bims-mibica 2023-01-22 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2023–01–22
twenty papers selected by
Kelsey Fisher-Wellman, East Carolina University

Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.
Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.
Time to hit pause on mitochondria-targeting cancer therapies.
Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.
Lineage-Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells.
SERS uncovers the link between conformation of cytochrome c heme and mitochondrial membrane potential.
SDHB reduction promotes oral lichen planus by impairing mitochondrial respiratory function.
Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.
Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.
Acetyl-CoA metabolism in cancer.
Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance.
Neuroblastoma Differentiation: The Untapped Potential of Mitochondrial Uncouplers.
Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review.
Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.
Impact of aging on mitochondrial respiration in various organs.
Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.
A novel Mcl-1 inhibitor synergizes with venetoclax to induce apoptosis in cancer cells.
Thioalbamide inhibits FoF1-ATPase in breast cancer cells and reduces tumor proliferation and invasiveness in breast cancer in vivo models.
Fasting and fasting mimicking diets in cancer prevention and therapy.

Cancers (Basel). 2023 Jan 12. pii: 484. [Epub ahead of print]15(2):

Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.

Rebecca Anderson, Kristin M Pladna, Nathaniel J Schramm, Frances B Wheeler, Steven Kridel, Timothy S Pardee.

  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.

Keywords:  leukemia; metabolism; mitochondria; therapy

DOI:  https://doi.org/10.3390/cancers15020484
Nat Med. 2023 Jan 19.

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Timothy A Yap, Naval Daver, Mikhila Mahendra, Jixiang Zhang, Carlos Kamiya-Matsuoka, Funda Meric-Bernstam, Hagop M Kantarjian, Farhad Ravandi, Meghan E Collins, Maria Emilia Di Francesco, Ecaterina E Dumbrava, Siqing Fu, Sisi Gao, Jason P Gay, Sonal Gera, Jing Han, David S Hong, Elias J Jabbour, Zhenlin Ju, Daniel D Karp, Alessia Lodi, Jennifer R Molina, Natalia Baran, Aung Naing, Maro Ohanian, Shubham Pant, Naveen Pemmaraju, Prithviraj Bose, Sarina A Piha-Paul, Jordi Rodon, Carolina Salguero, Koji Sasaki, Anand K Singh, Vivek Subbiah, Apostolia M Tsimberidou, Quanyun A Xu, Musa Yilmaz, Qi Zhang, Yuan Li, Christopher A Bristow, Meenakshi B Bhattacharjee, Stefano Tiziani, Timothy P Heffernan, Christopher P Vellano, Philip Jones, Cobi J Heijnen, Annemieke Kavelaars, Joseph R Marszalek, Marina Konopleva.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

DOI: https://doi.org/10.1038/s41591-022-02103-8
Nat Med. 2023 Jan 19.

Time to hit pause on mitochondria-targeting cancer therapies.

Xue Zhang, Chi V Dang.

DOI: https://doi.org/10.1038/s41591-022-02129-y
Nat Cell Biol. 2023 Jan 19.

Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.

Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.

Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.

DOI: https://doi.org/10.1038/s41556-022-01071-y
J Biol Chem. 2023 Jan 12. pii: S0021-9258(23)00036-4. [Epub ahead of print] 102904

Goldilocks calcium concentrations and the regulation of oxidative phosphorylation: too much, too little, or just right.

Eloisa A Vilas-Boas, João Victor Cabral-Costa, Vitor M Ramos, Camille C Caldeira da Silva, Alicia J Kowaltowski.

  Calcium (Ca2+) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture, and cell death. Moderate Ca2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) Ca2+ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact cells, both low and high cytosolic Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation.

Keywords:  calcium transport; electron transfer chain; metabolic flux; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2023.102904
Adv Biol (Weinh). 2023 Jan 18. e2200246

Lineage-Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells.

Fausto Capelluto, Hannah Alberico, Paula Ledo-Hopgood, Jonathan L Tilly, Dori C Woods.

