Special Issue "Mitochondrial function and dysfunction in cancer and their potential as anti-cancer targets"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (29 February 2020).

Special Issue Editor

Prof. Varda Shoshan-Barmatz
Website
Guest Editor
Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.

Special Issue Information

Dear Colleagues,

The mitochondrion, a discrete sub-cellular organelle comprising some 1000 different proteins, mediates basic life functions and contains key components of biosynthetic pathways, as well as serving as the site where cellular decisions leading to apoptosis (programmed cell death) are taken. Mitochondria perform a variety of crucial cell functions, including energy production, Ca2+ signaling and maintenance of Ca2+ homeostasis, metabolism of amino acids, lipids, and iron, modulation of the cell’s redox potential, osmotic regulation and pH control, as well as being the  site of reactive oxygen species (ROS) generation and an essential component of the apoptotic machinery. Changes in these parameters can impact biosynthetic pathways, cellular signal transduction pathways, and epigenetics, shifting the cell from the quiescent, differentiated state to one of actively proliferation, as occurs in cancer. Indeed, the signaling pathways that govern mitochondrial function, mitochondrial integrity, cell viability and apoptosis have been addressed in many studies, with mitochondrial targeting strategies having recently gained momentum.

The association of mitochondria with cancer was first presented over 70 years ago by Otto Heinrich Warburg and his colleagues, who hypothesized that dysfunctional mitochondria may be the cause of higher rates of aerobic glycolysis (termed the 'Warburg effect”), with this gradual and cumulative decrease in mitochondrial activity being associated with malignant transformation. However, many studies conducted since have demonstrated that functional mitochondria are essential for the cancer cell and have identified pleiotropic roles of mitochondria in tumorigenesis.

Given their roles in bioenergetics, in biosynthetic pathways and as signaling organelles sensing stress, mitochondria are central to cellular adaptation to the environment. As such, it is not surprising that mitochondria are important mediators of tumorigenesis, a process requiring flexibility in adapting to cellular and environmental alterations. Indeed, differences in mitochondrial structure and function between normal and cancer cells have been reported. These changes can provide the biological basis for preferential targeting of cancer cells. Thus, uncovering the mechanisms responsible for altered mitochondrial function during tumorigenesis is critical for developing the next generation of cancer therapeutics. Indeed, appreciation that mitochondria play central roles in cellular energy generation, metabolism, apoptosis and necrosis carry far-reaching implications and provide solid rationale and a strong biological basis for developing mitochondria-targeted anti-cancer agents.

Scientists studying mitochondria- and cancer-associated topics, including but not limited to oxidative stress, organelle biogenesis, apoptosis, necrosis, import and folding of mitochondrial proteins, membrane synthesis, structure and dynamics, Ca2+ homeostasis, the mitochondrial genetic system, mitochondria-interacting proteins, such as hexokinase, anti- and pro-apoptotic proteins, p53, as well as ER-mitochondria interactions and cancer, are invited to contribute to this special issue.

