Mitochondrial Function and Dysfunction in Cancer and Their Potential as Anti-cancer Targets (Volume II)

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (10 July 2023) | Viewed by 5788

Special Issue Editors


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Guest Editor
1. Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
2. The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
Interests: mitochondria; cancer; metabolism-dysfunction-associated diseases; cell death; inflammation
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
1. Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
2. The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
Interests: mitochondria; cancer; protein–protein interaction; apoptosis

Special Issue Information

Dear Colleagues,

This collection is the second edition of the previous one, "Mitochondrial function and dysfunction in cancer and their potential as anti-cancer targets" (https://www.mdpi.com/journal/cancers/special_issues/mfdctpaat).

The mitochondrion, a discrete sub-cellular organelle comprising some 1000 different proteins, mediates basic life functions and contains key components of biosynthetic pathways. It also serves as the site where cellular decisions leading to apoptosis (programmed cell death) are taken. Mitochondria perform a variety of crucial cell functions, including energy production; Ca2+ signaling and the maintenance of Ca2+ homeostasis; the metabolism of amino acids, lipids, and iron; modulation of the cell’s redox potential; osmotic regulation and pH control; in addition to being the site of reactive oxygen species (ROS) generation and an essential component of the apoptotic machinery. Changes in these parameters can impact biosynthetic pathways, cellular signal transduction pathways, and epigenetics, shifting the cell from the quiescent, differentiated state to one of active proliferation, as occurs in cancer. Indeed, the signaling pathways that govern mitochondrial function, mitochondrial integrity, cell viability and apoptosis have been addressed in many studies, with mitochondrial targeting strategies having recently gained momentum.

The association of mitochondria with cancer was first presented over 70 years ago by Otto Heinrich Warburg and his colleagues, who hypothesized that dysfunctional mitochondria may be the cause of higher rates of aerobic glycolysis (termed the “Warburg effect”), with this gradual and cumulative decrease in mitochondrial activity being associated with malignant transformation. However, many studies conducted since have demonstrated that functional mitochondria are essential for the cancer cell and have identified pleiotropic roles of mitochondria in tumorigenesis.

Given their multifunctionality it is not surprising that mitochondria are important mediators of tumorigenesis—a process requiring flexibility in adapting to cellular and environmental alterations. Thus, uncovering the mechanisms responsible for altered mitochondrial function during tumorigenesis is critical for developing the next generation of cancer therapeutics. Indeed, appreciation that mitochondria play central roles in cellular energy generation, metabolism, apoptosis and necrosis carry far-reaching implications and provide solid rationale and a strong biological basis for developing mitochondria-targeted anti-cancer agents.

Scientists studying mitochondria- and cancer-associated topics, including but not limited to oxidative stress, organelle biogenesis, apoptosis, necrosis, import and folding of mitochondrial proteins, membrane synthesis, structure and dynamics, Ca2+ homeostasis, the mitochondrial genetic system, mitochondria-interacting proteins (e.g., hexokinase, anti- and pro-apoptotic proteins, p53), as well as ER–mitochondria interactions and cancer, are invited to contribute to this Special Issue.

Prof. Dr. Varda Shoshan-Barmatz
Dr. Manikandan Santhanam
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

  • apoptosis
  • mitochondria
  • metabolism
  • cancer
  • tumor microenvironment
  • apoptogenic proteins
  • oxidative stress
  • mitochondrial DNA
  • Ca2+ signaling

Published Papers (2 papers)

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Research

25 pages, 13138 KiB  
Article
Pro-Apoptotic and Anti-Cancer Activity of the Vernonanthura Nudiflora Hydroethanolic Extract
by Almog Nadir, Anna Shteinfer-Kuzmine, Swaroop Kumar Pandey, Juan Ortas, Daniel Kerekes and Varda Shoshan-Barmatz
Cancers 2023, 15(5), 1627; https://doi.org/10.3390/cancers15051627 - 6 Mar 2023
Cited by 1 | Viewed by 2464
Abstract
The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, Vernonanthura nudiflora (Vern), Baccharis [...] Read more.
The mitochondrial voltage-dependent anion channel 1 (VDAC1) protein is involved in several essential cancer hallmarks, including energy and metabolism reprogramming and apoptotic cell death evasion. In this study, we demonstrated the ability of hydroethanolic extracts from three different plants, Vernonanthura nudiflora (Vern), Baccharis trimera (Bac), and Plantago major (Pla), to induce cell death. We focused on the most active Vern extract. We demonstrated that it activates multiple pathways that lead to impaired cell energy and metabolism homeostasis, elevated ROS production, increased intracellular Ca2+, and mitochondria-mediated apoptosis. The massive cell death generated by this plant extract’s active compounds involves the induction of VDAC1 overexpression and oligomerization and, thereby, apoptosis. Gas chromatography of the hydroethanolic plant extract identified dozens of compounds, including phytol and ethyl linoleate, with the former producing similar effects as the Vern hydroethanolic extract but at 10-fold higher concentrations than those found in the extract. In a xenograft glioblastoma mouse model, both the Vern extract and phytol strongly inhibited tumor growth and cell proliferation and induced massive tumor cell death, including of cancer stem cells, inhibiting angiogenesis and modulating the tumor microenvironment. Taken together, the multiple effects of Vern extract make it a promising potential cancer therapeutic. Full article
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13 pages, 2923 KiB  
Article
Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia
by Rebecca Anderson, Kristin M. Pladna, Nathaniel J. Schramm, Frances B. Wheeler, Steven Kridel and Timothy S. Pardee
Cancers 2023, 15(2), 484; https://doi.org/10.3390/cancers15020484 - 12 Jan 2023
Cited by 7 | Viewed by 2958
Abstract
Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting [...] Read more.
Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML. Full article
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