  In addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type-specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage-mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria-depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria-even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria.

Keywords:  Parkin; mitochondria; mitochondrial depletion; mitochondrial transplantation; proteomics

DOI:  https://doi.org/10.1002/adbi.202200246
Free Radic Biol Med. 2023 Jan 14. pii: S0891-5849(23)00021-7. [Epub ahead of print]

SERS uncovers the link between conformation of cytochrome c heme and mitochondrial membrane potential.

Nadezda A Brazhe, Evelina I Nikelshparg, Adil A Baizhumanov, Vera G Grivennikova, Anna A Semenova, Sergey M Novikov, Valentyn S Volkov, Aleksey V Arsenin, Dmitry I Yakubovsky, Andrey B Evlyukhin, Zhanna V Bochkova, Eugene A Goodilin, Georgy V Maksimov, Olga Sosnovtseva, Andrey B Rubin.

  The balance between the mitochondrial respiratory chain activity and the cell's needs in ATP ensures optimal cellular function. Cytochrome c is an essential component of the electron transport chain (ETC), which regulates ETC activity, oxygen consumption, ATP synthesis and can initiate apoptosis. The impact of conformational changes in cytochrome c on its function is not understood for lack of access to these changes in intact mitochondria. We have developed a novel sensor that uses unique properties of label-free surface-enhanced Raman spectroscopy (SERS) to identify conformational changes in heme of cytochrome c and to elucidate their role in functioning mitochondria. We verify that molecule bond vibrations assessed by SERS is a reliable indicator of the heme conformation during changes in the inner mitochondrial membrane potential and ETC activity. We have demonstrated that cytochrome c heme reversibly switches between planar and ruffled conformations in response to the inner mitochondrial membrane potential (ΔΨ) and H+ concentration in the intermembrane space to regulate the efficiency of the mitochondrial respiratory chain, thus, adjusting the mitochondrial respiration to the cell's consumption of ATP and the overall activity. We have found that under hypertensive conditions cytochrome c heme lose its sensitivity to ΔΨ that can affect the regulation of ETC activity. The ability of the proposed SERS-based sensor to track mitochondrial function opens wide perspectives on cell bioenergetics.

Keywords:  Cytochrome c; Electron transport chain; Heme; Mitochondria; Surface-enhanced Raman spectroscopy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.01.013
Ann Transl Med. 2022 Dec;10(24): 1367

SDHB reduction promotes oral lichen planus by impairing mitochondrial respiratory function.

Hui Zhang, Beiyun Xu, Jin Liu, Bin Guo, Hongying Sun, Qiaozhen Yang.

   Background: Oral lichen planus (OLP) is a type of chronic inflammatory disorder, which represents a potential risk of malignant transformation. Understanding the mechanism of OLP-related malignant transformation could reduce the risk of cancer. Accumulating evidence indicates that the expression of succinate dehydrogenase enzyme B (SDHB) is associated with the carcinogenesis of oral squamous cell carcinoma (OSCC). However, the function and underlying mechanism of SDHB in OLP remains unknown.
Methods: In this study, we examined the expression of SDHB in tissues from OLP patients and normal oral mucosa (NOM) through immunohistochemical (IHC) staining, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blot (WB). Adenosine triphosphate (ATP) assay, reactive oxygen species (ROS) assay, mitochondrial membrane potential (MMP) assay, and glucose uptake assay were used to explore the function of SDHB in mitochondrial injury and bioenergetic changes in OLP cell model and SDHB-overexpressing cells.
Results: In current study, we found that the messenger RNA (mRNA) and protein expression of SDHB was significantly decreased in OLP patients, accompanied by the accumulation of succinate. In the lipopolysaccharide (LPS) or CoCl2-stimulated OLP cell model, the expression of SDHB was decreased along with treatment time and concentration. Mechanistically, decreased SDHB enhanced hypoxia-inducible factor (HIF)-1α activity, induced mitochondrial injury, bioenergetic changes, and cytokine release. Overexpression of SDHB could reverse the above biological process and switch bioenergetic metabolism during OLP process.
Conclusions: Our study suggests that SDHB reduction promotes OLP by impairing mitochondrial respiratory function.

