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Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy. Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

Colorectal cancer (CRC) exhibits significant diversity and heterogeneity, posing a requirement for novel therapeutic targets. Polysulfides are associated with CRC progression and immune evasion, but the underlying mechanisms are not fully understood. Sulfide: quinone oxidoreductase (SQR), a mitochondrial flavoprotein, catalyzes hydrogen sulfide (H₂S) oxidation and polysulfides production. Herein, we explored its role in CRC pathogenesis and its potential as a therapeutic target. Our findings revealed that SQR knockout disrupted polysulfides homeostasis, diminished mitochondrial function, impaired cell proliferation, and triggered early apoptosis in HCT116 CRC cells. Moreover, the SQR knockout led to markedly reduced tumor sizes in mice models of colon xenografts. Although the transcription of glycolytic genes remained largely unchanged, metabolomic analysis demonstrated a reprogramming of glycolysis at the fructose-1,6-bisphosphate degradation step, catalyzed by aldolase A (ALDOA). Both Western blot analysis and enzymatic assays confirmed the decrease in ALDOA levels and activity. In conclusion, the study establishes the critical role of SQR in mitochondrial function and metabolic regulation in CRC, with its knockout leading to metabolic reprogramming and diminished tumor growth in HCT116 tumor xenografts. These insights lay a foundation for the development of SQR-targeted therapies for CRC. Show less

Academic Editor: Dooil Jeoung Received: 5 November 2025 Revised: 24 November 2025 Accepted: 26 November 2025 Published: 28 November 2025 Citation: Lee, J.; Roh, J.-L. Dihydroorotate Dehydrogenase in Mitochondrial Ferroptosis and Cancer Therapy. Cells 2025, 14, 1889. https://doi.org/10.3390/ cells14231889 Show less

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation, which plays a critical role in the pathogenesis of various diseases, including ischemic tissue injury, infectious diseases, neurodegenerative disorders, and cancer. The regulatory mechanisms underlying ferroptosis involve a complex interplay of multiple subcellular organelles, orchestrating iron homeostasis, lipid metabolism, and the generation of reactive oxygen species (ROS) that drive peroxidation processes, ultimately leading to membrane damage and cell death. Numerous antioxidant systems play pivotal roles in regulating and preventing ferroptosis, among which the recently identified mitochondrial inner membrane enzyme dihydroorotate dehydrogenase (DHODH) represents a novel therapeutic target for ferroptosis intervention. This systematic review comprehensively elucidates several key cellular defense mechanisms against ferroptosis that counteract ROS-driven peroxidation and operate through distinct subcellular localizations. We particularly focus on delineating the molecular mechanisms by which DHODH regulates ferroptosis, with special emphasis on its role in suppressing mitochondrial lipid peroxidation. Furthermore, we systematically evaluate the therapeutic potential of DHODH inhibitors in oncology, virology, and immune-inflammatory disorders. By integrating ferroptosis biology with DHODH-mediated cytoprotective networks, this review aims to provide mechanistic insights and novel therapeutic strategies for cancer and oxidative stress-related disorders. Show less

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acidcontaining phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase Show less

