid leukemia CSC are characterized by a low ROS level, reduced OXPHOS, and up-regulated Bcl-2 gene compared with non-CSC. [39]

More recently, in the study CSC isolated from patients with epithelial ovarian cancer, Pastü et al. have determined that CSC present with the overexpressed genes and associated with glucose uptake, OXPHOS, and fatty acid β-oxidation, indicating higher ability to direct pyruvate toward the Krebs cycle. [40] In addition, as compared with non-CSC, ovarian CSC exhibited higher mitochondrial ROS production and membrane potential. In another case of ovarian CSC, Alvero et al. reported that targeting mitochondrial biogenetics induced caspase-independent cell death in ovarian CSCs. [41]

In the study of glioma CSCs, Vlashi et al. revealed that glioma CSCs have less glycolytic capacity than differentiated cells, and this finding correlated with a higher mitochondrial reserve capacity. [42] While, in the case of breast CSCs, they found that breast CSCs consumed more glucose, produced less lactate, and have higher ATP content compared to their differentiated progeny. [43] In the case of glioblastoma CSCs, a study has showed that these CSCs also rely on OXPHOS for their energy production and survival. [44]

Based on these previous reports, different types of cancer exhibited distinct features and roles of CSCs mitochondria. Therefore, understanding these characteristics of CSCs is the important initial step in developing a potential therapeutic drug directed to mitochondria in the cancer development.

 > Mitochondrial dna mutations in cancer Top

Although the role of nDNA mutations in carcinogenesis is well-established, the importance of mtDNA alterations in the development and maintenance of cancers is only now beginning to be focused by researchers. There is considerable evidence suggesting that mitochondria may serve as potential contributors to carcinogenesis even though the exact mechanism of how mitochondria involved is still debatable and is not well-documented. Thus, mtDNA is now being targeted organelle by an increasing number of laboratories to investigate its potential role as a biomarker for tumorigenesis in various types of tissues. [45],[46]

DNA alterations in mitochondria are believed to become fast hotspots of cancer research. Indeed, numerous mutations in mtDNA have now been observed in multiple cancer types [47],[48],[49] since the first somatic mtDNA mutation was detected 15 years ago by Bert Vogelstein's group in human colorectal cancer cells. [50] After these initial findings, mtDNA mutations or alterations have also been identified in bladder cancer, [51],[52] breast cancer, [53],[54],[55],[56] esophageal cancer, [57],[58],[59] head and neck cancer, [60],[61],[62] hepatocellular carcinoma, [63],[64],[65],[66] lung cancer, [67],[68],[69],[70],[71] ovarian cancer, [72],[73],[74] prostate cancer, [75],[76],[77] renal cancer, [78],[79] thyroid cancer, [80],[81] and a number of blood cancers. [82],[83],[84] More recently, various types of molecular abnormalities in mtDNA such as point mutations, depletion, insertions, microsatellite instability, polymorphisms, and changes in mtDNA copy number have been characterized throughout the mitochondrial genome in human cancers. [85],[86]

 > Somatic mitochondrial dna alterations in brain tumors Top

Although there have been studies reporting about the association of mtDNA mutations with brain tumors, there is still no clear evidence whether mitochondrial abnormalities are contributing factors in brain tumorigenesis. To date, according to Mitomap (http://www.mitomap.org), a mitochondrial genome database, more than 30 mutations and sequence variations in mtDNA associated with brain tumors have been reported. The most commonly mutated mtDNA locus in all brain tumors is the displacement loop (D-loop) region. Several types of somatic mtDNA alterations have been identified in brain tumors. These mtDNA alterations include point mutations, deletions, insertions, mitochondrial microsatellite instability, and copy number changes.

