bims-mibica 2024-02-04 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–02–04
27 papers selected by
Kelsey Fisher-Wellman, East Carolina University

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.
Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.
Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.
The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.
Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.
Acute myeloid leukemia-derived bone marrow mesenchymal cells exhibit improved support for leukemic cell proliferation.
Decreased pyruvate dehydrogenase activity in Tafazzin-deficient cells is caused by dysregulation of pyruvate dehydrogenase phosphatase 1 (PDP1).
The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions.
Linear DNA-driven recombination in mammalian mitochondria.
A mitochondria-targeted anticancer copper dithiocarbamate amplifies immunogenic cuproptosis and macrophage polarization.
A Potential "Anti-Warburg Effect" in Circulating Tumor Cell-mediated Metastatic Progression?
ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling.
Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in osteosarcoma.
Regulating Lipid Metabolism via Mitochondrial Dynamics in Tongue Squamous Cell Carcinoma Cancer Stem Cells.
ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells.
Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.
Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma.
Enhancement of de novo lipogenesis by the IDH1 and IDH2-dependent reverse TCA cycle maintains the growth and angiogenic capacity of bone marrow-derived endothelial progenitor cells under hypoxia.
Optineurin provides a mitophagy contact site for TBK1 activation.
Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.
7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.
Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials.
Rescue of mitochondrial import failure by intercellular organellar transfer.

bioRxiv. 2024 Jan 19. pii: 2024.01.16.575895. [Epub ahead of print]

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jacek Biesiada, Katherine E Vest, Pier P Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, J Tom Cunningham, Maria F Czyzyk-Krzeska.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.

DOI: https://doi.org/10.1101/2024.01.16.575895
J Biol Chem. 2024 Jan 30. pii: S0021-9258(24)00078-4. [Epub ahead of print] 105702

The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.

Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.

  Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly six-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.

Keywords:  BT2; ROS production; branched-chain amino acids; cardiometabolic disease; chemical uncoupling; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2024.105702
Nat Cancer. 2024 Jan 29.

Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.

Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

DOI: https://doi.org/10.1038/s43018-023-00721-w
J Biol Chem. 2024 Jan 25. pii: S0021-9258(24)00066-8. [Epub ahead of print] 105690

The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.

Joe Carroll, Ian N Watt, Charlotte J Wright, Shujing Ding, Ian M Fearnley, John E Walker.

  The hydrolytic activity of the ATP synthase in bovine mitochondria is inhibited by a protein called IF1, but bovine IF1 has no effect on the synthetic activity of the bovine enzyme in mitochondrial vesicles in the presence of a proton motive force. In contrast, it has been suggested based on indirect observations that human IFI inhibits both the hydrolytic and synthetic activities of the human ATP synthase, and that the activity of human IF1 is regulated by the phosphorylation of serine-14 of mature IF1. Here, we have made both human and bovine IF1 which are 81 and 84 amino acids long, respectively, and identical in 71.4% of their amino acids, and have investigated their inhibitory effects on the hydrolytic and synthetic activities of ATP synthase in bovine sub-mitochondrial particles. Over a wide range of conditions, including physiological conditions, both human and bovine IF1 are potent inhibitors of ATP hydrolysis, with no effect on ATP synthesis. Also, substitution of serine-14 with phosphomimetic aspartic and glutamic acids had no effect on inhibitory properties, and serine-14 is not conserved throughout mammals. Therefore, it is unlikely that the inhibitory activity of mammalian IF1 is regulated by phosphorylation of this residue.

Keywords:  ATP synthase; inhibitor protein IF(1); mitochondria; regulation; unidirectional inhibition

DOI:  https://doi.org/10.1016/j.jbc.2024.105690
Eur J Clin Invest. 2024 Jan 30. e14174

Mitochondrial HER2 stimulates respiration and promotes tumorigenicity.

Eliska Novotna, Mirko Milosevic, Dana Prukova, Silvia Magalhaes-Novais, Sarka Dvorakova, Kristina Dmytruk, Jakub Gemperle, Dagmar Zudova, Tereza Nickl, Marek Vrbacky, Daniel Rosel, Vlada Filimonenko, Jan Prochazka, Jan Brabek, Jiri Neuzil, Katerina Rohlenova, Jakub Rohlena.

   BACKGROUND: Amplification of HER2, a receptor tyrosine kinase and a breast cancer-linked oncogene, is associated with aggressive disease. HER2 protein is localised mostly at the cell membrane, but a fraction translocates to mitochondria. Whether and how mitochondrial HER2 contributes to tumorigenicity is currently unknown.
METHODS: We enriched the mitochondrial (mt-)HER2 fraction in breast cancer cells using an N-terminal mitochondrial targeting sequence and analysed how this manipulation impacts bioenergetics and tumorigenic properties. The role of the tyrosine kinase activity of mt-HER2 was assessed in wild type, kinase-dead (K753M) and kinase-enhanced (V659E) mtHER2 constructs.
RESULTS: We document that mt-HER2 associates with the oxidative phosphorylation system, stimulates bioenergetics and promotes larger respiratory supercomplexes. mt-HER2 enhances proliferation and invasiveness in vitro and tumour growth and metastatic potential in vivo, in a kinase activity-dependent manner. On the other hand, constitutively active mt-HER2 provokes excessive mitochondria ROS generation, sensitises to cell death, and restricts growth of primary tumours, suggesting that regulation of HER2 activity in mitochondria is required for the maximal pro-tumorigenic effect.
CONCLUSIONS: mt-HER2 promotes tumorigenicity by supporting bioenergetics and optimal redox balance.