Introduction Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990–2023. Methods Bibliometric analysis was performed by extracting data linking mitochondria to cancer pathogenesis over the period 1990–2023 from the PubMed database which has a precise and specific search engine. Only articles and reviews were considered. Since PubMed does not support analyses by countries or institutions, we utilized InCites, an analytical tool developed and marketed by Clarivate Analytics. We also used the VOSviewer software developed by the Centre for Science and Technology Studies (Bibliometric Department of Leiden University, Leiden, Netherlands), which enables us to graphically represent links between countries, authors or keywords in cluster form. Finally, we used iCite, a tool developed by the NIH (USA) to access a dashboard of bibliometrics for papers associated with a portfolio. This module can therefore be used to measure whether the research carried out is still basic, translational or clinical. Results In total, 169,555 publications were identified in PubMed relating to ‘mitochondria’, of which 34,949 (20.61%) concerned ‘mitochondria’ and ‘dysfunction’ and 22,406 (13.21%) regarded ‘mitochondria’ and ‘cancer’. Hence, not all mitochondrial dysfunctions may lead to cancer or enhance its progression. Qualitatively, the disciplines of journals were classified into 166 categories among which cancer specialty accounts for only 4.7% of publications. Quantitatively, our analysis showed that cancer/neoplasms in the liver (2569 articles) were placed in the first position. USA occupied the first position among countries contributing the highest number of publications (5695 articles), whereas Egypt came in the thirty-eight position with 84 publications (0.46%). Importantly, USA is the first-ranked country having both the top 1% and 10% impact indicators with 207 and 1459 articles, respectively. By crossing the query ‘liver neoplasms’ (155,678) with the query ‘mitochondria’ (169,555), we identified 1336 articles in PubMed over the study period. Among these publications, research areas were classified into 65 categories with the highest percentage of documents included in biochemistry and molecular biology (28.92%), followed by oncology (23.31%). Conclusions This study underscores the crucial yet underrepresented role of mitochondria in cancer research. Despite their significance in cancer pathogenesis, the proportion of related publications remains relatively low. Our findings Supplementary Information The online version contains supplementary material available at https://​doi.​org/​10.​1007/​s12672-​025-​ 02139-5. * Abeer El Wakil, abeer_elwakil@alexu.edu.eg; Patrick Devos, patrick.devos@univ-lille.fr; Heba Abdelmegeed, hn.abdelmegeed@ nrc.sci.eg; Alaa Kamel, alaa.kamel_pg@alexu.edu.eg | 1Department of Biological and Geological Sciences, Faculty of Education, Alexandria University, Alexandria 21526, Egypt. 2Université Lille, Lillometrics, 59000 Lille, France. 3CHU Lille, Direction de la Recherche et de l’Innovation, 59000 Lille, France. 4Department of Chemistry of Natural Compounds, National Research Centre, Giza, Egypt. 5Department of Zoology, Faulty of Science, Alexandria University, Alexandria, Egypt. Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 Vol.:(0123456789) Research Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 highlight the need for further research to deepen our understanding of mitochondrial mechanisms in cancer, which could pave the way for new therapeutic strategies. Graphical Abstract Show less

Introduction Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990–2023. Methods Bibliometric analysis was performed by extracting data linking mitochondria to cancer pathogenesis over the period 1990–2023 from the PubMed database which has a precise and specific search engine. Only articles and reviews were considered. Since PubMed does not support analyses by countries or institutions, we utilized InCites, an analytical tool developed and marketed by Clarivate Analytics. We also used the VOSviewer software developed by the Centre for Science and Technology Studies (Bibliometric Department of Leiden University, Leiden, Netherlands), which enables us to graphically represent links between countries, authors or keywords in cluster form. Finally, we used iCite, a tool developed by the NIH (USA) to access a dashboard of bibliometrics for papers associated with a portfolio. This module can therefore be used to measure whether the research carried out is still basic, translational or clinical. Results In total, 169,555 publications were identified in PubMed relating to ‘mitochondria’, of which 34,949 (20.61%) concerned ‘mitochondria’ and ‘dysfunction’ and 22,406 (13.21%) regarded ‘mitochondria’ and ‘cancer’. Hence, not all mitochondrial dysfunctions may lead to cancer or enhance its progression. Qualitatively, the disciplines of journals were classified into 166 categories among which cancer specialty accounts for only 4.7% of publications. Quantitatively, our analysis showed that cancer/neoplasms in the liver (2569 articles) were placed in the first position. USA occupied the first position among countries contributing the highest number of publications (5695 articles), whereas Egypt came in the thirty-eight position with 84 publications (0.46%). Importantly, USA is the first-ranked country having both the top 1% and 10% impact indicators with 207 and 1459 articles, respectively. By crossing the query ‘liver neoplasms’ (155,678) with the query ‘mitochondria’ (169,555), we identified 1336 articles in PubMed over the study period. Among these publications, research areas were classified into 65 categories with the highest percentage of documents included in biochemistry and molecular biology (28.92%), followed by oncology (23.31%). Conclusions This study underscores the crucial yet underrepresented role of mitochondria in cancer research. Despite their significance in cancer pathogenesis, the proportion of related publications remains relatively low. Our findings Supplementary Information The online version contains supplementary material available at https://​doi.​org/​10.​1007/​s12672-​025-​ 02139-5. * Abeer El Wakil, abeer_elwakil@alexu.edu.eg; Patrick Devos, patrick.devos@univ-lille.fr; Heba Abdelmegeed, hn.abdelmegeed@ nrc.sci.eg; Alaa Kamel, alaa.kamel_pg@alexu.edu.eg | 1Department of Biological and Geological Sciences, Faculty of Education, Alexandria University, Alexandria 21526, Egypt. 2Université Lille, Lillometrics, 59000 Lille, France. 3CHU Lille, Direction de la Recherche et de l’Innovation, 59000 Lille, France. 4Department of Chemistry of Natural Compounds, National Research Centre, Giza, Egypt. 5Department of Zoology, Faulty of Science, Alexandria University, Alexandria, Egypt. Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 Vol.:(0123456789) Research Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 highlight the need for further research to deepen our understanding of mitochondrial mechanisms in cancer, which could pave the way for new therapeutic strategies. Graphical Abstract Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis forma‑ tion. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its pres‑ Show less