Point mutations

A number of studies have detected mtDNA point mutations in cancer of the brain and other CNS, including gliomas, astrocytomas, gliomatosis cerebri, medulloblastoma, meningiomas, schwannomas, and neurofibromas. [8],[9],[10],[87],[88],[89] Mitochondrial genome somatic point mutations were most frequently found in the D-loop region, especially in a poly-cytosine (poly-C) mononucleotide repeat tract located between 303 and 315 nucleotides known as D310. This location has been identified as a hot spot region for somatic mtDNA mutations in various human cancers, including brain cancer. In 2005, Montanini's groups analyzed the D-loop region of mtDNA in 42 patients affected by malignant gliomas and found sequence alterations in 36% of the patients including 16 somatic mutations, mostly in the D310 area. The authors suggested that mtDNA mutations were easily amplified from postsurgical tumor cavities and could be used for the clinical follow-up of malignant gliomas. [90] Instead of focusing on D-loop region, the complete mitochondrial genome was also examined by various researchers in brain cancer patients. In a study that involved the entire mtDNA mutation scanning by temporal temperature gel electrophoresis in medulloblastomas, 40% of the cases (6/15) were found to have at least one somatic mutation. [10] Seven matched cerebrospinal fluid (CSF) samples were also analyzed to detect mtDNA mutations, where some of them were harbored mtDNA mutations in the tumors. This study suggests that somatic mtDNA mutations in CSF show some promise as potentially useful biomarkers for disease prognosis. On the other hand, Lueth's group also reported the existence of somatic mtDNA mutations in 6 of 15 medulloblastoma patients. These results are in support of their previous findings on the frequency of somatic mitochondrial mutations in medulloblastoma. [91] Before investigation on medulloblastoma patients, Lueth et al. have sequenced entire mitochondrial genome of tumor tissue and matched blood samples from 19 pilocytic astrocytomas patients and identified somatic mutations in as many as 16 (84%) cases. [11]

In the cases of neurofibromas, Kurtz et al. analyzed the whole mitochondrial genome in 37 neurofibromatosis type 1 patients and found somatic mutations in 7 individuals with cutaneous neurofibromas (37%) and 9 patients with plexiform neurofibromas (50%). [88] All of the mtDNA somatic mutations detected in this study occurred in the D-loop region. The reason of most genetic mutations to occur in noncoding regions of the mitochondrial genome is currently unknown. However, mutations in the D-loop are believed to influence the origin of replication and promoter region and thus may lead to impair mitochondrial biogenesis and defective transcription and protein expression. [92],[93]


Among the large-scale deletions identified in the mitochondrial genome, the 4977-bp deletion is the most common mtDNA deletion detected in various types of cancers including breast cancer, cervix cancer, colorectal cancer, lung cancer, and esophageal cancer. [56],[94],[95],[96],[97],[98],[99] This deletion recognized as "common deletion" removes all 5 tRNA genes and 7 genes encoding 4 complex I subunits, 1 complex IV subunit, and 2 complex V subunits, which are essential for maintaining normal mitochondrial OXPHOS function. The consequence of this deletion could cause a complete defect of ATP production and increase abnormal ROS generation. [100],[101] Although the 4977-bp deletion has been implicated in the process of carcinogenesis, the involvement or role of this deletion in brain tumors has not yet been investigated. Besides no study to date on the brain tumors, Wallace's group examined the existence of 4977-bp deletion in the aging process using brain normal individuals. [102] They found a significant increase in the 4977-bp deletion from young to old individuals, in different regions of the brain between cortex, putamen, and cerebellum. Therefore, it was suggested that this mtDNA deletion might contribute to the neurological impairment associated with aging. The 4977-bp deletion was also detected in the autopsied brains of patients with bipolar disorder. [103]

Mitochondrial microsatellite instability

In 1999, Kirches et al. revealed high mtDNA sequence variants in 12 astrocytic tumors. [8] Two years later, the same group extended the study by examining 55 gliomas specimens for mtDNA instability in the poly-C tract of mitochondrial D-loop using a combination of laser microdissection and PCR technique. [9] They found a lower frequency of 9% of specimens with the poly-C tract alterations. In addition, they also sequenced the entire D-loop in 17 frozen glioblastoma samples and corresponding blood samples for detecting the somatic mutation. In 2003, a follow-up study of mitochondrial genome instability was carried out, and the author later determined that poly-C tract of the hypervariable region as a clonal marker in gliomatosis cerebri patients. [87]

Most recently, Yeung et al. investigated the contribution of mitochondrial genome variants in glioblastoma multiforme (GBM). [12] In this study, mtDNA variants were analyzed in a series of GBM cell lines using a combination of next generation sequencing and high-resolution melt analysis. They reported the greatest frequency of mtDNA variants in the D-loop and origin of light strand replication in noncoding regions. Moreover, in coding region, ND4 and ND6 were the most affected genes to mutation which both of them encode subunits of complex I of the electron transport chain. The author concluded that these novel variants at the mitochondrial genome offer an advantage to cells for promoting GBM tumorigenesis. [12]