Keywords:  HER2; cancer; electron transport chain; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1111/eci.14174
Cancer Res. 2024 Jan 29.

Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.

Andrew J Monteith, Haley E Ramsey, Alexander J Silver, Donovan Brown, Dalton Greenwood, Brianna N Smith, Ashley D Wise, Juan Liu, Sarah D Olmstead, Jackson Watke, Maria P Arrate, Agnieszka E Gorska, Londa Fuller, Jason W Locasale, Matthew C Stubbs, Jeffrey C Rathmell, Michael R Savona.

Impairing the BET-family co-activator BRD4 with small molecule inhibitors (BETi) showed encouraging pre-clinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0291
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00018-8. [Epub ahead of print]1870(3): 167033

The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.

Valeria Balmaceda, Timea Komlódi, Marten Szibor, Erich Gnaiger, Anthony L Moore, Erika Fernandez-Vizarra, Carlo Viscomi.

  Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.

Keywords:  Coenzyme Q redox state; Complex I deficiency; Complex III deficiency; Isolated mitochondria; Oxygen consumption; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbadis.2024.167033
J Exp Clin Cancer Res. 2024 Jan 27. 43(1): 33

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

Sonia Alcalá, Lara Villarino, Laura Ruiz-Cañas, José R Couceiro, Miguel Martínez-Calvo, Adrián Palencia-Campos, Diego Navarro, Pablo Cabezas-Sainz, Iker Rodriguez-Arabaolaza, Alfonso Cordero-Barreal, Lucia Trilla-Fuertes, Juan A Rubiolo, Sandra Batres-Ramos, Mireia Vallespinos, Cristina González-Páramos, Jéssica Rodríguez, Angelo Gámez-Pozo, Juan Ángel Fresno Vara, Sara Fra Fernández, Amparo Benito Berlinches, Nicolás Moreno-Mata, Ana María Torres Redondo, Alfredo Carrato, Patrick C Hermann, Laura Sánchez, Susana Torrente, Miguel Ángel Fernández-Moreno, José L Mascareñas, Bruno Sainz.

   BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.
METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action.
RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration.
CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Keywords:  Anti-cancer agents; Cancer stem cells; Colon cancer; Mitochondrial DNA; Oxidative phosphorylation; Pancreatic ductal adenocarcinoma; Patient-derived xenografts; Ruthenium complexes

DOI:  https://doi.org/10.1186/s13046-023-02931-7
Hematol Transfus Cell Ther. 2023 Dec 27. pii: S2531-1379(23)02602-0. [Epub ahead of print]

Acute myeloid leukemia-derived bone marrow mesenchymal cells exhibit improved support for leukemic cell proliferation.

Mariane Cristina do Nascimento, Diego A Pereira-Martins, João Agostinho Machado-Neto, Eduardo M Rego.

   INTRODUCTION: The bone marrow (BM) microenvironment plays a significant role in acute myeloid leukemia (AML) genesis and there is evidence that BM mesenchymal stromal cells (BMMSCs) can support leukemia progenitor cell proliferation and survival and provide resistance to cytotoxic therapies.
HYPOTHESIS AND METHOD: Nevertheless, currently unknown are the relevance of the spatial localization of AML cells relative to the BMMSCs and whether BMMSCs from patients with AML and healthy subjects have similar properties. To address these issues, we performed a differential gene expression analysis using RNA-sequencing data generated from healthy donors (HDs) and leukemic BMMSCs.
RESULTS: The Gene Set Enrichment Analysis (GSEA) revealed that leukemic BMMSCs were associated with the terms "positive regulation of cell cycle", "angiogenesis" and "signaling by the estimated glomerular filtration rate (eGFR)", whereas healthy donor (HD)-derived BMMSCs were associated with "programmed cell death in response to the reactive oxygen species (ROS)", "negative regulation of the cytochrome C from the mitochondria" and "interferon signaling". Next, we evaluated the mitochondrial superoxide production in AML cells in a co-culture layered model. The superoxide production was reduced in leukemic cells in close contact (adhered to the surface or beneath the cell layer) with BMMSCs, indicating lower oxidative stress.
CONCLUSION: Taken together, our results suggest that AML-derived BMMSCs are transcriptionally rewired and can reduce the metabolic stress of leukemic cells.