Ferroptosis, a form of regulated cell death mediated by lipid peroxidation (LPO), has become the subject of intense research due to its potential therapeutic applications in cancer chemotherapy as well as its pathophysiological role in ischemic organ injury. The role of mitochondrial lipid peroxidation (LPO) in ferroptosis remains poorly understood. We show that supplementation of exogenous iron in the form of ferric ammonium citrate (FAC) in combination with buthionine sulfoximine (BSO, an inhibitor of glutathione biosynthesis) induces mitochondrial lipid peroxidation that precedes ferroptosis in normal human fibroblasts. The mitochondrial-targeted antioxidant SkQ1 and the redox mediator methylene blue, which inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, prevent both mitochondrial lipid peroxidation and ferroptosis, but do not affect the cytosolic ROS accumulation. These data indicate that mitochondrial lipid peroxidation is required for ferroptosis induced by exogenous iron. FAC in the absence of BSO stimulates mitochondrial peroxidation without reducing cell viability. Glutathione depletion by BSO does not affect FAC-induced mitochondrial LPO but strongly stimulates the accumulation of ROS in the cytosol. These data allow us to conclude that mitochondrial LPO is not sufficient for ferroptosis and that cytosolic ROS mediates additional oxidative events that stimulate ferroptosis in conjunction with mitochondrial LPO. Show less

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU. Show less

Cancer cells strongly upregulate glucose uptake and glycolysis to produce vital biomolecules for cancer cell survival, proliferation, and metastasis as ATP, lipids, proteins, nucleotides, and lactate. The Warburg effect is tumours' unique glucose oxidation to give lactate (not pyruvate) even in the presence of oxygen. Nicotinamide adenine dinucleotide (NAD/NADH.H) is used in glycolysis via glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH). Both catalyse reversible biochemical reactions to produce 1,3-diphosphoglycerate and lactate, respectively. In this expert opinion and based on published evidence, the author suggests that: "In transformed cells and hyperglycolytic cancer cells, the Warburg effect (permanent conversion of pyruvate to lactate) occurs secondary to a vicious cycle and a closed circuit between GAPDH and LDH (reaction of carcinogenesis) causing increased endogenous oxidative stress and subsequent carcinogenesis. Mitochondrial defects in cancer cells cause hyperglycolysis resulting in NADH.H accumulation (produced during GAPDH step) that obligatorily drives LDH to become an irreversible reaction in the direction of lactate formation (Warburg effect) but not pyruvate formation. Likewise, LDH oxidizes NADH.H producing excessive NAD⁺ that secondarily drives GAPDH reaction to be irreversible to produce NADH.H and so on. Pyruvate is an antioxidant while lactate is pro-oxidant, causing increased endogenous oxidative stress in cancer cells, tumour's hypoxia and obligatory hyperglycolysis with NADH.H overproduction (GAPDH step) to be consumed in the LDH step for lactate production and NAD⁺ generation (utilized by GAPDH) and so on". This confirms Warburg's origin of cancer cells. Best anticancer applications based on this hypothesis are: breaking this closed vicious circle using siRNA to target GAPDH and LDH, avoiding strong oxidants (as many cancer chemotherapeutics), and using strong antioxidants for causing antioxidant-oxidant antagonism or antioxidant-lactate antagonism to inhibit the Warburg effect. Strong natural antioxidants of prophetic medicine (related to Prophet Muhammad peace be upon him) such as Zamzam water, Nigella sativa, costus, Ajwa date fruit, olive oil, Al-hijamah and natural honey are strongly recommended to prevent and antagonize the Warburg effect. Show less

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease. Show less

Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell death is essentially important and vital for maintaining homeostasis, thus any type of disturbing occurrence might lead to different sorts of diseases and dysfunctions. Cell death has various modalities and yet, every now and then, a new type of this elegant procedure gets to be discovered. The diversity of cell death compels the need for a universal organizing system in order to facilitate further studies, therapeutic strategies and the invention of new methods of research. Considering all that, we attempted to review most of the known cell death mechanisms and sort them all into one arranging system that operates under a simple but subtle decision-making (If \ Else) order as a sorting algorithm, in which it decides to place and sort an input data (a type of cell death) into its proper set, then a subset and finally a group of cell death. By proposing this algorithm, the authors hope it may solve the problems regarding newer and/or undiscovered types of cell death and facilitate research and therapeutic applications of cell death. Show less

