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Mitochondrial Metabolism in Cancer
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Mitochondrial Metabolism in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 12063

Special Issue Editors

Dr. Patrizia Bottoni

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Guest Editor
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy
Interests: cell differentiation; cancer; cancer cell metabolism; mitochondria; mitochondrial metabolism; oxidative phosphorylation; tumor markers; Warburg effect
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Alvaro Mordente

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Co-Guest Editor
Dipartimento di Scienze Biotecnologiche di base, Cliniche Intensivologiche e Perioperatorie, Sezione di Biochimica, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Roma, Italy
Dipartimento di Medicina di Laboratorio, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, L.go A. Gemelli 8, 00168 Roma, Italy
Interests: Mitochondria, Anthracyclines, Cardiotoxicity

Special Issue Information

Dear Colleagues,

Mitochondrial contribution to the pathogenesis of cancer has tended to be neglected for many years. In fact, Warburg's original observation that cancer cell preferentially uses glycolysis for energetic and anabolic purposes, producing large quantities of lactic acid, due to impaired mitochondrial function led for a long time to neglect the role of mitochondria in the pathophysiology of cancer, confining them to a simple secondary role, i.e. a damaged and hypofunctional organelle. Over time, it has become evident that the strongly induced aerobic glycolitic state of cancer cells is only a tip of an iceberg, one aspect of a more complex metabolic rearrangement aimed to satisfy high energy demands of cells during oncogenesis process. In this context, in which cancer cell singularly reprograms its metabolism to support the new needs for a rapid and uncontrolled proliferation, mitochondria have been recognized to play a crucial role not only in tumor formation but also in its progression. Besides being the powerhouse of the cell, as they have classically described, mitochondria control calcium homeostasis and thermogenesis, regulate cell death by apoptosis, contribute to transcriptional regulation and influence different signal transduction pathways by producing ROS, thus promoting genomic instability and cancer cell dissemination. In the light recent findings assigning an active and crucial role to mitochondrial physiology in cancer cell metabolism, this special issue on “Mitochondrial metabolism in cancer” aims to explore the various aspects of the tight connection between mitochondrial bioenergetics and tumourigenesis, by defining how the different mitochondrial activities could support cancer cell proliferation and identifying the mechanisms through which mitochondria can influence malignant transformation and tumor progression. Elucidating molecular relationships between mitochondria and cancer is essential step to realize new therapeutic strategies of targeting mitochondrial metabolism for cancer therapy.

Dr. Patrizia Bottoni
Guest Editor

Manuscript Submission Information

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Keywords

  • Cancer
  • Cancer Cell Metabolism
  • Cancer Therapy
  • Mitochondria
  • Mitochondrial Metabolism
  • Warburg Effect

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Published Papers (3 papers)