Keywords:  Acute myeloid leukemia; Bone marrow microenvironment; Cell proliferation; Metabolism

DOI:  https://doi.org/10.1016/j.htct.2023.10.007
J Biol Chem. 2024 Jan 30. pii: S0021-9258(24)00073-5. [Epub ahead of print] 105697

Decreased pyruvate dehydrogenase activity in Tafazzin-deficient cells is caused by dysregulation of pyruvate dehydrogenase phosphatase 1 (PDP1).

Zhuqing Liang, Tyler Ralph-Epps, Michael W Schmidtke, Vikalp Kumar, Miriam L Greenberg.

Cardiolipin (CL), the signature lipid of the mitochondrial inner membrane, is critical for maintaining optimal mitochondrial function and bioenergetics. Disruption of CL metabolism, caused by mutations in the CL remodeling enzyme TAFAZZIN, results in the rare and life-threatening disorder Barth syndrome (BTHS). While the clinical manifestations of BTHS, such as dilated cardiomyopathy and skeletal myopathy, point to defects in mitochondrial bioenergetics, the disorder is also characterized by broad metabolic dysregulation, including abnormal levels of metabolites associated with the tricarboxylic acid (TCA) cycle. In line with this, recent studies have identified inhibition of pyruvate dehydrogenase (PDH), the gatekeeper enzyme for TCA cycle carbon influx, as a key deficiency in various BTHS model systems. However, the molecular mechanisms linking aberrant CL remodeling, particularly the primary, direct consequence of reduced tetralinoleoyl-CL (TLCL) levels, to PDH activity deficiency are not yet understood. This knowledge gap has limited our understanding of lipid-mediated metabolic regulation in BTHS and hindered the development of effective treatment strategies. In the current study, we provide evidence that remodeled TLCL promotes PDH function by directly binding to and enhancing the activity of PDH phosphatase 1 (PDP1). This is supported by our findings that TLCL uniquely activates PDH in a dose-dependent manner, TLCL binds to PDP1 in vitro, TLCL-mediated PDH activation is attenuated in the presence of phosphatase inhibitor, and PDP1 activity is decreased in Tafazzin-knockout (TAZ-KO) C2C12 myoblasts. Additionally, we observed decreased mitochondrial calcium levels in TAZ-KO cells, which may affect the calcium-sensitive activity of PDP1. Treating TAZ-KO cells with calcium lactate (CaLac) increases mitochondrial calcium and restores PDH activity and mitochondrial oxygen consumption rate. Based on our findings, we conclude that reduced mitochondrial calcium levels and decreased binding of PDP1 to TLCL contribute to decreased PDP1 activity in TAZ-KO cells.

DOI: https://doi.org/10.1016/j.jbc.2024.105697
Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010950. [Epub ahead of print]

The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.

Marc Usart, Nils Hansen, Jan Stetka, Tiago Almeida Fonseca, Alexandre Guy, Quentin Kimmerlin, Shivam Rai, Hui Hao-Shen, Julien Roux, Stefan Dirnhofer, Radek C Skoda.

Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, i.e. the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when co-targeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from PV patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting glutaminase alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.

DOI: https://doi.org/10.1182/bloodadvances.2023010950
Free Radic Biol Med. 2024 Jan 31. pii: S0891-5849(24)00051-0. [Epub ahead of print]

The opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions.

Chaoran Jia, Yulun Wu, Feng Gao, Wei Liu, Na Li, Yao Chen, Luguo Sun, Shuyue Wang, Chunlei Yu, Yongli Bao, Zhenbo Song.

  Due to insufficient and defective vascularization, the tumor microenvironment is often nutrient-depleted. LDHA has been demonstrated to play a tumor-promoting role by facilitating the glycolytic process. However, whether and how LDHA regulates cell survival in the nutrient-deficient tumor microenvironment are still unclear. Here, we sought to investigate the role and mechanism of LDHA in regulating cell survival and proliferation under energy stress conditions. Our results showed that the aerobic glycolysis levels, cell survival and proliferation of cervical cancer cells decreased significantly after inhibition of LDHA under normal culture condition while LDHA deficiency greatly inhibited glucose starvation-induced ferroptosis and promoted cell proliferation and tumor formation under energy stress conditions. Mechanistic studies suggested that glucose metabolism shifted from aerobic glycolysis to mitochondrial OXPHOS under energy stress conditions and LDHA knockdown increased accumulation of pyruvate in the cytosol, which entered the mitochondria and upregulated the level of oxaloacetate by phosphoenolpyruvate carboxylase (PC). Importantly, the increase in oxaloacetate production after absence of LDHA remarkably activated AMP-activated protein kinase (AMPK), which increased mitochondrial biogenesis and mitophagy, promoted mitochondrial homeostasis, thereby decreasing ROS level. Moreover, repression of lipogenesis by activation of AMPK led to elevated levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which effectively resisted ROS-induced cell ferroptosis and enhanced cell survival under energy stress conditions. These results suggested that LDHA played an opposing role in survival and proliferation of cervical cancer cells under energy stress conditions, and inhibition of LDHA may not be a suitable treatment strategy for cervical cancer.