Keywords:  Succinate dehydrogenase enzyme B (SDHB); glycolytic metabolism; hypoxia-inducible factor-1α (HIF-1α); mitochondrial respiratory function; oral lichen planus (OLP)

DOI:  https://doi.org/10.21037/atm-22-5999
Cell Death Dis. 2023 Jan 19. 14(1): 42

Dual inhibition of thioredoxin reductase and proteasome is required for auranofin-induced paraptosis in breast cancer cells.

Min Ji Seo, In Young Kim, Dong Min Lee, Yeon Jung Park, Mi-Young Cho, Hyo Joon Jin, Kyeong Sook Choi.

Auranofin (AF), a gold (I)-containing phosphine compound, is being investigated for oncological application as a repurposed drug. We show here that 4~5 µM AF induces paraptosis, a non-apoptotic cell death mode characterized by dilation of the endoplasmic reticulum (ER) and mitochondria, in breast cancer cells. Although the covalent inhibition of thioredoxin reductase (TrxR), an enzyme that critically controls intracellular redox homeostasis, is considered the primary mechanism of AF's anticancer activity, knockdown of TrxR1 did not induce paraptosis. Instead, both TrxR1 knockdown plus the proteasome inhibitor (PI), bortezomib (Bz), and 2 μM AF plus Bz induced paraptosis, thereby mimicking the effect of 5 μM AF. These results suggest that the paraptosis induced by 5 μM AF requires the inhibition of both TrxR1 and proteasome. We found that TrxR1 knockdown/Bz or subtoxic doses of AF and Bz induced paraptosis selectively in breast cancer cells, sparing non-transformed MCF10A cells, whereas 4~5 μM AF killed both cancer and MCF10A cells. GSH depletion was found to be more critical than ROS generation for the paraptosis induced by dual TrxR1/proteasome inhibition. In this process, the ATF4/CHAC1 (glutathione-specific gamma-glutamylcyclotransferase 1) axis leads to GSH degradation, contributing to proteotoxic stress possibly due to the accumulation of misfolded thiol-containing proteins. These results suggest that the paraptosis-inducing strategy of AF plus a PI may provide an effective therapeutic strategy against pro-apoptotic therapy-resistant cancers and reduce the potential side effects associated with high-dose AF.

DOI: https://doi.org/10.1038/s41419-023-05586-6
Nat Genet. 2023 Jan 19.

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

Emilie Abby, Stefan C Dentro, Michael W J Hall, Joanna C Fowler, Swee Hoe Ong, Roshan Sood, Albert Herms, Gabriel Piedrafita, Irina Abnizova, Christian W Siebel, Moritz Gerstung, Benjamin A Hall, Philip H Jones.

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.

DOI: https://doi.org/10.1038/s41588-022-01280-z
Nat Rev Cancer. 2023 Jan 19.

Acetyl-CoA metabolism in cancer.

David A Guertin, Kathryn E Wellen.

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

DOI: https://doi.org/10.1038/s41568-022-00543-5
Cancers (Basel). 2023 Jan 10. pii: 445. [Epub ahead of print]15(2):

Dexamethasone-Induced Fatty Acid Oxidation and Autophagy/Mitophagy Are Essential for T-ALL Glucocorticoid Resistance.

Miguel Olivas-Aguirre, Jesús Pérez-Chávez, Liliana Torres-López, Arturo Hernández-Cruz, Igor Pottosin, Oxana Dobrovinskaya.