Prof. Varda Shoshan-Barmatz
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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Open AccessFeature PaperArticle
The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link
Cancers 2020, 12(4), 1031; https://doi.org/10.3390/cancers12041031 - 22 Apr 2020
Abstract
Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, [...] Read more.
Carcinogenesis is a complicated process that involves the deregulation of epigenetics, resulting in cellular transformational events, such as proliferation, differentiation, and metastasis. Most chromatin-modifying enzymes utilize metabolites as co-factors or substrates and thus are directly dependent on such metabolites as acetyl-coenzyme A, S-adenosylmethionine, and NAD+. Here, we show that using specific siRNA to deplete a tumor of VDAC1 not only led to reprograming of the cancer cell metabolism but also altered several epigenetic-related enzymes and factors. VDAC1, in the outer mitochondrial membrane, controls metabolic cross-talk between the mitochondria and the rest of the cell, thus regulating the metabolic and energetic functions of mitochondria, and has been implicated in apoptotic-relevant events. We previously demonstrated that silencing VDAC1 expression in glioblastoma (GBM) U-87MG cell-derived tumors, resulted in reprogramed metabolism leading to inhibited tumor growth, angiogenesis, epithelial–mesenchymal transition and invasiveness, and elimination of cancer stem cells, while promoting the differentiation of residual tumor cells into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. As the epigenome is sensitive to cellular metabolism, this study was designed to assess whether depleting VDAC1 affects the metabolism–epigenetics axis. Using DNA microarrays, q-PCR, and specific antibodies, we analyzed the effects of si-VDAC1 treatment of U-87MG-derived tumors on histone modifications and epigenetic-related enzyme expression levels, as well as the methylation and acetylation state, to uncover any alterations in epigenetic properties. Our results demonstrate that metabolic rewiring of GBM via VDAC1 depletion affects epigenetic modifications, and strongly support the presence of an interplay between metabolism and epigenetics. Full article
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Open AccessArticle
Pan-Cancer Analysis of Mitochondria Chaperone-Client Co-Expression Reveals Chaperone Functional Partitioning
Cancers 2020, 12(4), 825; https://doi.org/10.3390/cancers12040825 - 30 Mar 2020
Abstract
Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and [...] Read more.
Metabolic reprogramming is a hallmark of cancer. Such reprogramming entails the up-regulation of the expression of specific mitochondrial proteins, thus increasing the burden on the mitochondrial protein quality control. However, very little is known about the specificity of interactions between mitochondrial chaperones and their clients, or to what extent the mitochondrial chaperone–client co-expression is coordinated. We hypothesized that a physical interaction between a chaperone and its client in mitochondria ought to be manifested in the co-expression pattern of both transcripts. Using The Cancer Genome Atlas (TCGA) gene expression data from 13 tumor entities, we constructed the mitochondrial chaperone-client co-expression network. We determined that the network is comprised of three distinct modules, each populated with unique chaperone-clients co-expression pairs belonging to distinct functional groups. Surprisingly, chaperonins HSPD1 and HSPE1, which are known to comprise a functional complex, each occupied a different module: HSPD1 co-expressed with tricarboxylic acid cycle cycle enzymes, while HSPE1 co-expressed with proteins involved in oxidative phosphorylation. Importantly, we found that the genes in each module were enriched for discrete transcription factor binding sites, suggesting the mechanism for the coordinated co-expression. We propose that our mitochondrial chaperone–client interactome can facilitate the identification of chaperones supporting specific mitochondrial pathways and bring forth a fundamental principle in metabolic adaptation. Full article
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Open AccessArticle
Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps
Cancers 2020, 12(4), 815; https://doi.org/10.3390/cancers12040815 - 28 Mar 2020
Abstract
This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue [...] Read more.
This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: KRAS mutated, BRAF mutated and KRAS/BRAF wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (Vmax) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. KRAS mutated CRC group had lower Vmax values compared to wild-type; however, the Vmax value was higher than in the control group, while MOM permeability did not change. This suggests that KRAS mutation status might be involved in acquiring oxidative phenotype. KRAS mutated polyps had higher Vmax values and elevated MOM permeability as compared to the control. BRAF mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification. Full article
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Open AccessArticle
Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma
Cancers 2020, 12(3), 755; https://doi.org/10.3390/cancers12030755 - 23 Mar 2020
Abstract
Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and [...] Read more.
Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93–28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine. Full article
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Open AccessArticle
Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas
Cancers 2020, 12(3), 599; https://doi.org/10.3390/cancers12030599 - 05 Mar 2020
Abstract
Pheochromocytoma/paragangliomas (Pheo/PGL) are rare endocrine cancers with strong genetic background. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) predispose patients to malignant disease with limited therapeutic options and poor prognosis. Using a host of cellular and molecular biology techniques in 2D and [...] Read more.
Pheochromocytoma/paragangliomas (Pheo/PGL) are rare endocrine cancers with strong genetic background. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) predispose patients to malignant disease with limited therapeutic options and poor prognosis. Using a host of cellular and molecular biology techniques in 2D and 3D cell culture formats we show that SDH inhibition had cell line specific biological and biochemical consequences. Based on our studies performed on PC12 (rat chromaffin cell line), Hela (human cervix epithelial cell line), and H295R (human adrenocortical cell line) cells, we demonstrated that chromaffin cells were not affected negatively by the inhibition of SDH either by siRNA directed against SDHB or treatment with SDH inhibitors (itaconate and atpenin A5). Cell viability and intracellular metabolite measurements pointed to the cell line specific consequences of SDH impairment and to the importance of glutamate metabolism in chromaffin cells. A significant increase in glutaminase-1 (GLS-1) expression after SDH impairment was observed in PC12 cells. GLS-1 inhibitor BPTES was capable of significantly decreasing proliferation of SDH impaired PC12 cells. Glutaminase-1 and SDHB expressions were tested in 35 Pheo/PGL tumor tissues. Expression of GLS1 was higher in the SDHB low expressed group compared to SDHB high expressed tumors. Our data suggest that the SDH-associated malignant potential of Pheo/PGL is strongly dependent on GLS-1 expression and glutaminases may be novel targets for therapy. Full article
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Open AccessArticle
Establishment of a Temperature-Sensitive Model of Oncogene-Induced Senescence in Angiosarcoma Cells
Cancers 2020, 12(2), 395; https://doi.org/10.3390/cancers12020395 - 08 Feb 2020
Abstract
Lesions with driver mutations, including atypical nevi and seborrheic keratoses, are very common in dermatology, and are prone to senescence. The molecular events that prevent senescent lesions from becoming malignant are not well understood. We have developed a model of vascular proliferation using [...] Read more.
Lesions with driver mutations, including atypical nevi and seborrheic keratoses, are very common in dermatology, and are prone to senescence. The molecular events that prevent senescent lesions from becoming malignant are not well understood. We have developed a model of vascular proliferation using a temperature-sensitive, large T antigen and oncogenic HRas. By elevating the temperature to 39 °C, we can turn off large T antigen and study the molecular events in cells with the Ras driver mutation. To assess the signaling events associated with the switch from a proliferative to a nonproliferative state in the constant presence of a driver oncogene, SVR cells were cultivated for 24 and 48 h and compared with SVR cells at 37 °C. Cells were evaluated by Western Blot (WB) gene chip microarray (GC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR). Upon evaluation, a novel phenotype was observed in endothelial cells after switching off the large T antigen. This phenotype was characterized by Notch activation, downregulation of p38 phosphorylation, downregulation of the master immune switch IRF7, and downregulation of hnRNP A0. Switching off proliferative signaling may result in immune privilege and Notch activation, which may account, in part, for the survival of common skin lesions. Full article
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Review