Keywords:  AMPK; Cervical cancer; Energy stress; Ferroptosis; LDHA

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.043
Nucleic Acids Res. 2024 Feb 01. pii: gkae040. [Epub ahead of print]

Linear DNA-driven recombination in mammalian mitochondria.

Georgios Fragkoulis, Anu Hangas, Zsófia Fekete, Craig Michell, Carlos T Moraes, Smaranda Willcox, Jack D Griffith, Steffi Goffart, Jaakko L O Pohjoismäki.

Mitochondrial DNA (mtDNA) recombination in animals has remained enigmatic due to its uniparental inheritance and subsequent homoplasmic state, which excludes the biological need for genetic recombination, as well as limits tools to study it. However, molecular recombination is an important genome maintenance mechanism for all organisms, most notably being required for double-strand break repair. To demonstrate the existence of mtDNA recombination, we took advantage of a cell model with two different types of mitochondrial genomes and impaired its ability to degrade broken mtDNA. The resulting excess of linear DNA fragments caused increased formation of cruciform mtDNA, appearance of heterodimeric mtDNA complexes and recombinant mtDNA genomes, detectable by Southern blot and by long range PacBio® HiFi sequencing approach. Besides utilizing different electrophoretic methods, we also directly observed molecular complexes between different mtDNA haplotypes and recombination intermediates using transmission electron microscopy. We propose that the known copy-choice recombination by mitochondrial replisome could be sufficient for the needs of the small genome, thus removing the requirement for a specialized mitochondrial recombinase. The error-proneness of this system is likely to contribute to the formation of pathological mtDNA rearrangements.

DOI: https://doi.org/10.1093/nar/gkae040
J Mater Chem B. 2024 Jan 31.

A mitochondria-targeted anticancer copper dithiocarbamate amplifies immunogenic cuproptosis and macrophage polarization.

Yao Lu, Xi Fan, Qingqing Pan, Bin He, Yuji Pu.

The way that cancer cells die inspires treatment regimens and cytolytic cuproptosis induced by copper complexes, like copper(II) bis(diethyldithiocarbamate) (CuET), has emerged as a novel therapeutic target. Herein, a triphenylphosphonium-modified CuET (TPP-CuET) is designed to target mitochondrial metabolism, triggering intense immunogenic cuproptosis in breast cancer cells and remodeling tumor-associated macrophages. TPP-CuET enables an enhanced mitochondrial copper accumulation in comparison to CuET (29.0% vs. 19.4%), and severely disrupts the morphology and functions of mitochondria, encompassing the tricarboxylic acid cycle, ATP synthesis, and electron transfer chain. Importantly, it triggers amplified immunogenic death of cancer cells, and the released damage-associated molecular patterns effectively induce M1 polarization and migration of macrophages. Transcriptome analysis further reveals that TPP-CuET promotes antigen processing and presentation in cancer cells through the MHC I pathway, activating the immune response of CD8 T cells and natural killer cells. To the best of our knowledge, TPP-CuET is the first mitochondrial targeted immunogenic cuproptosis inducer and is expected to flourish in antitumor immunotherapy.

DOI: https://doi.org/10.1039/d3tb02886k
Aging Dis. 2024 Jan 11.

A Potential "Anti-Warburg Effect" in Circulating Tumor Cell-mediated Metastatic Progression?

Zhuofeng Jiang, Jiapeng He, Binyu Zhang, Liping Wang, Chunhao Long, Boxi Zhao, Yufan Yang, Longxiang Du, Weiren Luo, Jianyang Hu, Xin Hong.

Metabolic reprogramming is a defining hallmark of cancer metastasis, warranting thorough exploration. The tumor-promoting function of the "Warburg Effect", marked by escalated glycolysis and restrained mitochondrial activity, is widely acknowledged. Yet, the functional significance of mitochondria-mediated oxidative phosphorylation (OXPHOS) during metastasis remains controversial. Circulating tumor cells (CTCs) are considered metastatic precursors that detach from primary or secondary sites and harbor the potential to seed distant metastases through hematogenous dissemination. A comprehensive metabolic characterization of CTCs faces formidable obstacles, including the isolation of these rare cells from billions of blood cells, coupled with the complexities of ex vivo-culturing of CTC lines or the establishment of CTC-derived xenograft models (CDX). This review summarized the role of the "Warburg Effect" in both tumorigenesis and CTC-mediated metastasis. Intriguingly, bioinformatic analysis of single-CTC transcriptomic studies unveils a potential OXPHOS dominance over Glycolysis signature genes across several important cancer types. From these observations, we postulate a potential "Anti-Warburg Effect" (AWE) in CTCs-a metabolic shift bridging primary tumors and metastases. The observed AWE could be clinically important as they are significantly correlated with therapeutic response in melanoma and prostate patients. Thus, unraveling dynamic metabolic regulations within CTC populations might reveal an additional layer of regulatory complexities of cancer metastasis, providing an avenue for innovative anti-metastasis therapies.