Copy number changes

In addition to mtDNA mutations and deletion, changes in the mtDNA copy number have been studied in gliomas. [104],[105],[106],[107],[108] There are no consistent results regarding the mtDNA copy number changes in gliomas. As first previously reported by Liang, 15 of low-grade were assessed with cDNA homologous to mtDNA at position 1,679-1,946 and 2,017-2,057, and the results revealed that these tumors had increased mtDNA copy number when compared to normal brain tissue controls. [104] In a separate study done by Liang and Hays (1996), 39 out of 45 (87%) examined gliomas, both low-grade and high-grade specimens, had increased up to 25-fold in mtDNA copy numbers. [105] They claimed that this frequency was much higher than erb-b gene amplification which was present in only 18% of these tumors.

In the human astrocytoma U87 cell line, Isaac et al. determined that depletion of mtDNA results in a decrease in glutathione and alterations of manganese superoxide dismutase and other antioxidant enzymes. [109] It also has been reported that the low mtDNA copy content in diffusely infiltrating astrocytomas is significantly associated with higher tumor malignancy. [110]

The mtDNA copy number alterations have been first described in oncocytic GBM samples by Marucci et al. [106] In 2013, Dickinson's group investigated the effect of mtDNA copy number on stemness and differentiation potential of GBM cell lines. [107] They found that defective mtDNA copy number reduces astrocytic differentiation of GBM cells compared to human neural SCs. These outcomes suggest that mtDNA content controls the initiation and maintenance of tumorigenesis in GBM. In more recent study, Zhang et al. revealed that the alterations in mtDNA copy number are closely correlated with longer survival in glioma patients. [108]

Mitochondrial gene expression changes

In 2005, Dmitrenko's group screened cDNA libraries of human fetal glioblastoma and normal human brain samples and revealed 80 differentially expressed genes. [111] They identified 30 were corresponded to mitochondrial genes for ATP6, COXII, COXIII, ND1, ND4, and 12S rRNA. According to their data, all these mitochondrial transcripts were expressed at lower level in glioblastomas as compared to tumor-adjacent histologically normal brain. [111]

Alterations in the oxidative phosphorylation complexes

The OXPHOS enzyme activities and protein levels have been reported to be increased in some tumors and decreased in other. In a series of 25 astrocytic tumors, the activity levels of OXPHOS complexes and citrate synthase were examined using immunohistochemical staining. [112] Activities of complexes I-V and citrate synthase were detected decreased by 56-92% as compared with a normal brain.

In more recent study, Lloyd et al. used next-generation sequencing assay to detect alterations in the whole mitochondrial genome in 10 cell lines and 32 tissues of GBM. [113] They identified over 200 mtDNA mutations with 25 nonsynonymous mutations in complex III and IV. Furthermore, by using 3D structural mapping and analysis to the mutations, they revealed that 9 mutations showed significant functional impact at the level of protein structural changes, whereas the remaining 16 are likely to be nonfunctional. [113]

 > Prognostic Impact of Mitochondrial DNA Alterations in Brain Tumor Top

A number of studies have investigated the prognostic value of mtDNA mutations and/or changes in mtDNA copy number in various types of cancers. Studies in breast cancer, esophageal cancer, and colorectal cancer showed mtDNA alterations are associated with poor prognosis. [114],[115],[116] For instances, Zhang's group showed that mtDNA D-loop polymorphisms are independent poor prognostic markers in patients with esophageal squamous cell carcinoma. [115] Similarly, Cui et al. published their study suggested that a reduced copy number of mtDNA is correlated with poor prognosis in colorectal cancer. [116]

Other studies, however, did not demonstrate such a correlation. [60],[117],[118] For example, Challen et al. suggested in their study that mtDNA D-loop somatic mutations were uncommon and may not have an impact on the prognosis in head and neck cancer patients. [117] Lee et al. observed that changes in mtDNA content were not associated with any clinicopathological characteristics in gastric cancer. [118]

On the other hand, some authors have reported the positive impact on this matter. [119],[120] In the study of Liu et al. on 59 oral cancer patients, mtDNA somatic mutations had a significant impact on survival. [119] Moreover, in other study, Lin et al. also found that oral squamous cell carcinoma patients with mtDNA D-loop region somatic mutation had a better prognosis when compared with those without. [120]

