bims-mibica 2024-09-01 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–09–01
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial membrane lipids in the regulation of bioenergetic flux.
Lactate helps cancer cells resist chemotherapy.
Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.
Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia.
Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.
Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.
ATP synthase as a negative regulator versus a functional-structural component of the high conductance state of mitochondrial permeability transition pore.
Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.
Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells.
Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.
Establishment of a prognostic model for pancreatic cancer based on mitochondrial metabolism related genes.
MitoTam induces ferroptosis and increases radiosensitivity in head and neck cancer cells.
Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.
P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.
Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.
A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.
6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells.
Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.
Insights into metabolic heterogeneity of colorectal cancer gained from fluorescence lifetime imaging.
BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.
MTCH2 promotes the malignant progression of ovarian cancer through the upregulation of AIMP2 expression levels, mitochondrial dysfunction and by mediating energy metabolism.

Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]

Mitochondrial membrane lipids in the regulation of bioenergetic flux.

Stephen Thomas Decker, Katsuhiko Funai.

  Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.

Keywords:  bioenergetics; mitochondria; phospholipids

DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
Nature. 2024 Aug 23.

Lactate helps cancer cells resist chemotherapy.



Keywords:  Cancer; Metabolism

DOI:  https://doi.org/10.1038/d41586-024-02731-9
Biol Direct. 2024 Aug 24. 19(1): 73

Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.

Ziqi Guo, Yaping Liu, Xin Li, Yuying Huang, Zuping Zhou, Cheng Yang.

  Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.

Keywords:  2-DG; Glycolysis; Hematopoietic stem cells; Lung cancer; Metabolic reprogramming; Oxidative phosphorylation; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13062-024-00514-w
iScience. 2024 Aug 16. 27(8): 110560

Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.

Kristýna Čunátová, Marek Vrbacký, Guillermo Puertas-Frias, Lukáš Alán, Marie Vanišová, María José Saucedo-Rodríguez, Josef Houštěk, Erika Fernández-Vizarra, Jiří Neužil, Alena Pecinová, Petr Pecina, Tomáš Mráček.

  Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.

Keywords:  Biochemistry; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110560
Leuk Res. 2024 Aug 22. pii: S0145-2126(24)00134-6. [Epub ahead of print]145 107568

Evolution of transcriptomic profiles in relapsed inv(16) acute myeloid leukemia.

Serena Travaglini, Giorgia Silvestrini, Enrico Attardi, Maurizio Fanciulli, Stefano Scalera, Silvia Antonelli, Luca Maurillo, Raffaele Palmieri, Mariadomenica Divona, Ludovica Ciuffreda, Arianna Savi, Giovangiacinto Paterno, Tiziana Ottone, Caterina Barbieri, Jaroslaw P Maciejewski, Carmelo Gurnari, Gennaro Ciliberto, Maria Teresa Voso.

  Acute myeloid leukemia (AML) with inv(16) is typically associated with a favourable prognosis. However, up to 40 % of patients will eventually experience disease relapse. Herein, we dissected the genomic and transcriptomic profile of inv(16) AML to identify potential prognostic markers and therapeutic vulnerabilities. Sequencing data from 222 diagnostic samples, including 44 relapse/refractory patients, revealed a median of 1 concomitant additional mutation, cooperating with inv(16) in leukemogenesis. Notably, the mutational landscape at diagnosis did not differ significantly between patients experiencing primary induction failure or relapse when compared to the rest of the cohort, except for an increase in the mutational burden in the relapse/refractory group. RNA-Seq of unpaired diagnostic(n=7) and relapse(n=6) samples allowed the identification of oxidative phosphorylation (OXPHOS) as one of the most significantly downregulated pathways at relapse. Considering that OXPHOS could be targeted by Venetoclax/Azacitidine combination, we explored its biological effects on an inv(16) cell-line ME-1, but there was no additional advantage in terms of cell death over Azacitidine alone. To enhance Venetoclax efficacy, we tested in vitro effects of Metformin as a potential drug able to enhance chemosensitivity of AML cells by inhibiting the mitochondrial transfer. By challenging ME-1 with this combination, we observed a significant synergistic interaction at least similar to that of Venetoclax/Azacitidine. In conclusions, we identified a downregulated expression of oxidative phosphorylation (OXPHOS) at relapse in AML with inv(16), and explored the in vitro effects of metformin as a potential drug to enhance chemosensitivity in this setting.