DOI: https://doi.org/10.14336/AD.2023.1227
Acta Biochim Biophys Sin (Shanghai). 2024 Jan 29.

ATIP/ATIP1 regulates prostate cancer metastasis through mitochondrial dynamic-dependent signaling.

Haokun Yuan, Ruiqin Fang, Chi Fu, Shuo Wang, Xiaoqin Tong, Deyi Feng, Xiaoqing Wei, Xirong Hu, Yuan Wang.

  Mitochondria play a fundamental role in cell survival and motility. Abnormalities in mitochondria are associated with carcinogenesis, especially with tumor metastasis. In this study, we explore the biological function of ATIP1, which is a mitochondrial-located isoform of angiotensin II AT2 receptor interacting proteins (ATIPs) in prostate cancer cells. The results showed that ATIP is downregulated in prostate cancer tissues and is negatively correlated with the disease-free survival rate of prostate cancer patients. Silencing of ATIP promotes mitochondrial fission and enhances tumor cell migration and invasion. Reconstitution of ATIP1 in ATIP-deficient cells significantly attenuates mitochondrial trafficking and tumor cell movement. Therefore, ATIP1 is a negative regulator of mitochondrial dynamics and tumor cell motility and is also a potential biomarker for predicting prostate cancer malignancy.

Keywords:  ATIP/ATIP1; Drp1; metastasis; mitochondrial dynamics

DOI:  https://doi.org/10.3724/abbs.2024006
Genes Dis. 2024 May;11(3): 100988

Aberrant LETM1 elevation dysregulates mitochondrial functions and energy metabolism and promotes lung metastasis in osteosarcoma.

Yulu Shi, Quan Kang, Hong Zhou, Xiaohan Yue, Yang Bi, Qing Luo.

  Osteosarcoma is a differentiation-deficient disease, and despite the unique advantages and great potential of differentiation therapy, there are only a few known differentiation inducers, and little research has been done on their targets. Cell differentiation is associated with an increase in mitochondrial content and activity. The metabolism of some tumor cells is characterized by impaired oxidative phosphorylation, as well as up-regulation of aerobic glycolysis and pentose phosphate pathways. Leucine-containing zipper and EF-hand transmembrane protein 1 (LETM1) is involved in the maintenance of mitochondrial morphology and is closely associated with tumorigenesis and progression, as well as cancer cell stemness. We found that MG63 and 143B osteosarcoma cells overexpress LETM1 and exhibit abnormalities in mitochondrial structure and function. Knockdown of LETM1 partially restored the mitochondrial structure and function, inhibited the pentose phosphate pathway, promoted oxidative phosphorylation, and led to osteogenic differentiation. It also inhibited spheroid cell formation, proliferation, migration, and invasion in an in vitro model. When LETM1 was knocked down in vivo, there was reduced tumor formation and lung metastasis. These data suggest that mitochondria are aberrant in LETM1-overexpressing osteosarcoma cells, and knockdown of LETM1 partially restores the mitochondrial structure and function, inhibits the pentose phosphate pathway, promotes oxidative phosphorylation, and increases osteogenic differentiation, thereby reducing malignant biological behavior of the cells.

Keywords:  Cancer metabolism; Differentiation; LETM1; Osteosarcoma; Stemness

DOI:  https://doi.org/10.1016/j.gendis.2023.05.005
Recent Pat Anticancer Drug Discov. 2024 Jan 16.

Regulating Lipid Metabolism via Mitochondrial Dynamics in Tongue Squamous Cell Carcinoma Cancer Stem Cells.

Fan Wu, Suling Chen, Siqi Ren, Ruixin Wang, Yongmei Tan, Rongxi Chen, Bowen Li, Haotian Cao, Jinsong Li.