  ALL is a highly aggressive subtype of leukemia that affects children and adults. Glucocorticoids (GCs) are a critical component of the chemotherapeutic strategy against T-ALL. Cases of resistance to GC therapy and recurrent disease require novel strategies to overcome them. The present study analyzed the effects of Dex, one of the main GCs used in ALL treatment, on two T-ALL cell lines: resistant Jurkat and unselected CCRF-CEM, representing a mixture of sensitive and resistant clones. In addition to nuclear targeting, we observed a massive accumulation of Dex in mitochondria. Dex-treated leukemic cells suffered metabolic reprogramming from glycolysis and glutaminolysis towards lipolysis and increased FAO, along with increased membrane polarization and ROS production. Dex provoked mitochondrial fragmentation and induced autophagy/mitophagy. Mitophagy preceded cell death in susceptible populations of CCRF-CEM cells while serving as a pro-survival mechanism in resistant Jurkat. Accordingly, preventing FAO or autophagy greatly increased the Dex cytotoxicity and overcame GC resistance. Dex acted synergistically with mitochondria-targeted drugs, curcumin, and cannabidiol. Collectively, our data suggest that GCs treatment should not be neglected even in apparently GC-resistant clinical cases. Co-administration of drugs targeting mitochondria, FAO, or autophagy can help to overcome GC resistance.

Keywords:  acute lymphoblastic leukemia; autophagy; dexamethasone; glucocorticoid resistance; glucocorticoids; leukemic microenvironment; metabolic reprogramming; mitophagy

DOI:  https://doi.org/10.3390/cancers15020445
Cancer Res. 2023 Jan 18. 83(2): 167-169

Neuroblastoma Differentiation: The Untapped Potential of Mitochondrial Uncouplers.

F L Byrne, J L Bell.

While the goal of most anticancer treatments is to kill cancer cells, some therapies halt cancer progression by inducing cancer cell differentiation. For example, retinoic acid induces neuroblastoma cell differentiation in vitro and is used as maintenance therapy for children with high-risk neuroblastoma. A new study by Jiang and colleagues has revealed the mitochondrial uncoupler niclosamide ethanolamine (NEN) induces neuroblastoma cell differentiation in vitro and slows neuroblastoma tumor growth in vivo. Mitochondrial uncoupler molecules alter cell metabolism by forcing cells to "burn" more nutrients, resulting in a switch from anabolic to catabolic metabolism. NEN-induced neuroblastoma cell differentiation was associated with disruption of Warburg metabolism, epigenetic remodeling, and downregulation of key oncogenic drivers of neuroblastoma development, including MYCN. NEN is currently used as an antiparasitic worm treatment and is safe to use in children but has poor pharmacokinetic properties. However, derivatives of NEN and structurally distinct uncouplers that have improved pharmacokinetic properties are in development. Results of this study ignite the idea that mitochondrial uncouplers could be used as differentiating agents and expand the pharmacotherapy toolkit to treat cancer, including neuroblastoma. See related article by Jiang et al., p. 181.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3350
Cancers (Basel). 2023 Jan 08. pii: 411. [Epub ahead of print]15(2):

Role of Mitochondrial Transporters on Metabolic Rewiring of Pancreatic Adenocarcinoma: A Comprehensive Review.

Graziantonio Lauria, Rosita Curcio, Paola Lunetti, Stefano Tiziani, Vincenzo Coppola, Vincenza Dolce, Giuseppe Fiermonte, Amer Ahmed.

