Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival

Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.

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The anti-oxidant and pro-oxidant dichotomy of Bcl-2

Biological Chemistry ◽

10.1515/hsz-2016-0127 ◽

2016 ◽

Vol 397 (7) ◽

pp. 585-593 ◽

Cited By ~ 5

Author(s):

Yi Hui Yee ◽

Stephen Jun Fei Chong ◽

Shazib Pervaiz

Keyword(s):

Cell Fate ◽

Wide Spectrum ◽

Survival Function ◽

Short Review ◽

Redox Status ◽

Aberrant Expression ◽

Cellular Redox ◽

Cell Fate Decisions ◽

Anti Oxidant ◽

Novel Therapeutic Strategies

Abstract Across a wide spectrum of cellular redox status, there emerges a dichotomy of responses in terms of cell survival/proliferation and cell death. Of note, there is emerging evidence that the anti-apoptotic protein, Bcl-2, in addition to its conventional activity of titrating the pro-apoptotic effects of proteins such as Bax and Bak at the mitochondria, also impacts cell fate decisions via modulating cellular redox metabolism. In this regard, both pro- and anti-oxidant effects of Bcl-2 overexpression have been described under different conditions and cellular contexts. In this short review, we attempt to analyze existing observations and present a probable explanation for the seemingly conflicting redox regulating activity of Bcl-2 from the standpoint of its pro-survival function. The consequential effect(s) of the dual redox functions of Bcl-2 are also discussed, particularly from the viewpoint of developing novel therapeutic strategies against cancers rendered refractory due to the aberrant expression of Bcl-2.

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Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors

Biochemical Society Transactions ◽

10.1042/bst0310292 ◽

2003 ◽

Vol 31 (1) ◽

pp. 292-297 ◽

Cited By ~ 176

Author(s):

K.U. Birkenkamp ◽

P.J. Coffer

Keyword(s):

Transcription Factors ◽

Cell Survival ◽

Cell Fate ◽

Nuclear Export ◽

Molecular Mechanisms ◽

Target Genes ◽

Acute Lymphocytic Leukaemia ◽

Cell Fate Decisions ◽

Forkhead Transcription Factors ◽

Forkhead Box

Recently, the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors has been identified as direct targets of phosphoinositide 3-kinase-mediated signal transduction. The AFX (acute-lymphocytic-leukaemia-1 fused gene from chromosome X), FKHR (Forkhead in rhabdomyosarcoma) and FKHR-L1 (FKHR-like 1) transcription factors are directly phosphorylated by protein kinase B, resulting in nuclear export and inhibition of transcription. This signalling pathway was first identified in the nematode worm Caenorhabditis elegans, where it has a role in regulation of the life span of the organism. Studies have shown that this evolutionarily conserved signalling module has a role in regulation of both cell-cycle progression and cell survival in higher eukaryotes. These effects are co-ordinated by FOXO-mediated induction of a variety of specific target genes that are only now beginning to be identified. Interestingly, FOXO transcription factors appear to be able to regulate transcription through both DNA-binding-dependent and -independent mechanisms. Our understanding of the regulation of FOXO activity, and defining specific transcriptional targets, may provide clues to the molecular mechanisms controlling cell fate decisions to divide, differentiate or die.

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Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways

Biomolecules ◽

10.3390/biom11101444 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1444

Author(s):

Robert H. Whitaker ◽

Jeanette Gowen Cook

Keyword(s):

Cell Cycle ◽

Cell Survival ◽

Signaling Pathways ◽

Protein Kinases ◽

Cell Fate ◽

P38 Mapk ◽

Cell Function ◽

Cellular Division ◽

Cell Fate Decisions ◽

Bcl2 Family

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.

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Redesign of Genetically Encoded Biosensors for Monitoring Mitochondrial Redox Status in a Broad Range of Model Eukaryotes

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057113499634 ◽

2013 ◽

Vol 19 (3) ◽

pp. 379-386 ◽

Cited By ~ 36

Author(s):

Simone C. Albrecht ◽

Mirko C. Sobotta ◽

Daniela Bausewein ◽

Isabel Aller ◽

Rüdiger Hell ◽

...

Keyword(s):

Cell Fate ◽

Fluorescent Proteins ◽

Redox Homeostasis ◽

Redox Status ◽

Model Organisms ◽

Green Fluorescent Proteins ◽

Cell Fate Decisions ◽

Major Interest ◽

Green Fluorescent

The development of genetically encoded redox biosensors has paved the way toward chemically specific, quantitative, dynamic, and compartment-specific redox measurements in cells and organisms. In particular, redox-sensitive green fluorescent proteins (roGFPs) have attracted major interest as tools to monitor biological redox changes in real time and in vivo. Most recently, the engineering of a redox relay that combines glutaredoxin (Grx) with roGFP2 as a translational fusion (Grx1-roGFP2) led to a biosensor for the glutathione redox potential ( EGSH). The expression of this probe in mitochondria is of particular interest as mitochondria are the major source of oxidants, and their redox status is closely connected to cell fate decisions. While Grx1-roGFP2 can be expressed in mammalian mitochondria, it fails to enter mitochondria in various nonmammalian model organisms. Here we report that inversion of domain order from Grx1-roGFP2 to roGFP2-Grx1 yields a biosensor with perfect mitochondrial targeting while fully maintaining its biosensor capabilities. The redesigned probe thus allows extending in vivo observations of mitochondrial redox homeostasis to important nonmammalian model organisms, particularly plants and insects.