   BACKGROUND: Cancer stem cells (CSCs) are a sub-population of cancer cells present in many kinds of malignant tumors that have the potential for self-proliferation and differentiation. These cells have been demonstrated as the main cause of tumor recurrence and metastasis. Strong evidence indicates that CSCs prefer reprogrammed fatty acid β-oxidation over oxidative phosphorylation for sustaining energy supply. Although mitochondrial dynamics participate in the regulation of cancer stemness, the correlation between the inhibition of mitochondrial fission and the regulation of lipid metabolism in CSCs remains poorly understood.
METHODS: The human tongue squamous cell carcinoma (TSCC) cell lines CAL27 and SAS were used to obtain the CSCs by 3D Spheroid Culture. Then,western blot methods, RT-PCR and flow cytometry analysis were used to identify the TSCC CSCs. Next, Immunofluorescence method, transmission electron microscopy detection and western blot methods were used to evaluate the mitochondrial morphology and the quantity of lipid droplets (LDs). Lastly, lipidomic analysis was applied to explored the lipidomic alterations of TSCC CSCs with different mitochondrial morphology.
RESULTS: Here, we show that the quantity of lipid droplets containing intracellular triglyceride (TG) can be decreased by regulating mitochondrial morphology. Lipidomic analysis using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) also compared alterations in lipid metabolites in tongue squamous cell carcinoma (TSCC) CSCs, TSCC cells (non-CSCs), and CSCs with different mitochondrial morphology. Discriminant lipids of statistical significance were successfully annotated, including phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), sphingomyelins (SMs), triacylglycerols (TGs), phosphatidylglycerols (PGs), phosphatidylserines (PSs), lysophosphatidylcholines (LPCs), and lysophosphatidylethanolamines (LPEs).
CONCLUSION: This study provides a deeper insight into the alterations of lipid metabolism associated with TSCC CSCs, non-CSCs and CSCs regulated by mitochondrial dynamics and thus serves as a guide toward novel targeted therapies.

Keywords:  Tongue squamous cell carcinoma; cancer stem cells; lipid droplets; lipid metabolism; lipid metabolite.; mitochondrial dynamics

DOI:  https://doi.org/10.2174/0115748928275772231226063458
Cell Death Discov. 2024 Jan 29. 10(1): 56

ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells.

Sivasundaram Karnan, Ichiro Hanamura, Akinobu Ota, Lam Quang Vu, Kaori Uchino, Tomohiro Horio, Satsuki Murakami, Shohei Mizuno, Md Lutfur Rahman, Md Wahiduzzaman, Muhammad Nazmul Hasan, Mrityunjoy Biswas, Toshinori Hyodo, Hideaki Ito, Atsushi Suzuki, Hiroyuki Konishi, Shinobu Tsuzuki, Yoshitaka Hosokawa, Akiyoshi Takami.

5' adenosine monophosphate-activated protein kinase-related kinase 5 (ARK5) is involved in mitochondrial ATP production and associated with poor prognosis of multiple myeloma (MM). However, the molecular mechanisms of ARK5 in MM remain largely unknown. This study examined the pathogenic role of ARK5 in mitochondria by using genetically modified isogenic cell clones with or without ARK5 in human myeloma cell lines, KMS-11 and Sachi, which overexpress ARK5. The biallelic knockout of ARK5 (ARK5-KO) inhibited cell proliferation, colony formation, and migration with increased apoptosis. Mitochondrial fusion was enhanced in ARK5-KO cells, unlike in ARK5 wild-type (ARK5-WT) cells, which exhibited increased mitochondrial fission. Furthermore, ARK5-KO cells demonstrated a lower phosphorylated dynamin-related protein 1 at serine 616, higher protein expression of mitofusin-1 (MFN1) and MFN2, optic atrophy 1 with a lower level of ATP, and higher levels of lactate and reactive oxygen species than ARK5-WT cells. Our findings suggest that ARK5-enhanced myeloma cells can survive associated mitochondrial fission and activity. This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.

DOI: https://doi.org/10.1038/s41420-024-01814-w
Biochimie. 2024 Jan 31. pii: S0300-9084(24)00036-1. [Epub ahead of print]

Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.

Alessandro Maria Morelli, Felix Scholkmann.

  The process of cellular respiration occurs for energy production through catabolic reactions, generally with glucose as the first process step. In the present work, we introduce a novel concept for understanding this process, based on our conclusion that glucose metabolism is coupled to the pentose phosphate pathway (PPP) and extra-mitochondrial oxidative phosphorylation in a closed-loop process. According to the current standard model of glycolysis, glucose is first converted to glucose 6-phosphate (glucose 6-P) and then to fructose 6-phosphate, glyceraldehyde 3-phosphate and pyruvate, which then enters the Krebs cycle in the mitochondria. However, it is more likely that the pyruvate will be converted to lactate. In the PPP, glucose 6-P is branched off from glycolysis and used to produce NADPH and ribulose 5-phosphate (ribulose 5-P). Ribulose 5-P can be converted to fructose 6-P and glyceraldehyde 3-P. In our view, a circular process can take place in which the ribulose 5-P produced by the PPP enters the glycolysis pathway and is then retrogradely converted to glucose 6-P. This process is repeated several times until the complete degradation of glucose 6-P. The role of mitochondria in this process is to degrade lipids by beta-oxidation and produce acetyl-CoA; the function of producing ATP appears to be only secondary. This proposed new concept of cellular bioenergetics allows the resolution of some previously unresolved controversies related to cellular respiration and provides a deeper understanding of metabolic processes in the cell, including a new insights into the Warburg effect.

Keywords:  Cancer metabolism; Cellular respiration; Endoplasmic reticulum; Extra-mitochondrial OXPHOS; Glycolysis; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.biochi.2024.01.018
Nat Commun. 2024 Feb 01. 15(1): 963

Nuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma.