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Research

12 pages, 1842 KiB  
Article
Doxorubicin-Induced Autophagolysosome Formation Is Partly Prevented by Mitochondrial ROS Elimination in DOX-Resistant Breast Cancer Cells
by Seyedeh Tayebeh Ahmadpour, Valérie Desquiret-Dumas, Ulku Yikilmaz, Julie Dartier, Isabelle Domingo, Celine Wetterwald, Charlotte Orre, Naïg Gueguen, Lucie Brisson, Karine Mahéo and Jean-François Dumas
Int. J. Mol. Sci. 2021, 22(17), 9283; https://doi.org/10.3390/ijms22179283 - 27 Aug 2021
Cited by 12 | Viewed by 3265
Abstract
Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional [...] Read more.
Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional mitochondria by mitophagy could thus prevent the initiation of the apoptotic cascade. In breast cancer patients, resistance to doxorubicin (DOX), one of the most widely used cancer drugs, is an important cause of poor clinical outcomes. However, the role played by mitophagy in the context of DOX resistance in breast cancer cells is not well understood. We therefore tried to determine whether an increase in mitophagic flux was associated with the resistance of breast cancer cells to DOX. Our first objective was to explore whether DOX-resistant breast cancer cells were characterized by conditions that favor mitophagy induction. We next tried to determine whether mitophagic flux was increased in DOX-resistant cells in response to DOX treatment. For this purpose, the parental (MCF-7) and DOX-resistant (MCF-7dox) breast cancer cell lines were used. Our results show that mitochondrial reactive oxygen species (ROS) production and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression are higher in MCF-7dox in a basal condition compared to MCF-7, suggesting DOX-resistant breast cancer cells are prone to stimuli to induce a mitophagy-related event. Our results also showed that, in response to DOX, autophagolysosome formation is induced in DOX-resistant breast cancer cells. This mitophagic step following DOX treatment seems to be partly due to mitochondrial ROS production as autophagolysosome formation is moderately decreased by the mitochondrial antioxidant mitoTEMPO. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism in Cancer)
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22 pages, 3474 KiB  
Article
Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line
by Dorina Coricovac, Cristina Adriana Dehelean, Iulia Pinzaru, Alexandra Mioc, Oana-Maria Aburel, Ioana Macasoi, George Andrei Draghici, Crina Petean, Codruta Soica, Madalina Boruga, Brigitha Vlaicu and Mirela Danina Muntean
Int. J. Mol. Sci. 2021, 22(9), 4870; https://doi.org/10.3390/ijms22094870 - 4 May 2021
Cited by 36 | Viewed by 4099
Abstract
Melanoma represents one of the most aggressive and drug resistant skin cancers with poor prognosis in its advanced stages. Despite the increasing number of targeted therapies, novel approaches are needed to counteract both therapeutic resistance and the side effects of classic therapy. Betulinic [...] Read more.
Melanoma represents one of the most aggressive and drug resistant skin cancers with poor prognosis in its advanced stages. Despite the increasing number of targeted therapies, novel approaches are needed to counteract both therapeutic resistance and the side effects of classic therapy. Betulinic acid (BA) is a bioactive phytocompound that has been reported to induce apoptosis in several types of cancers including melanomas; however, its effects on mitochondrial bioenergetics are less investigated. The present study performed in A375 human melanoma cells was aimed to characterize the effects of BA on mitochondrial bioenergetics and cellular behavior. BA demonstrated a dose-dependent inhibitory effect in both mitochondrial respiration and glycolysis in A375 melanoma cells and at sub-toxic concentrations (10 μM) induced mitochondrial dysfunction by eliciting a decrease in the mitochondrial membrane potential and changes in mitochondria morphology and localization. In addition, BA triggered a dose-dependent cytotoxic effect characterized by apoptotic features: morphological alterations (nuclear fragmentation, apoptotic bodies) and the upregulation of pro-apoptotic markers mRNA expression (Bax, Bad and Bak). BA represents a viable therapeutic option via a complex modulatory effect on mitochondrial metabolism that might be useful in advanced melanoma or as reliable strategy to counteract resistance to standard therapy. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism in Cancer)
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18 pages, 3413 KiB  
Article
Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma
by Alan Chun Kit Lee, Pui Man Lau, Yiu Wa Kwan and Siu Kai Kong
Int. J. Mol. Sci. 2021, 22(7), 3315; https://doi.org/10.3390/ijms22073315 - 24 Mar 2021
Cited by 27 | Viewed by 3840
Abstract
Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, [...] Read more.
Chemo-resistance hinders treatment of patients with hepatocellular carcinoma. Although there are many models that can be found in the literature, the root mechanism to explain chemo-resistance is still not fully understood. To gain a better understanding of this phenomenon, a chemo-resistant line, R-HepG2, was developed from a chemo-sensitive HepG2 line through an exposure of doxorubicin (DOX). The R-HepG2 exhibited a cancer stem cell (CSC) phenotype with an over-expression of P-glycoprotein (P-gp), conferring it a significant enhancement in drug efflux and survival. With these observations, we hypothesize that metabolic alteration in this drug-resistant CSC is the root cause of chemo-resistance. Our results show that, unlike other metabolic-reprogrammed CSCs that exhibit glycolytic phenotype described by the “Warburg effect”, the R-HepG2 was metabolically quiescent with glucose independence, high metabolic plasticity, and relied on glutamine metabolism via the mitochondria for its chemo-resistance Intriguingly, drug efflux by P-gp in R-HepG2 depended on the mitochondrial ATP fueled by glutamine instead of glycolytic ATP. Armed with these observations, we blocked the glutamine metabolism in the R-HepG2 and a significant reduction of DOX efflux was obtained. We exploited this metabolic vulnerability using a combination of DOX and metformin in a glutamine-free condition to target the R-HepG2, resulting in a significant DOX sensitization. In conclusion, our findings highlight the metabolic modulation of chemo-resistance in CSCs. We delineate the altered metabolism that drives chemo-resistance and offer a new approach to target this CSC through metabolic interventions. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism in Cancer)
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