Special Issue "Mitochondria, Metabolism and Cancer"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: 30 September 2020.

Special Issue Editor

Dr. Benny Abraham Kaipparettu
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Guest Editor
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, BCM-T835, Houston, USA
Interests: cancer; mitochondrial metabolism; metabolic reprogramming; hybrid metabolic status; transmitocondrial cybrids and fatty acid oxidation
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Though the presence of abnormal metabolic activities in cancer tissues is well-established, it remains unclear how the cellular oncogenic states lead to the unusual metabolism and how the cancer metabolism contributes to tumorigenesis. In the traditional view based on the Warburg effect, cancer cells largely depend on glycolysis to produce energy even in the presence of oxygen. However, recent developments in cancer metabolism have established that both glycolysis and oxidative phosphorylation (OXPHOS) can be active in several aggressive cancer cells. Importantly, more and more experimental evidence upholds the critical role that actively functional mitochondria play in tumorigenesis and drug resistance. It has also been proposed that the metabolic plasticity in tumor cells might play a crucial role in cancer stemness and metastasis. Cancer mitochondria can utilize different kinds of resources, such as glucose, glutamine, and fatty acids, to fuel the electron transport chain (ETC) for OXPHOS. Moreover, the involvement of mitochondria in cell death mechanisms makes them important targets for tumor therapy.

Dr. Benny Abraham Kaipparettu
Guest Editor

Manuscript Submission Information

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Keywords

  • mitochondria
  • cancer metabolism
  • transmitochondrial hybrids
  • metabolic reprogramming
  • mitochondria–nuclear crosstalk
  • hybrid metabolic status
  • reactive oxygen species
  • glycolysis
  • electron transport chain
  • metabolic inhibitors
  • apoptosis

Published Papers (6 papers)

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Research

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Open AccessArticle
Moderate Exercise Modulates Tumor Metabolism of Triple-Negative Breast Cancer
Cells 2020, 9(3), 628; https://doi.org/10.3390/cells9030628 - 05 Mar 2020
Abstract
Triple-negative breast cancer (TNBC) stands out for its aggressiveness and accelerated rate of proliferation. Evidence shows that exercise may exert antitumorigenic effects, but the biochemical mechanisms underlying them remain unclear. Our objective was to evaluate the ability of exercise to modulate tumor growth [...] Read more.
Triple-negative breast cancer (TNBC) stands out for its aggressiveness and accelerated rate of proliferation. Evidence shows that exercise may exert antitumorigenic effects, but the biochemical mechanisms underlying them remain unclear. Our objective was to evaluate the ability of exercise to modulate tumor growth and energy metabolism in an experimental TNBC model. Female BALB/c mice were sedentary or trained for 12 weeks and inoculated with 1 × 104 4T1 cells in the eighth week. Analyzes of macronutrient oxidation, mitochondrial respiration, and expression of genes related to cell metabolism were performed. The results showed that the trained group had a smaller tumor mass and the mitochondria in the tumors presented lower respiratory rates in the state of maximum electron transport capacity. Additionally, the tumors of the exercised group showed a higher expression of genes related to tumor suppressors, while the genes linked with cellular growth were similar between groups. Furthermore, the training modulated the corporal macronutrient oxidation to almost exclusive carbohydrate oxidation, while the sedentary condition metabolized both carbohydrate and lipids. Therefore, the exercise reduced tumor growth, with an impact on mitochondrial and macronutrient metabolism. Our results shed light on the understanding of the antitumorigenic effects of physical exercise, particularly regarding the metabolic transformations in TNBC. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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Open AccessArticle
Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells
Cells 2020, 9(2), 407; https://doi.org/10.3390/cells9020407 - 11 Feb 2020
Cited by 2
Abstract
The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that [...] Read more.
The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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Review