Anja Deutzmann, Delaney K Sullivan, Renumathy Dhanasekaran, Wei Li, Xinyu Chen, Ling Tong, Wadie D Mahauad-Fernandez, John Bell, Adriane Mosley, Angela N Koehler, Yulin Li, Dean W Felsher.

The MYC oncogene is often dysregulated in human cancer, including hepatocellular carcinoma (HCC). MYC is considered undruggable to date. Here, we comprehensively identify genes essential for survival of MYChigh but not MYClow cells by a CRISPR/Cas9 genome-wide screen in a MYC-conditional HCC model. Our screen uncovers novel MYC synthetic lethal (MYC-SL) interactions and identifies most MYC-SL genes described previously. In particular, the screen reveals nucleocytoplasmic transport to be a MYC-SL interaction. We show that the majority of MYC-SL nucleocytoplasmic transport genes are upregulated in MYChigh murine HCC and are associated with poor survival in HCC patients. Inhibiting Exportin-1 (XPO1) in vivo induces marked tumor regression in an autochthonous MYC-transgenic HCC model and inhibits tumor growth in HCC patient-derived xenografts. XPO1 expression is associated with poor prognosis only in HCC patients with high MYC activity. We infer that MYC may generally regulate and require altered expression of nucleocytoplasmic transport genes for tumorigenesis.

DOI: https://doi.org/10.1038/s41467-024-45128-y
Free Radic Biol Med. 2024 Jan 26. pii: S0891-5849(24)00036-4. [Epub ahead of print]213 327-342

Enhancement of de novo lipogenesis by the IDH1 and IDH2-dependent reverse TCA cycle maintains the growth and angiogenic capacity of bone marrow-derived endothelial progenitor cells under hypoxia.

Qiwei He, Tiantian Yu, Junxiong Chen, Jianli Liang, Dongni Lin, Kaihao Yan, Zijing Xie, Yuqi Song, Zhenzhou Chen.

   BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) play a dynamic role in maintaining the structure and function of blood vessels. But how these cells maintain their growth and angiogenic capacity under bone marrow hypoxic niche is still unclear. This study aims to explore the mechanisms from a perspective of cellular metabolism.
METHODS: XFe96 Extracellular Flux Analyzer was used to analyze the metabolic status of EPCs. Gas Chromatography-Mass Spectrometry (GC-MS) was used to trace the carbon movement of 13C-labeled glucose and glutamine under 1 % O2 (hypoxia) and ∼20 % O2 (normoxia). Moreover, RNA interference, targeting isocitrate dehydrogenase-1 (IDH1) and IDH2, was used to inhibit the reverse tricarboxylic acid (TCA) cycle and analyze metabolic changes via isotope tracing as well as changes in cell growth and angiogenic potential under hypoxia. The therapeutic potential of EPCs under hypoxia was investigated in the ischemic hindlimb model.
RESULTS: Compared with normoxic cells, hypoxic cells showed increased glycolysis and decreased mitochondrial respiration. Isotope metabolic tracing revealed that under hypoxia, the forward TCA cycle was decreased and the reverse TCA cycle was enhanced, mediating the conversion of α-ketoglutarate (α-KG) into isocitrate/citrate, and de novo lipid synthesis was promoted. Downregulation of IDH1 or IDH2 under hypoxia suppressed the reverse TCA cycle, attenuated de novo lipid synthesis (DNL), elevated α-KG levels, and decreased the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA), eventually inhibiting the growth and angiogenic capacity of EPCs. Importantly, the transplantation of hypoxia-cultured EPCs in a mouse model of limb ischemia promoted new blood vessel regeneration and blood supply recovery in the ischemic area better than the transplantation of normoxia-cultured EPCs.
CONCLUSIONS: Under hypoxia, the IDH1- and IDH2-mediated reverse TCA cycle promotes glutamine-derived de novo lipogenesis and stabilizes the expression of α-KG and HIF-1α, thereby enhancing the growth and angiogenic capacity of EPCs.

Keywords:  Endothelial progenitor cells; HIF-1α; Hypoxia; Lipid synthesis; Reverse TCA cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.028
EMBO J. 2024 Jan 29.

Optineurin provides a mitophagy contact site for TBK1 activation.

Koji Yamano, Momoha Sawada, Reika Kikuchi, Kafu Nagataki, Waka Kojima, Ryu Endo, Hiroki Kinefuchi, Atsushi Sugihara, Tomoshige Fujino, Aiko Watanabe, Keiji Tanaka, Gosuke Hayashi, Hiroshi Murakami, Noriyuki Matsuda.

