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Mitochondrial Functions, Alterations and Dynamics in Cancer

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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 (15 February 2021) | Viewed by 41610

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Special Issue Editors

Dr. Monica Montopoli

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Guest Editor

Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
Interests: chemoresistance; cancer metabolism; chemosensitizers; cisplatin; mitochondria; molecular pharmacology; antioxidants; inflammation
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Pierre Sonveaux

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Co-Guest Editor

Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium
Interests: tumor metabolism; hypoxia; angiogenesis; metastasis; chemoresistance; radioresistance; glycolysis; oxidative phosphorylation; lactate; mitochondrial reactive oxygen species (mtROS); translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer cells are metabolic entities presenting a wide pattern of metabolic alterations. At the core of metabolic pathways, mitochondria are subcellular organelles specialized in energy production and biosynthesis. In the process of anaplerosis, they are fueled by several metabolic pathways (e.g., glycolysis, glutaminolysis, and fatty acid oxidation), while for cataplerosis they provide metabolites and cofactors for fatty acid and protein synthesis and resistance to redox stress. As dynamic organelles, mitochondria also control cell survival and death. As metabolic sensors, they signal through the activation of molecular pathways that affect the cell as a whole, supporting phenotypes that characterize things such as cancer-initiating cells, cancer stem cells, metastatic progenitor cells, and cancer cells resistant to therapy. Mitochondrial processes are thus harnessed and/or altered by cancer cells and contribute to the malignant phenotype, which is the topic of this Special Issue of the International Journal of Molecular Sciences. A special focus will be set on original strategies targeting mitochondria for anticancer treatment.

Prof. Monica Montopoli
Prof. Pierre Sonveaux
Guest Editors

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 submissions that pass pre-check are 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

tumor metabolism
mitochondria
anaplerosis
cataplerosis
energy production
biosynthesis
TCA cycle
electron transport chain (ETC)
mitochondrial potential
mitochondrial reactive oxygen species (mtROS)
mitochondrial DNA (mtDNA)
mtDNA mutations
mtDNA repair
mtDNA epigenetics
mitochondrial fusion
mitochondrial fission
mitophagy
mitochondrial transfer
homoplasmy
heteroplasmy
apoptosis
tumorigenesis
chemoresistance
radioresistance
cancer stem cells
metastatic progenitor cells

Published Papers (6 papers)

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Research

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15 pages, 2574 KiB

Open AccessArticle

Aspirin Induces Mitochondrial Ca²⁺ Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca²⁺ Entry

by Itsuho Fujikawa, Takashi Ando, Manami Suzuki-Karasaki, Miki Suzuki-Karasaki, Toyoko Ochiai and Yoshihiro Suzuki-Karasaki

Int. J. Mol. Sci. 2020, 21(13), 4771; https://doi.org/10.3390/ijms21134771 - 5 Jul 2020

Cited by 9 | Viewed by 3022

Abstract

Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca²⁺ entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin’s anti-melanoma effect. Aspirin and to a lesser extent, salicylate (≥2.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca²⁺ channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca²⁺ (Ca²⁺_m) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Ca_v1.2 isoform of l-type Ca²⁺ channel, and knockdown of Ca_v1.2 abolished the decrease in Ca²⁺_m. Our findings suggest that aspirin and salicylate induce Ca²⁺_m remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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Review

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22 pages, 2207 KiB

Open AccessReview

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

by Russel J Reiter, Ramaswamy Sharma, Sergio Rosales-Corral, Walter Manucha, Luiz Gustavo de Almeida Chuffa and Debora Aparecida Pires de Campos Zuccari

Int. J. Mol. Sci. 2021, 22(22), 12494; https://doi.org/10.3390/ijms222212494 - 19 Nov 2021

Cited by 21 | Viewed by 7144

Abstract

Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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27 pages, 2238 KiB

Open AccessReview

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

by Stine F. Pedersen, Mette Flinck and Luis A. Pardo

Int. J. Mol. Sci. 2021, 22(10), 5209; https://doi.org/10.3390/ijms22105209 - 14 May 2021

Cited by 14 | Viewed by 3586

Abstract

Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca²⁺, H⁺, and K⁺, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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Figure 1

14 pages, 895 KiB

Open AccessReview

Hexokinase 2 in Cancer: A Prima Donna Playing Multiple Characters

by Francesco Ciscato, Lavinia Ferrone, Ionica Masgras, Claudio Laquatra and Andrea Rasola

Int. J. Mol. Sci. 2021, 22(9), 4716; https://doi.org/10.3390/ijms22094716 - 29 Apr 2021

Cited by 89 | Viewed by 10041

Abstract

Hexokinases are a family of ubiquitous exose-phosphorylating enzymes that prime glucose for intracellular utilization. Hexokinase 2 (HK2) is the most active isozyme of the family, mainly expressed in insulin-sensitive tissues. HK2 induction in most neoplastic cells contributes to their metabolic rewiring towards aerobic glycolysis, and its genetic ablation inhibits malignant growth in mouse models. HK2 can dock to mitochondria, where it performs additional functions in autophagy regulation and cell death inhibition that are independent of its enzymatic activity. The recent definition of HK2 localization to contact points between mitochondria and endoplasmic reticulum called Mitochondria Associated Membranes (MAMs) has unveiled a novel HK2 role in regulating intracellular Ca²⁺ fluxes. Here, we propose that HK2 localization in MAMs of tumor cells is key in sustaining neoplastic progression, as it acts as an intersection node between metabolic and survival pathways. Disrupting these functions by targeting HK2 subcellular localization can constitute a promising anti-tumor strategy. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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14 pages, 3699 KiB

Open AccessReview

Mitochondrial Transfer in Cancer: A Comprehensive Review

by Luca X. Zampieri, Catarina Silva-Almeida, Justin D. Rondeau and Pierre Sonveaux

Int. J. Mol. Sci. 2021, 22(6), 3245; https://doi.org/10.3390/ijms22063245 - 23 Mar 2021

Cited by 63 | Viewed by 7421

Abstract

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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16 pages, 1951 KiB

Open AccessReview

Cardiolipin, the Mitochondrial Signature Lipid: Implication in Cancer

by Seyedeh Tayebeh Ahmadpour, Karine Mahéo, Stéphane Servais, Lucie Brisson and Jean-François Dumas

Int. J. Mol. Sci. 2020, 21(21), 8031; https://doi.org/10.3390/ijms21218031 - 28 Oct 2020

Cited by 35 | Viewed by 6111

Abstract

Cardiolipins (CLs) are specific phospholipids of the mitochondria composing about 20% of the inner mitochondria membrane (IMM) phospholipid mass. Dysregulation of CL metabolism has been observed in several types of cancer. In most cases, the evidence for a role for CL in cancer is merely correlative, suggestive, ambiguous, and cancer-type dependent. In addition, CLs could play a pivotal role in several mitochondrial functions/parameters such as bioenergetics, dynamics, mitophagy, and apoptosis, which are involved in key steps of cancer aggressiveness (i.e., migration/invasion and resistance to treatment). Therefore, this review focuses on studies suggesting that changes in CL content and/or composition, as well as CL metabolism enzyme levels, may be linked with the progression and the aggressiveness of some types of cancer. Finally, we also introduce the main mitochondrial function in which CL could play a pivotal role with a special focus on its implication in cancer development and therapy. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

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