Keywords:  Acute myeloid leukemia; Core binding factor; Metformin; OXPHOS; Venetoclax

DOI:  https://doi.org/10.1016/j.leukres.2024.107568
Biology (Basel). 2024 Aug 21. pii: 639. [Epub ahead of print]13(8):

Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.

Ebrima D Cham, Tsung-I Peng, Mei-Jie Jou.

  According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.

Keywords:  cardiolipin; complex V; high glucose toxicity; mROS; mitochondrial DNA (mtDNA); mitochondrial calcium stress [Ca2+]m; mitochondrial permeability transition pore (MPTP); oxidative stress

DOI:  https://doi.org/10.3390/biology13080639
Front Pharmacol. 2024 ;15 1434988

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Jing Zhang, Wenjuan He, Dongmei Liu, Wenyu Zhang, Huan Qin, Song Zhang, Ailan Cheng, Qiang Li, Feilong Wang.

   Background: It is unknown how cancer cells override apoptosis and maintain progression under nutrition-deprived conditions within the tumor microenvironment. Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting reaction in gluconeogenesis, which is an essential metabolic alteration that is required for the proliferation of cancer cells under glucose-limited conditions. However, if PCK-mediated gluconeogenesis affects apoptotic cell death of non small cell lung cancer (NSCLC) and its potential mechanisms remain unknown.
Methods: RNA-seq, Western blot and RT-PCR were performed in A549 cell lines cultured in medium containing low or high concentrations of glucose (1 mM vs. 20 mM) to gain insight into how cancer cells rewire their metabolism under glucose-restriction conditions. Stable isotope tracing metabolomics technology (LC-MS) was employed to allow precise quantification of metabolic fluxes of the TCA cycle regulated by PCK2. Flow Cytometry was used to assess the rates of early and later apoptosis and mitochondrial ROS in NSCLC cells. Transwell assays and luciferase-based in vivo imaging were used to determine the role of PCK2 in migration and invasion of NSCLC cells. Xenotransplants on BALB/c nude mice to evaluate the effects of PCK2 on tumor growth in vivo. Western blot, Immunohistochemistry and TUNEL assays to evaluate the protein levels of mitochondrial apoptosis.
Results: This study report that the mitochondrial resident PCK (PCK2) is upregulated in dependent of endoplasmic reticulum stress-induced expression of activating transcription factor 4 (ATF4) upon glucose deprivation in NSCLC cells. Further, the study finds that PCK2-mediated metabolism is required to decrease the burden of the TCA cycles and oxidative phosphorylation as well as the production of mitochondrial reactive oxygen species. These metabolic alterations in turn reduce the activation of Caspase9-Caspase3-PARP signal pathway which drives apoptotic cell death. Importantly, silencing PCK2 increases apoptosis of NSCLC cells under low glucose condition and inhibits tumor growth both in vitro and in vivo.
Conclusion: In summary, PCK2-mediated metabolism is an important metabolic adaptation for NSCLC cells to acquire resistance to apoptosis under glucose deprivation.

Keywords:  lung tumorigenesis; metabolic reprogramming; mitochondrial apoptosis; phosphoenolpyruvate carboxykinase 2; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2024.1434988
J Biochem Mol Toxicol. 2024 Sep;38(9): e23821

ATP synthase as a negative regulator versus a functional-structural component of the high conductance state of mitochondrial permeability transition pore.

Salvatore Nesci.

DOI: https://doi.org/10.1002/jbt.23821
Nat Commun. 2024 Aug 29. 15(1): 7463

Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.

Rong-Hsuan Wang, Pin-Ru Chen, Yue-Ting Chen, Yi-Chang Chen, Yu-Hsin Chu, Chia-Chen Chien, Po-Chen Chien, Shao-Yun Lo, Zhong-Liang Wang, Min-Chen Tsou, Ssu-Yu Chen, Guang-Shen Chiu, Wen-Ling Chen, Yi-Hsuan Wu, Lily Hui-Ching Wang, Wen-Ching Wang, Shu-Yi Lin, Hsing-Jien Kung, Lu-Hai Wang, Hui-Chun Cheng, Kai-Ti Lin.

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.

DOI: https://doi.org/10.1038/s41467-024-51875-9
J Transl Med. 2024 Aug 28. 22(1): 797

Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells.

Marta Mascaraque, Sarah Courtois, Alba Royo-García, David Barneda, Andrei M Stoian, Isabel Villaoslada, Pilar Espiau-Romera, Ansooya Bokil, Andrés Cano-Galiano, Petra Jagust, Christopher Heeschen, Patricia Sancho.