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Promotion of cancer cell stemness by Ras

Biochemical Society Transactions ◽

10.1042/bst20200964 ◽

2021 ◽

Author(s):

Rohan Chippalkatti ◽

Daniel Abankwa

Keyword(s):

Cell Fate ◽

Cancer Cell ◽

Mapk Pathway ◽

Cancer Genes ◽

Cell Fate Decisions ◽

Oncogenic Ras ◽

Ras Activation ◽

Cancer Cell Population ◽

Cellular Machinery ◽

Cycle Dependent

Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

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Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Science ◽

10.1126/science.aaz2740 ◽

2021 ◽

Vol 372 (6543) ◽

pp. 716-721

Author(s):

Marlies P. Rossmann ◽

Karen Hoi ◽

Victoria Chan ◽

Brian J. Abraham ◽

Song Yang ◽

...

Keyword(s):

Cell Fate ◽

Transcriptional Control ◽

Cell Function ◽

Coenzyme Q ◽

Elongation Factor ◽

Erythroid Differentiation ◽

Mitochondrial Metabolism ◽

Dihydroorotate Dehydrogenase ◽

Functional Link ◽

Cell Fate Decisions

Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon’s bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.

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Abstract 5518: BPM 31510 exposure alters fluidity and molecular organization of cancer cell membranes, influencing signaling and cell fate decisions

10.1158/1538-7445.am2014-5518 ◽

2014 ◽

Author(s):

Michael Kiebish ◽

Sumit Garg ◽

Vivek Vishnudas ◽

Fei Gao ◽

Min Du ◽

...

Keyword(s):

Cell Fate ◽

Cancer Cell ◽

Cell Membranes ◽

Molecular Organization ◽

Cell Fate Decisions

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Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.702974 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sindhushree Raghunandan ◽

Srinivasan Ramachandran ◽

Eugene Ke ◽

Yifei Miao ◽

Ratnesh Lal ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Stress Response ◽

Cell Surface ◽

Cell Survival ◽

Cell Fate ◽

Heme Oxygenase ◽

Molecular Mechanisms ◽

Heme Oxygenase 1 ◽

Cell Fate Decisions

Endothelial cells (ECs) form the inner lining of blood vessels and are central to sensing chemical perturbations that can lead to oxidative stress. The degree of stress is correlated with divergent phenotypes such as quiescence, cell death, or senescence. Each possible cell fate is relevant for a different aspect of endothelial function, and hence, the regulation of cell fate decisions is critically important in maintaining vascular health. This study examined the oxidative stress response (OSR) in human ECs at the boundary of cell survival and death through longitudinal measurements, including cellular, gene expression, and perturbation measurements. 0.5 mM hydrogen peroxide (HP) produced significant oxidative stress, placed the cell at this junction, and provided a model to study the effectors of cell fate. The use of systematic perturbations and high-throughput measurements provide insights into multiple regimes of the stress response. Using a systems approach, we decipher molecular mechanisms across these regimes. Significantly, our study shows that heme oxygenase-1 (HMOX1) acts as a gatekeeper of cell fate decisions. Specifically, HP treatment of HMOX1 knockdown cells reversed the gene expression of about 51% of 2,892 differentially expressed genes when treated with HP alone, affecting a variety of cellular processes, including anti-oxidant response, inflammation, DNA injury and repair, cell cycle and growth, mitochondrial stress, metabolic stress, and autophagy. Further analysis revealed that these switched genes were highly enriched in three spatial locations viz., cell surface, mitochondria, and nucleus. In particular, it revealed the novel roles of HMOX1 on cell surface receptors EGFR and IGFR, mitochondrial ETCs (MTND3, MTATP6), and epigenetic regulation through chromatin modifiers (KDM6A, RBBP5, and PPM1D) and long non-coding RNA (lncRNAs) in orchestrating the cell fate at the boundary of cell survival and death. These novel aspects suggest that HMOX1 can influence transcriptional and epigenetic modulations to orchestrate OSR affecting cell fate decisions.

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Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids

International Journal of Molecular Sciences ◽

10.3390/ijms22052466 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2466

Author(s):

Kenza Mamouni ◽

Georgios Kallifatidis ◽

Bal L. Lokeshwar

Keyword(s):

Prostate Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Mitochondrial Metabolism ◽

Metabolic Reprogramming ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Cancer Cell Survival ◽

The Impact

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.

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