  Pancreatic cancer is among the deadliest cancers worldwide and commonly presents as pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming is a hallmark of PDAC. Glucose and glutamine metabolism are extensively rewired in order to fulfil both energetic and synthetic demands of this aggressive tumour and maintain favorable redox homeostasis. The mitochondrial pyruvate carrier (MPC), the glutamine carrier (SLC1A5_Var), the glutamate carrier (GC), the aspartate/glutamate carrier (AGC), and the uncoupling protein 2 (UCP2) have all been shown to influence PDAC cell growth and progression. The expression of MPC is downregulated in PDAC and its overexpression reduces cell growth rate, whereas the other four transporters are usually overexpressed and the loss of one or more of them renders PDAC cells unable to grow and proliferate by altering the levels of crucial metabolites such as aspartate. The aim of this review is to comprehensively evaluate the current experimental evidence about the function of these carriers in PDAC metabolic rewiring. Dissecting the precise role of these transporters in the context of the tumour microenvironment is necessary for targeted drug development.

Keywords:  PDAC; aspartate; glutamine; metabolic rewiring; mitochondrial carriers

DOI:  https://doi.org/10.3390/cancers15020411
Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2208176120

Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells.

Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, François Lemonnier, Wanda Y Li, Miki S Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M Robinson, Annick You-Ten, Daniel J Butler, Thorsten Berger, Mark D Minden, Ross L Levine, Cynthia J Guidos, Ari M Melnick, Christopher E Mason, Tak W Mak.

  Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

Keywords:  IDH; TET2; epigenetics; myeloid neoplasm

DOI:  https://doi.org/10.1073/pnas.2208176120
Physiol Res. 2022 Dec 31. 71(S2): S227-S236

Impact of aging on mitochondrial respiration in various organs.

J Jedlička, Z Tůma, K Razak, R Kunc, A Kala, S Proskauer Pena, T Lerchner, K Ježek, J Kuncová.

Mitochondria are considered central regulator of the aging process; however, majority of studies dealing with the impact of age on mitochondrial oxygen consumption focused on skeletal muscle concluding (although not uniformly) a general declining trend with advancing age. In addition, gender related differences in mitochondrial respiration have not been satisfactorily described yet. The aim of the present study was to evaluate mitochondrial oxygen consumption in various organs of aging male and female Fischer 344 rats at the ages of 6, 12 and 24 months. Mitochondrial respiration of homogenized (skeletal muscle, left and right heart ventricle, hippocampus, cerebellum, kidney cortex), gently mechanically permeabilized (liver) tissue or intact cells (platelets) was determined using high-resolution respirometry (oxygraphs O2k, Oroboros, Austria). The pattern of age-related changes differed in each tissue: in the skeletal muscle and kidney cortex of both sexes and in female heart, parameters of mitochondrial respiration significantly declined with age. Resting respiration of intact platelets displayed an increasing trend and it did not correlate with skeletal muscle respiratory states. In the heart of male rats and brain tissues of both sexes, respiratory states remained relatively stable over analyzed age categories with few exceptions of lower mitochondrial oxygen consumption at the age of 24 months. In the liver, OXPHOS capacity was higher in females than in males with either no difference between the ages of 6 and 24 months or even significant increase at the age of 24 months in the male rats. In conclusion, the results of our study indicate that the concept of general pattern of age-dependent decline in mitochondrial oxygen consumption across different organs and tissues could be misleading. Also, the statement of higher mitochondrial respiration in females seems to be conflicting, since the gender-related differences may vary with the tissue studied, combination of substrates used and might be better detectable at younger ages than in old animals.
Cell Mol Bioeng. 2023 Feb;16(1): 69-80

Stiffer-Matrix-Induced PGC-1α Upregulation Enhanced Mitochondrial Biogenesis and Oxidative Stress Resistance in Non-small Cell Lung Cancer.

Xiaorong Fu, Yasuhiro Kimura, Yuhki Toku, Guanbin Song, Yang Ju.

