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Cancers
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Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and...
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Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and Its Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 7418

Special Issue Editors

Dr. Patricio Fernández-Silva

E-Mail Website
Guest Editor
GENOXPHOS Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, and Biocomputation and Complex Systems Physics Institute (BIFI), Zaragoza, Spain
Interests: OXPHOS system biogenesis and organization and its role in pathology
Dr. Raquel Moreno-Loshuertos

E-Mail Website
Guest Editor
GENOXPHOS Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, and Biocomputation and Complex Systems Physics Institute (BIFI), Zaragoza, Spain
Interests: OXPHOS system biogenesis and organization and its role in pathology

Special Issue Information

Dear Colleagues,

Mutations and variants in OXPHOS genes, either nuclear or mtDNA encoded, have been associated with different tumors and with changes in cancer risk and outcomes. However, the establishment of a causal relationship and the determination of the molecular mechanisms explaining their role and effects in carcinogenesis are challenging.

OXPHOS dysfunction, which can be also caused by mtDNA copy number and expression alterations or by mito-nuclear mismatch, directly impacts ATP and ROS production and can have, among others, effects on metabolic remodeling, on the control of apoptosis or on gene expression through epigenetic modifications. These effects can drive the transformation process or facilitate cancer cell adaptation to its microenvironment, having consequences in all stages of tumorigenesis, including the escape from immune surveillance or response to treatment. Integration of different data types, from high-throughput analysis comparing tumor and non-tumor cells in large patient cohorts to the identification of relevant associations and candidate mutations/variants, to single detailed functional studies of particular mutations in specific cancer types, will be needed to elucidate the involved pathways and mechanisms, which are probably complex and with different weights depending on the cell types and the whole genetic context. This knowledge will help us to design more efficient therapeutic strategies.

The aim of this Special Issue is to present and review advances in the understanding of the molecular mechanisms that explain the multiple influences of OXPHOS dysfunction in the carcinogenesis process.

Dr. Patricio Fernández-Silva
Dr. Raquel Moreno-Loshuertos
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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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.

Keywords

  • OXPHOS
  • respiratory complex
  • cancer
  • metastasis
  • mtDNA mutations
  • ROS
  • apoptosis
  • mitophagy
  • metabolic remodeling
  • therapy
  • epigenetics

Published Papers (4 papers)