   BACKGROUND: We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression.
METHODS & RESULTS: Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality.
CONCLUSION: Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.

Keywords:  Cancer stem cells; Chemoresistance; Fatty acid; Lipid metabolism; Oxidative phosphorylation; Pancreatic cancer

DOI:  https://doi.org/10.1186/s12967-024-05598-6
Leukemia. 2024 Aug 26.

Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation.

Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C James, Samantha Atkinson, Jozef Durko, Lydia M Wang, Joana Campos, Aoife M S Magee, Keith Woodley, Michael J Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A Copland Iii, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli.

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

DOI: https://doi.org/10.1038/s41375-024-02390-9
Discov Oncol. 2024 Aug 28. 15(1): 376

Establishment of a prognostic model for pancreatic cancer based on mitochondrial metabolism related genes.

Qinwen Ba, Xiong Wang, Yanjun Lu.

   AIM: Pancreatic ductal adenocarcinoma (PAAD) is recognized as an exceptionally aggressive cancer that both highly lethal and unfavorable prognosis. The mitochondrial metabolism pathway is intimately involved in oncogenesis and tumor progression, however, much remains unknown in this area. In this study, the bioinformatic tools have been used to construct a prognostic model with mitochondrial metabolism-related genes (MMRGs) to evaluate the survival, immune status, mutation profile, and drug sensitivity of PAAD patients.
METHOD: Univariate Cox regression and LASSO regression were used to screen the differentially expressed genes (DEGs), and multivariate Cox regression was used to develop the risk model. Kaplan-Meier estimator was employed to identify MMRGs signatures associated with overall survival (OS). ROC curves were utilized to evaluate the model's performance. Maftools, immunedeconv and CIBERSORT R packages were applied to analyze the gene mutation profiles and immune status. The corresponding sensitivity to pharmaceutical agents was assessed using oncoPredict R packages.
RESULTS: A prognostic model with five MMRGs was developed, which defined the patients as high-risk showed lower survival rates. There was good consistency among individuals categorized as high-risk, showing elevated rates of genetic alterations, particularly in the TP53 and KRAS genes. Furthermore, these patients exhibited increased levels of immunosuppression, characterized by an increased presence of macrophages, neutrophils, Th2 cells, and regulatory T cells. Additionally, high-risk patients showed increased sensitivity to Sabutoclax and Venetoclax.
CONCLUSION: By utilizing a gene signature associated with mitochondrial metabolism, a prognostic model has been established which could be a highly efficient method for predicting the outcomes of PAAD patients.

Keywords:  Bioinformatic; Mitochondrial metabolism related genes; Pancreatic ductal adenocarcinoma; Risk model

DOI:  https://doi.org/10.1007/s12672-024-01255-y
Radiother Oncol. 2024 Aug 24. pii: S0167-8140(24)00773-4. [Epub ahead of print]200 110503

MitoTam induces ferroptosis and increases radiosensitivity in head and neck cancer cells.

F V Reinema, N Hudson, G J Adema, W J M Peeters, J Neuzil, J Stursa, L Werner, F C G J Sweep, J Bussink, P N Span.

   BACKGROUND AND PURPOSE: Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT.
MATERIALS AND METHODS: We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment.
RESULTS: Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone.
CONCLUSION: MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers.
STATEMENT OF SIGNIFICANCE: Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy.

Keywords:  Antioxidants; Ferroptosis; Head and neck cancer; MitoTam; ROS; Radioresistance; Radiosensitivity; Radiosensitization

DOI:  https://doi.org/10.1016/j.radonc.2024.110503
Nat Commun. 2024 Aug 27. 15(1): 7352

Infection-induced peripheral mitochondria fission drives ER encapsulations and inter-mitochondria contacts that rescue bioenergetics.

William A Hofstadter, Katelyn C Cook, Elene Tsopurashvili, Robert Gebauer, Vojtěch Pražák, Emily A Machala, Ji Woo Park, Kay Grünewald, Emmanuelle R J Quemin, Ileana M Cristea.