   Introduction: Metabolic strategies in different microenvironments can affect cancer metabolic adaptation, ultimately influencing the therapeutic response. Understanding the metabolic alterations of cancer cells in different microenvironments is critical for therapeutic success.
Methods: In this study, we cultured non-small cell lung cancer cells in three different microenvironments (two-dimensional (2D) plates, soft elastic three-dimensional (3D) porous 2 wt% scaffolds, and stiff elastic 3D porous 4 wt% scaffolds) to investigate the effects of different matrix elasticity as well as 2D and 3D culture settings on the metabolic adaptation of cancer cells.
Results: The results revealed that PGC-1α expression is sensitive to the elasticity of the 3D scaffold. PGC-1α expression was markedly increased in cancer cells cultured in stiff elastic 3D porous 4 wt% scaffolds compared with cells cultured in soft elastic 3D porous 2 wt% scaffolds or 2D plates, enhancing mitochondrial biogenesis and oxidative stress resistance of non-small cell lung cancer through increased reactive oxygen species (ROS) detoxification capacity. However, phosphofructokinase-1 (PFK-1) expression, a key rate-limiting enzyme in glycolysis, did not change significantly in the three microenvironments, indicating that microenvironments may not affect the early stage of glycolysis. Conversely, monocarboxylate transporter 1 (MCT1) expression in 3D culture was significantly reduced compared to 2D culture but without significant difference between soft and stiff scaffolds, indicating that MCT1 expression is more sensitive to the shape of the different cultures of 2D and 3D microenvironment surrounding cells but is unaffected by the scaffold elasticity.
Conclusions: Together, these results demonstrate that differences in the microenvironment of cancer cells profoundly impact their metabolic response.

Keywords:  Metabolic alternation; Microenvironments; Mitochondrial biogenesis; Non-small cell lung cancer; ROS detoxification capacities; Three-dimensional scaffolds

DOI:  https://doi.org/10.1007/s12195-022-00751-x
Mol Med. 2023 Jan 19. 29(1): 10

A novel Mcl-1 inhibitor synergizes with venetoclax to induce apoptosis in cancer cells.

Tianming Zhao, Qiang He, Shurong Xie, Huien Zhan, Cheng Jiang, Shengbin Lin, Fangshu Liu, Cong Wang, Guo Chen, Hui Zeng.

   BACKGROUND: Evading apoptosis by overexpression of anti-apoptotic Bcl-2 family proteins is a hallmark of cancer cells and the Bcl-2 selective inhibitor venetoclax is widely used in the treatment of hematologic malignancies. Mcl-1, another anti-apoptotic Bcl-2 family member, is recognized as the primary cause of resistance to venetoclax treatment. However, there is currently no Mcl-1 inhibitor approved for clinical use.
METHODS: Paired parental and Mcl-1 knockout H1299 cells were used to screen and identify a small molecule named MI-238. Immunoprecipitation (IP) and flow cytometry assay were performed to analyze the activation of pro-apoptotic protein Bak. Annexin V staining and western blot analysis of cleaved caspase 3 were employed to measure the cell apoptosis. Mouse xenograft AML model using luciferase-expressing Molm13 cells was employed to evaluate in vivo therapeutic efficacy. Bone marrow samples from newly diagnosed AML patients were collected to evaluate the therapeutic potency.
RESULTS: Here, we show that MI-238, a novel and specific Mcl-1 inhibitor, can disrupt the association of Mcl-1 with BH3-only pro-apoptotic proteins, selectively leading to apoptosis in Mcl-1 proficient cells. Moreover, MI-238 treatment also potently induces apoptosis in acute myeloid leukemia (AML) cells. Notably, the combined treatment of MI-238 with venetoclax exhibited strong synergistic anti-cancer effects in AML cells in vitro, MOLM-13 xenografts mouse model and AML patient samples.
CONCLUSIONS: This study identified a novel and selective Mcl-1 inhibitor MI-238 and demonstrated that the development of MI-238 provides a novel strategy to improve the outcome of venetoclax therapy in AML.

Keywords:  AML; Apoptosis; Bcl-2; Mcl-1 inhibitor; Venetoclax

DOI:  https://doi.org/10.1186/s10020-022-00565-7
Mol Metab. 2023 Jan 16. pii: S2212-8778(23)00008-X. [Epub ahead of print] 101674

Thioalbamide inhibits FoF1-ATPase in breast cancer cells and reduces tumor proliferation and invasiveness in breast cancer in vivo models.