Deregulation of tumor cell metabolism is widely recognized as a “hallmark of cancer.” Many of the selective pressures encountered by tumor cells, such as exposure to anticancer therapies, navigation of the metastatic cascade, and communication with the tumor microenvironment, can elicit further rewiring of tumor cell metabolism. Furthermore, phenotypic plasticity has been recently appreciated as an emerging “hallmark of cancer.” Mitochondria are dynamic organelles and central hubs of metabolism whose roles in cancers have been a major focus of numerous studies. Importantly, therapeutic approaches targeting mitochondria are being developed. Interestingly, both plastic (i.e., reversible) and permanent (i.e., stable) metabolic adaptations have been observed following exposure to anticancer therapeutics. Understanding the plastic or permanent nature of these mechanisms is of crucial importance for devising the initiation, duration, and sequential nature of metabolism-targeting therapies. In this review, we compare permanent and plastic mitochondrial mechanisms driving therapy resistance. We also discuss experimental models of therapy-induced metabolic adaptation, therapeutic implications for targeting permanent and plastic metabolic states, and clinical implications of metabolic adaptations. While the plasticity of metabolic adaptations can make effective therapeutic treatment challenging, understanding the mechanisms behind these plastic phenotypes may lead to promising clinical interventions that will ultimately lead to better overall care for cancer patients. Show less

Background

Targeting AKT suppresses tumor growth through inducing apoptosis, however, during which whether other forms of cell death occurring is poorly understood.

Methods

The effects of increasing PARP1 dependent cell death (parthanatos) induced by inhibiting AKT on cell proliferation were determined by CCK-8 assay, colony formation assay, Hoechst 33,258 staining and analysis of apoptotic cells by flow cytometry. For the detailed mechanisms during this process, Western blot analysis, qRT-PCR analysis, immunofluorescence and co-immunoprecipitation were performed. Moreover, the inhibition of tumor growth by inducing p53/SIRT6/PARP1-dependent parthanatos was further verified in the xenograft mouse model.

Results

For the first time, we identified that inhibiting AKT triggered parthanatos, a new form of regulated cell death, leading to colon cancer growth suppression. For the mechanism investigation, we found that after pharmacological or genetic AKT inhibition, p53 interacted with SIRT6 and PARP1 directly to activate it, and promoted the formation of PAR polymer. Subsequently, PAR polymer transported to outer membrane of mitochondria and resulted in AIF releasing and translocating to nucleus thus promoting cell death. While, blocking PARP1 activity significantly rescued colon cancer from death. Furthermore, p53 deletion or mutation eliminated PAR polymer formation, AIF translocation, and PARP1 dependent cell death, which was promoted by overexpression of SIRT6. Meanwhile, reactive oxygen species production was elevated after inhibition of AKT, which might also play a role in the occurrence of parthanatos. In addition, inhibiting AKT initiated protective autophagy simultaneously, which advanced tumor survival and growth.

Conclusion

Our findings demonstrated that AKT inhibition induced p53-SIRT6-PARP1 complex formation and the activation of parthanatos, which can be recognized as a novel potential therapeutic strategy for cancer. Video Abstract. Show less

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health (NIH) Introduction The prevalence of obesity continues to rise to unprecedented levels, and with it, a corresponding increase in the incidence of cardiovascular disease (CVD). While obesity is indeed accepted as one of the most prominent risk factors for CVD, the precise molecular mechanisms by which aberrant metabolism is linked to cardiovascular function remain incompletely understood. One prevailing hypothesis is that overproduction of reactive oxygen species (ROS) from increased metabolism significantly contributes to endothelial dysfunction, which precedes many cardiovascular events such as atherosclerosis and stroke. Purpose In this study, we hypothesized that a receptor for advanced glycation end products, Galectin-3 (GAL3), acts as a metabolic sensor and regulates endothelial ROS production in obesity. Methods Obese db/db mice were crossed with mice lacking GAL3, and endothelial gene expression, microvascular reactivity, and ROS production were assessed. Results We demonstrate that NADPH Oxidase I (NOX1), the predominant source of endothelial superoxide production, is down-regulated by GAL3 deletion, thereby rescuing endothelial function and ameliorating endothelial ROS production in obesity. Furthermore, we demonstrate that GAL3-mediated NOX1 over-expression is amenable to improvements in metabolic status, such as lowering blood glucose with metformin, improving glucose handling by augmenting muscle mass, or improving insulin signaling through deletion of Protein Tyrosine Phosphatase 1B (PTP1B). Conclusion Taken together, these data demonstrate that the overproduction of superoxide by endothelial NOX1 is regulated by the metabolic sensor GAL3 in obesity, leading to endothelial dysfunction and CVD. This pathway presents an attractive target for therapeutic intervention to break the link between aberrant metabolism in obesity and its corresponding vascular pathologies. Show less

Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to numerous diseases including neurodegenerative disorders, diabetes, thyroid squamous disease, cancer and septicemia. Thus, the design of specific mitochondria-targeting molecules and the realization of real-time acquisition of mitochondrial activity are powerful tools in the study and treatment of mitochondria dysfunction in related diseases. Recent advances in mitochondria-targeting agents have led to several important mitochondria chemical probes that offer the opportunity for selective targeting molecules, novel biological applications and therapeutic strategies. This review details the structural and physiological functional characteristics of mitochondria, and comprehensively summarizes and classifies mitochondria-targeting agents. In addition, their pros and cons and their related chemical biological applications are discussed. Finally, the potential biomedical applications of these agents are briefly prospected. Show less

Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm Show less

Few data are available on the clinical impact of drug-drug interactions (DDIs). Most of the studies are limited to the analysis of exposure to potential DDI or the targeted impact of the combination of a few drugs or therapeutic classes. The analysis of adverse drug reaction (ADR) reports could be a mean to study generally the adverse effects identified due to a DDI. Our objective was to describe the characteristics of ADRs resulting from DDIs reported to the French Pharmacovigilance system and to identify the drugs most often implicated in these ADRs. Considering all ADR reports from January 01, 2012, to December 31, 2016, we identified all cases of ADR resulting from a DDI (DDI-ADRs). We then described these in terms of patients' characteristics, ADR seriousness, drugs involved (two or more per case), and ADR type. Of the 4,027 reports relating to DDI-ADRs, 3,303 were related to serious ADRs. Patients with serious DDI-ADRs had a median age of 76 years (interquartile range: 63-84); 53% were male. Of all serious DDI-ADRs, 11% were life-threatening and 8% fatal. In 36% of cases, the DDI causing the ADR involved at least three drugs. Overall, 8,424 different drugs were mentioned in the 3,303 serious DDI-ADRs considered. Altogether, drugs from the "antithrombotic agents" subgroup were incriminated in 34% of serious DDI-ADRs. Antidepressants were the second most represented therapeutic/pharmacological subgroup (5% of serious DDI-ADRs). Among the 3,843 ADR types reported in the 3,303 serious DDI-ADRs considered, the most frequently represented were hemorrhage (40% clinical hemorrhage; 6% biological hemorrhage), renal failure (8%), pharmacokinetic alteration (5%), and cardiac arrhythmias (4%). Hemorrhagic accidents are still an important part of serious ADRs resulting from DDIs reported in France. The other clinical consequences of DDIs seem less well identified by pharmacovigilance. Moreover, more than one-third of serious DDI-ADRs involved at least three drugs. Show less

The specific autophagic elimination of mitochondria (mitophagy) plays the role of quality control for this organelle. Deregulation of mitophagy leads to an increased number of damaged mitochondria and triggers cell death. The deterioration of mitophagy has been hypothesized to underlie the pathogenesis of several neurodegenerative diseases, most notably Parkinson disease. Although some of the biochemical and molecular mechanisms of mitochondrial quality control are described in detail, physiological or pathological triggers of mitophagy are still not fully characterized. Here we show that the induction of mitophagy by the mitochondrial uncoupler FCCP is independent of the effect of mitochondrial membrane potential but dependent on acidification of the cytosol by FCCP. The ionophore nigericin also reduces cytosolic pH and induces PINK1/PARKIN-dependent and -independent mitophagy. The increase of intracellular pH with monensin suppresses the effects of FCCP and nigericin on mitochondrial degradation. Thus, a change in intracellular pH is a regulator of mitochondrial quality control. Show less

Key words: Mitochondrial uncoupling protein 2; Colon cancer; Uncoupling protein 2; Clinicopathologic characteristics AIM: To detect the expression of mitochondrial uncoupling protein 2 (UCP2) in colon cancer and analyze the relation between UCP2 expression and clinical pathological features of colon cancer. Peer reviewer: Guangcun Huang, MD, PhD, Research Institute at Nationwide Children’s Hospital, Center for Clinical and Translational Research, Columbus, OH 43205, United States METHODS: Fifteen colon tissue samples and 15 its adjacent tissue samples were obtained from colon cancer Show less