Until now, not much is known about the prognosis of brain tumor with mtDNA alterations. The study on this matter was very limited, and their results were considered controversial. Some authors reported no influence or impact on the prognosis of brain tumor patients with mtDNA alterations. In the previous study, Montanini et al. reported that mtDNA mutations had no prognostic effect in gliomas. [90] They claimed that mtDNA mutations could not be used as an indication in the diagnostic or prognostic evaluations of gliomas. Similarly, Vidone et al. suggested that mtDNA genotyping may not be an efficient molecular tool to predict prognosis. [121]

In contrast, recent research revealed that there is an association between the mtDNA content and clinical outcomes in glioma patients. Zhang et al. showed that glioma patients with high mtDNA content had significantly longer survival times than patients with low mtDNA content. [108] They concluded that the high copy number of mtDNA may be a useful good prognostic factor in glioma patients. Additionally, in the study of mitochondrial protein complex IV, cytochrome c oxidase, Griguer et al. revealed a higher activity of cytochrome c oxidase in high-grade glioma patients, suggesting high tumor cytochrome c oxidase activity as an independent predictor of poor outcome. [122]

There is still a lot of debate about the precise prognostic role of mtDNA alterations in brain tumor. Therefore, additional larger studies are needed to clarify the prognostic impact of mtDNA alterations status in brain tumor.

 > Conclusion Top

The role of mtDNA mutations in cancer remains largely unclear, and, therefore, more studies and attentions should be given before a clear conclusion could be achieved. There is a lot of evidence suggesting that some mtDNA mutations do play a role in certain stages of cancer development and progression, but further research is needed to clarify this possible link. There are still multiple potential experimental pitfalls and weaknesses; thus, relevant caution and basic guidelines in research should be followed to obtain the best results. [45],[123] Based on our ongoing research and previous studies from other researchers, it could be suggested that mtDNA mutations could be a genetic aberration target in cancer development, instead of nuclear oncogenes and tumor suppressor genes. Cancer cells are very mutagenic in the early stage either due to exposure to high levels of carcinogenic substances or conditions or because of lack of repair mechanism. Thus, mtDNA simply seems to be more prone to mutation at this stage and has a limited ability to repair itself.

Mitochondria produce energy, and their genome is responsible for regulating OXPHOS function. Aberrations in mtDNA may interrupt this process and ultimately lead to abnormal function of the cell. The unique properties of mtDNA, including its high copy number, high susceptibility to mutations, and quantitative and qualitative changes in cancer, stimulate researchers to closely be involved in the clinical relevance investigation of mtDNA alterations in cancers. In addition, the screening of mtDNA mutations is more easy and cost-effective than nDNA analysis, due to several advantages that mtDNA have such as a simple circular structure with a short sequence length. It has been shown that the existence of mtDNA mutations in cancer cells is particularly consistent with the intrinsic sensitivity of mtDNA to accumulate oxidative damage. Impairment of mitochondrial OXPHOS activity and mtDNA damage seem to be a common feature of malignant cells. Instability and abnormality in DNA and protein of mitochondria have been identified in various solid tumors and hematologic malignancies. However, up to now, many studies have been directed toward identifying and characterizing the altered mtDNA. There have been only limited studies, mainly in relation to its functional consequences and clinical relevance. The functional aspects of mtDNA mutations in cancer development will provide a mechanistic link between mitochondria and carcinogenesis and also will translate into some useful prevention and therapeutic strategies of cancer in the future research.

Although to date, mutations, polymorphisms, and variants of mtDNA have been described in brain tumors, there are more studies that need to be done to fully understand the role of mtDNA in these tumor cells. Further studies which include the assessment of the different types and stages of brain tumor need to be carried out. It is very crucial because perhaps that only certain stages and types will be sensitive to the effects of mtDNA mutations. Based on available evidence suggests that mtDNA may play a key role in the development and modulation of different steps of carcinogenesis. They could be used in the future as new potential target biomarkers for diagnosis, prognosis, and therapeutic purposes of brain cancers.


This work was supported in part by the Research University Grant for Individual from Universiti Sains Malaysia 1001/PPSP/812110.

Financial support and sponsorship

Research University Grant, Universiti Sains Malaysia, Kelantan, Malaysia 1001/PPSP/812110.

Conflicts of interest

There are no conflicts of interest.

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