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Research

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22 pages, 7309 KiB  
Article
Increased O-GlcNAcylation by Upregulation of Mitochondrial O-GlcNAc Transferase (mOGT) Inhibits the Activity of Respiratory Chain Complexes and Controls Cellular Bioenergetics
by Paweł Jóźwiak, Joanna Oracz, Angela Dziedzic, Rafał Szelenberger, Dorota Żyżelewicz, Michał Bijak and Anna Krześlak
Cancers 2024, 16(5), 1048; https://doi.org/10.3390/cancers16051048 - 05 Mar 2024
Viewed by 848
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible post-translational modification involved in the regulation of cytosolic, nuclear, and mitochondrial proteins. The interplay between O-GlcNAcylation and phosphorylation is critical to control signaling pathways and maintain cellular homeostasis. The addition of O-GlcNAc moieties to target proteins is [...] Read more.
O-linked β-N-acetylglucosamine (O-GlcNAc) is a reversible post-translational modification involved in the regulation of cytosolic, nuclear, and mitochondrial proteins. The interplay between O-GlcNAcylation and phosphorylation is critical to control signaling pathways and maintain cellular homeostasis. The addition of O-GlcNAc moieties to target proteins is catalyzed by O-linked N-acetylglucosamine transferase (OGT). Of the three splice variants of OGT described, one is destined for the mitochondria (mOGT). Although the effects of O-GlcNAcylation on the biology of normal and cancer cells are well documented, the role of mOGT remains poorly understood. In this manuscript, the effects of mOGT on mitochondrial protein phosphorylation, electron transport chain (ETC) complex activity, and the expression of VDAC porins were investigated. We performed studies using normal and breast cancer cells with upregulated mOGT or its catalytically inactive mutant. Proteomic approaches included the isolation of O-GlcNAc-modified proteins of the electron transport chain, followed by their analysis using mass spectrometry. We found that mitochondrial OGT regulates the activity of complexes I-V of the respiratory chain and identified a group of 19 ETC components as mOGT substrates in mammary cells. Furthermore, we observed that the upregulation of mOGT inhibited the interaction of VDAC1 with hexokinase II. Our results suggest that the deregulation of mOGT reprograms cellular energy metabolism via interaction with and O-GlcNAcylation of proteins involved in ATP production in mitochondria and its exchange between mitochondria and the cytosol. Full article
(This article belongs to the Special Issue Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and Its Therapies)
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21 pages, 4168 KiB  
Article
PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies
by Ruth Soler-Agesta, Joaquín Marco-Brualla, Martha Minjárez-Sáenz, Christina Y. Yim, Marta Martínez-Júlvez, Matthew R. Price, Raquel Moreno-Loshuertos, Tyler D. Ames, José Jimeno and Alberto Anel
Cancers 2022, 14(16), 3851; https://doi.org/10.3390/cancers14163851 - 09 Aug 2022
Cited by 3 | Viewed by 2355
Abstract
PT-112 is a novel pyrophosphate–platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer [...] Read more.
PT-112 is a novel pyrophosphate–platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112’s effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization—only in the sensitive cells harboring mitochondrial dysfunction—along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications. Full article
(This article belongs to the Special Issue Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and Its Therapies)
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Review

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14 pages, 2609 KiB  
Review
The ATPase Inhibitory Factor 1 (IF1) Contributes to the Warburg Effect and Is Regulated by Its Phosphorylation in S39 by a Protein Kinase A-like Activity
by José M. Cuezva and Sonia Domínguez-Zorita
Cancers 2024, 16(5), 1014; https://doi.org/10.3390/cancers16051014 - 29 Feb 2024
Viewed by 625
Abstract
The relevant role played by the ATPase Inhibitory Factor 1 (IF1) as a physiological in vivo inhibitor of mitochondrial ATP synthase in cancer and non-cancer cells, and in the mitochondria of different mouse tissues, as assessed in different genetic loss- and gain-of-function models [...] Read more.
The relevant role played by the ATPase Inhibitory Factor 1 (IF1) as a physiological in vivo inhibitor of mitochondrial ATP synthase in cancer and non-cancer cells, and in the mitochondria of different mouse tissues, as assessed in different genetic loss- and gain-of-function models of IF1 has been extensively documented. In this review we summarize our findings and those of others that favor the implication of IF1 in metabolic reprogramming to an enhanced glycolytic phenotype, which is mediated by its binding and inhibition of the ATP synthase. Moreover, we emphasize that IF1 is phosphorylated in vivo in its S39 by the c-AMP-dependent PKA activity of mitochondria to render an inactive inhibitor that is unable to interact with the enzyme, thus triggering the activation of ATP synthase. Overall, we discuss and challenge the results that argue against the role of IF1 as in vivo inhibitor of mitochondrial ATP synthase and stress that IF1 cannot be regarded solely as a pro-oncogenic protein because in some prevalent carcinomas, it prevents metastatic disease. Full article
(This article belongs to the Special Issue Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and Its Therapies)
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26 pages, 9105 KiB  
Review
The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention
by Sonia Domínguez-Zorita and José M. Cuezva
Cancers 2023, 15(15), 3775; https://doi.org/10.3390/cancers15153775 - 25 Jul 2023
Cited by 3 | Viewed by 2949
Abstract
Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. [...] Read more.
Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment. Full article
(This article belongs to the Special Issue Oxidative Phosphorylation System Dysfunction Role and Mechanisms in Cancer and Its Therapies)
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