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Open AccessReview
L-Glucose: Another Path to Cancer Cells
Cancers 2020, 12(4), 850; https://doi.org/10.3390/cancers12040850 - 01 Apr 2020
Abstract
Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l [...] Read more.
Cancerous tumors comprise cells showing metabolic heterogeneity. Among numerous efforts to understand this property, little attention has been paid to the possibility that cancer cells take up and utilize otherwise unusable substrates as fuel. Here we discuss this issue by focusing on l-glucose, the mirror image isomer of naturally occurring d-glucose; l-glucose is an unmetabolizable sugar except in some bacteria. By combining relatively small fluorophores with l-glucose, we generated fluorescence-emitting l-glucose tracers (fLGs). To our surprise, 2-NBDLG, one of these fLGs, which we thought to be merely a control substrate for the fluorescent d-glucose tracer 2-NBDG, was specifically taken up into tumor cell aggregates (spheroids) that exhibited nuclear heterogeneity, a major cytological feature of malignancy in cancer diagnosis. Changes in mitochondrial activity were also associated with the spheroids taking up fLG. To better understand these phenomena, we review here the Warburg effect as well as key studies regarding glucose uptake. We also discuss tumor heterogeneity involving aberrant uptake of glucose and mitochondrial changes based on the data obtained by fLG. We then consider the use of fLGs as novel markers for visualization and characterization of malignant tumor cells. Full article
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