Frattaruolo L, Malivindi R, Brindisi M, Rago V, Curcio R, Lauria G, Fiorillo M, Dolce V, A W Truman, A R Cappello.

   OBJECTIVE: Thioalbamide is a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the family of thioamitides, a rare class of microbial specialized metabolites with unusual post-translational modifications and promising biological activities. Recent studies have demonstrated the ability of thioalbamide to exert highly selective cytotoxic effects on tumor cells by affecting their energy metabolism, thus causing abnormal ROS production and triggering apoptotis. This study is aimed to investigate the molecular mechanisms underlying the antitumor activity of thioalbamide in order to identify its exact molecular target.
METHODS: Wild type MCF-7 and MDA-MB-231 breast cancer cell lines as well as cancer cells deprived of mitochondrial DNA (ρ0 cells) were employed in order to assess thioalbamide effects on tumor bioenergetics. In this regard, metabolic profile was evaluated by a Seahorse XFe96 analyzer, and the activity of the enzyme complexes involved in oxidative phosphorylation was quantified by spectrophotometric assays. Thioalbamide effects on tumor invasiveness were assessed by gelatin zymography experiments and invasion assays. In vivo experiments were carried out on breast cancer xenograft and "experimental metastasis" mouse models.
RESULTS: Experiments carried out on ρ0 breast cancer cells, together with Seahorse analysis and the application of spectrophotometric enzymatic assays, highlighted the ability of thioalbamide to affect the mitochondrial respiration process, and allowed to propose the FoF1-ATPase complex as its main molecular target in breast cancer cells. Additionally, thioalbamide-mediated OXPHOS inhibition was shown, for the first time, to reduce tumor invasiveness by inhibiting metalloproteinase-9 secretion. Furthermore, this study has confirmed the antitumor potential of thioalbamide in two different in vivo models. In particular, experiments on MCF-7 and MDA-MB-231 xenograft mouse models have confirmed in vivo its high anti-proliferative and pro-apoptotic activity, while experiments on MDA-MB-231 "experimental metastasis" mouse models have highlighted its ability to inhibit breast cancer cell invasiveness.
CONCLUSIONS: Overall, our results shed more light on the molecular mechanisms underlying the pharmacological potential of thioamidated peptides, thus reducing the gap that separates this rare class of microbial metabolites from clinical studies, which could validate them as effective tools for cancer treatment.

Keywords:  Breast cancer; Metabolism; Oxidative phosphorylation; RiPPs; Thioamitides

DOI:  https://doi.org/10.1016/j.molmet.2023.101674
Trends Cancer. 2023 Jan 14. pii: S2405-8033(22)00268-0. [Epub ahead of print]

Fasting and fasting mimicking diets in cancer prevention and therapy.

Olga Blaževitš, Maira Di Tano, Valter D Longo.

  Fasting mimicking diets (FMDs) are emerging as effective dietary interventions with the potential to improve healthspan and decrease the incidence of cancer and other age-related diseases. Unlike chronic dietary restrictions or water-only fasting, FMDs represent safer and less challenging options for cancer patients. FMD cycles increase protection in healthy cells while sensitizing cancer cells to various therapies, partly by generating complex environments that promote differential stress resistance (DSR) and differential stress sensitization (DSS), respectively. More recent data indicate that FMD cycles enhance the efficacy of a range of drugs targeting different cancers in mice by stimulating antitumor immunity. Here, we report on the effects of FMD cycles on cancer prevention and treatment and the mechanisms implicated in these effects.

Keywords:  cancer treatment; differential stress resistance (DSR); differential stress sensitization (DSS); fasting mimicking diet

DOI:  https://doi.org/10.1016/j.trecan.2022.12.006