  Tank-binding kinase 1 (TBK1) is a Ser/Thr kinase that is involved in many intracellular processes, such as innate immunity, cell cycle, and apoptosis. TBK1 is also important for phosphorylating the autophagy adaptors that mediate the selective autophagic removal of damaged mitochondria. However, the mechanism by which PINK1-Parkin-mediated mitophagy activates TBK1 remains largely unknown. Here, we show that the autophagy adaptor optineurin (OPTN) provides a unique platform for TBK1 activation. Both the OPTN-ubiquitin and the OPTN-pre-autophagosomal structure (PAS) interaction axes facilitate assembly of the OPTN-TBK1 complex at a contact sites between damaged mitochondria and the autophagosome formation sites. At this assembly point, a positive feedback loop for TBK1 activation is initiated that accelerates hetero-autophosphorylation of the protein. Expression of monobodies engineered here to bind OPTN impaired OPTN accumulation at contact sites, as well as the subsequent activation of TBK1, thereby inhibiting mitochondrial degradation. Taken together, these data show that a positive and reciprocal relationship between OPTN and TBK1 initiates autophagosome biogenesis on damaged mitochondria.

Keywords:  Autophagy; Mitochondria; PINK1; Parkin; Ubiquitin

DOI:  https://doi.org/10.1038/s44318-024-00036-1
Nat Commun. 2024 Jan 27. 15(1): 828

Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion.

Rani Pallavi, Elena Gatti, Tiphanie Durfort, Massimo Stendardo, Roberto Ravasio, Tommaso Leonardi, Paolo Falvo, Bruno Achutti Duso, Simona Punzi, Aobuli Xieraili, Andrea Polazzi, Doriana Verrelli, Deborah Trastulli, Simona Ronzoni, Simone Frascolla, Giulia Perticari, Mohamed Elgendy, Mario Varasi, Emanuela Colombo, Marco Giorgio, Luisa Lanfrancone, Saverio Minucci, Luca Mazzarella, Pier Giuseppe Pelicci.

Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR's impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.

DOI: https://doi.org/10.1038/s41467-023-44348-y
Nature. 2024 Jan 31.

7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.

Florencio Porto Freitas, Hamed Alborzinia, Ancély Ferreira Dos Santos, Palina Nepachalovich, Lohans Pedrera, Omkar Zilka, Alex Inague, Corinna Klein, Nesrine Aroua, Kamini Kaushal, Bettina Kast, Svenja M Lorenz, Viktoria Kunz, Helene Nehring, Thamara N Xavier da Silva, Zhiyi Chen, Sena Atici, Sebastian G Doll, Emily L Schaefer, Ifedapo Ekpo, Werner Schmitz, Aline Horling, Peter Imming, Sayuri Miyamoto, Ann M Wehman, Thiago C Genaro-Mattos, Karoly Mirnics, Lokender Kumar, Judith Klein-Seetharaman, Svenja Meierjohann, Isabel Weigand, Matthias Kroiss, Georg W Bornkamm, Fernando Gomes, Luis Eduardo Soares Netto, Manjima B Sathian, David B Konrad, Douglas F Covey, Bernhard Michalke, Kurt Bommert, Ralf C Bargou, Ana Garcia-Saez, Derek A Pratt, Maria Fedorova, Andreas Trumpp, Marcus Conrad, José Pedro Friedmann Angeli.

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation that tumours exploit to counteract phospholipid oxidation1,2. Here, we identify proferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected prosurvival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high concentrations of 7-DHC are cytotoxic to developing neurons by favouring lipid peroxidation3, we now show that 7-DHC accumulation confers a robust prosurvival function in cancer cells. Because of its far superior reactivity towards peroxyl radicals, 7-DHC effectively shields (phospho)lipids from autoxidation and subsequent fragmentation. We provide validation in neuroblastoma and Burkitt's lymphoma xenografts where we demonstrate that the accumulation of 7-DHC is capable of inducing a shift towards a ferroptosis-resistant state in these tumours ultimately resulting in a more aggressive phenotype. Conclusively, our findings provide compelling evidence of a yet-unrecognized antiferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

DOI: https://doi.org/10.1038/s41586-023-06878-9
J Clin Invest. 2024 Feb 01. pii: e176736. [Epub ahead of print]134(3):

Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials.

Karthik Vasan, Navdeep S Chandel.

DOI: https://doi.org/10.1172/JCI176736
Nat Commun. 2024 Feb 02. 15(1): 988

Rescue of mitochondrial import failure by intercellular organellar transfer.

Hope I Needs, Emily Glover, Gonçalo C Pereira, Alina Witt, Wolfgang Hübner, Mark P Dodding, Jeremy M Henley, Ian Collinson.

Mitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell's energy supplies - particularly troublesome for energy-demanding cells of nervous tissue and muscle. Unsurprisingly then, import breakdown is implicated in disease. Here, we explore the consequences of import failure in mammalian cells; wherein, blocking the import machinery impacts mitochondrial ultra-structure and dynamics, but, surprisingly, does not affect import. Our data are consistent with a response involving intercellular mitochondrial transport via tunnelling nanotubes to import healthy mitochondria and jettison those with blocked import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-024-45283-2