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Open AccessReview
The Molecular Landscape of Hürthle Cell Thyroid Cancer Is Associated with Altered Mitochondrial Function—A Comprehensive Review
Cells 2020, 9(7), 1570; https://doi.org/10.3390/cells9071570 - 27 Jun 2020
Abstract
Hürthle cell thyroid carcinoma (HTC) accounts for 3–5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other [...] Read more.
Hürthle cell thyroid carcinoma (HTC) accounts for 3–5% of all thyroid malignancies. Widely invasive HTC is characterized by poor prognosis and limited responsiveness to standard therapy with radioiodine. The molecular landscape of HTC is significantly different from the genetic signature seen in other forms of thyroid cancer. We performed a comprehensive literature review on the association between the molecular features of HTC and cancer metabolism. We searched the Pubmed, Embase, and Medline databases for clinical and translational studies published between 1980 and 2020 in English, coupling “HTC” with the following keywords: “genomic analysis”, “mutations”, “exome sequencing”, “molecular”, “mitochondria”, “metabolism”, “oxidative phosphorylation”, “glycolysis”, “oxidative stress”, “reactive oxygen species”, and “oncogenes”. HTC is characterized by frequent complex I mitochondrial DNA mutations as early clonal events. This genetic signature is associated with the abundance of malfunctioning mitochondria in cancer cells. HTC relies predominantly on aerobic glycolysis as a source of energy production, as oxidative phosphorylation-related genes are downregulated. The enhanced glucose utilization by HTC is used for diagnostic purposes in the clinical setting for the detection of metastases by fluorodeoxyglucose positron emission tomography (FGD-PET/CT) imaging. A comprehensive metabolomic profiling of HTC in association with its molecular landscape might be necessary for the implementation of tumor-specific therapeutic approaches. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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Open AccessReview
Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death
Cells 2020, 9(6), 1505; https://doi.org/10.3390/cells9061505 - 20 Jun 2020
Abstract
Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role [...] Read more.
Ferroptosis is a new type of oxidative regulated cell death (RCD) driven by iron-dependent lipid peroxidation. As major sites of iron utilization and master regulators of oxidative metabolism, mitochondria are the main source of reactive oxygen species (ROS) and, thus, play a role in this type of RCD. Ferroptosis is, indeed, associated with severe damage in mitochondrial morphology, bioenergetics, and metabolism. Furthermore, dysregulation of mitochondrial metabolism is considered a biochemical feature of neurodegenerative diseases linked to ferroptosis. Whether mitochondrial dysfunction can, per se, initiate ferroptosis and whether mitochondrial function in ferroptosis is context-dependent are still under debate. Cancer cells accumulate high levels of iron and ROS to promote their metabolic activity and growth. Of note, cancer cell metabolic rewiring is often associated with acquired sensitivity to ferroptosis. This strongly suggests that ferroptosis may act as an adaptive response to metabolic imbalance and, thus, may constitute a new promising way to eradicate malignant cells. Here, we review the current literature on the role of mitochondria in ferroptosis, and we discuss opportunities to potentially use mitochondria-mediated ferroptosis as a new strategy for cancer therapy. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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Open AccessReview
Genomic Balance: Two Genomes Establishing Synchrony to Modulate Cellular Fate and Function
Cells 2019, 8(11), 1306; https://doi.org/10.3390/cells8111306 - 23 Oct 2019
Cited by 1
Abstract
It is becoming increasingly apparent that cells require cooperation between the nuclear and mitochondrial genomes to promote effective function. However, it was long thought that the mitochondrial genome was under the strict control of the nuclear genome and the mitochondrial genome had little [...] Read more.
It is becoming increasingly apparent that cells require cooperation between the nuclear and mitochondrial genomes to promote effective function. However, it was long thought that the mitochondrial genome was under the strict control of the nuclear genome and the mitochondrial genome had little influence on cell fate unless it was extensively mutated, as in the case of the mitochondrial DNA diseases. However, as our understanding of the roles that epigenetic regulators, including DNA methylation, and metabolism play in cell fate and function, the role of the mitochondrial genome appears to have a greater influence than previously thought. In this review, I draw on examples from tumorigenesis, stem cells, and oocyte pre- and post-fertilisation events to discuss how modulating one genome affects the other and that this results in a compromise to produce functional mature cells. I propose that, during development, both of the genomes interact with each other through intermediaries to establish genomic balance and that establishing genomic balance is a key facet in determining cell fate and viability. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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Other

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Open AccessTechnical Note
Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation
Cells 2019, 8(12), 1583; https://doi.org/10.3390/cells8121583 - 06 Dec 2019
Abstract
Mitochondrial sirtuins (Sirts) control important cellular processes related to stress. Despite their regulatory importance, however, the dynamics and subcellular distributions of Sirts remain debatable. Here, we investigate the subcellular localization of sirtuin 4 (Sirt4), a sirtuin variant with a mitochondrial targeting sequence (MTS), [...] Read more.
Mitochondrial sirtuins (Sirts) control important cellular processes related to stress. Despite their regulatory importance, however, the dynamics and subcellular distributions of Sirts remain debatable. Here, we investigate the subcellular localization of sirtuin 4 (Sirt4), a sirtuin variant with a mitochondrial targeting sequence (MTS), by expressing Sirt4 fused to the superfolder green fluorescent protein (Sirt4-sfGFP) in HeLa and pancreatic β-cells. Super resolution fluorescence microscopy revealed the trapping of Sirt4-sfGFP to the outer mitochondrial membrane (OMM), possibly due to slow mitochondrial import kinetics. In many cells, Sirt4-sfGFP was also present within the cytosol and nucleus. Moreover, the expression of Sirt4-sfGFP induced mitochondrial swelling in HeLa cells. In order to bypass these effects, we applied the self-complementing split fluorescent protein (FP) technology and developed mito-STAR (mitochondrial sirtuin 4 tripartite abundance reporter), a tripartite probe for the visualization of Sirt4 distribution between mitochondria and the nucleus in single cells. The application of mito-STAR proved the importation of Sirt4 into the mitochondrial matrix and demonstrated its localization in the nucleus under mitochondrial stress conditions. Moreover, our findings highlight that the self-complementation of split FP is a powerful technique to study protein import efficiency in distinct cellular organelles. Full article
(This article belongs to the Special Issue Mitochondria, Metabolism and Cancer)
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