The dynamic regulation of mitochondria shape via fission and fusion is critical for cellular responses to stimuli. In homeostatic cells, two modes of mitochondrial fission, midzone and peripheral, provide a decision fork between either proliferation or clearance of mitochondria. However, the relationship between specific mitochondria shapes and functions remains unclear in many biological contexts. While commonly associated with decreased bioenergetics, fragmented mitochondria paradoxically exhibit elevated respiration in several disease states, including infection with the prevalent pathogen human cytomegalovirus (HCMV) and metastatic melanoma. Here, incorporating super-resolution microscopy with mass spectrometry and metabolic assays, we use HCMV infection to establish a molecular mechanism for maintaining respiration within a fragmented mitochondria population. We establish that HCMV induces fragmentation through peripheral mitochondrial fission coupled with suppression of mitochondria fusion. Unlike uninfected cells, the progeny of peripheral fission enter mitochondria-ER encapsulations (MENCs) where they are protected from degradation and bioenergetically stabilized during infection. MENCs also stabilize pro-viral inter-mitochondria contacts (IMCs), which electrochemically link mitochondria and promote respiration. Demonstrating a broader relevance, we show that the fragmented mitochondria within metastatic melanoma cells also form MENCs. Our findings establish a mechanism where mitochondria fragmentation can promote increased respiration, a feature relevant in the context of human diseases.

DOI: https://doi.org/10.1038/s41467-024-51680-4
Nat Commun. 2024 Aug 28. 15(1): 7458

P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.

Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.

DOI: https://doi.org/10.1038/s41467-024-51901-w
Cell Stem Cell. 2024 Aug 21. pii: S1934-5909(24)00285-6. [Epub ahead of print]

Mitochondrial serine catabolism safeguards maintenance of the hematopoietic stem cell pool in homeostasis and injury.

Changhong Du, Chaonan Liu, Kuan Yu, Shuzhen Zhang, Zeyu Fu, Xinliang Chen, Weinian Liao, Jun Chen, Yimin Zhang, Xinmiao Wang, Mo Chen, Fang Chen, Mingqiang Shen, Cheng Wang, Shilei Chen, Song Wang, Junping Wang.

  Hematopoietic stem cells (HSCs) employ a very unique metabolic pattern to maintain themselves, while the spectrum of their metabolic adaptations remains incompletely understood. Here, we uncover a distinct and heterogeneous serine metabolism within HSCs and identify mouse HSCs as a serine auxotroph whose maintenance relies on exogenous serine and the ensuing mitochondrial serine catabolism driven by the hydroxymethyltransferase 2 (SHMT2)-methylene-tetrahydrofolate dehydrogenase 2 (MTHFD2) axis. Mitochondrial serine catabolism primarily feeds NAD(P)H generation to maintain redox balance and thereby diminishes ferroptosis susceptibility of HSCs. Dietary serine deficiency, or genetic or pharmacological inhibition of the SHMT2-MTHFD2 axis, increases ferroptosis susceptibility of HSCs, leading to impaired maintenance of the HSC pool. Moreover, exogenous serine protects HSCs from irradiation-induced myelosuppressive injury by fueling mitochondrial serine catabolism to mitigate ferroptosis. These findings reframe the canonical view of serine from a nonessential amino acid to an essential niche metabolite for HSC pool maintenance.

Keywords:  NADPH; SHMT2; ferroptosis; hematopoietic stem cell; heterogeneity; ionizing radiation; mitochondrial serine catabolism; myelosuppressive injury

DOI:  https://doi.org/10.1016/j.stem.2024.07.009
Cell Death Dis. 2024 Aug 27. 15(8): 626

Drp1 depletion protects against ferroptotic cell death by preserving mitochondrial integrity and redox homeostasis.

Stephan Tang, Anneke Fuß, Zohreh Fattahi, Carsten Culmsee.

Mitochondria are highly dynamic organelles which undergo constant fusion and fission as part of the mitochondrial quality control. In genetic diseases and age-related neurodegenerative disorders, altered mitochondrial fission-fusion dynamics have been linked to impaired mitochondrial quality control, disrupted organelle integrity and function, thereby promoting neural dysfunction and death. The key enzyme regulating mitochondrial fission is the GTPase Dynamin-related Protein 1 (Drp1), which is also considered as a key player in mitochondrial pathways of regulated cell death. In particular, increasing evidence suggests a role for impaired mitochondrial dynamics and integrity in ferroptosis, which is an iron-dependent oxidative cell death pathway with relevance in neurodegeneration. In this study, we demonstrate that CRISPR/Cas9-mediated genetic depletion of Drp1 exerted protective effects against oxidative cell death by ferroptosis through preserved mitochondrial integrity and maintained redox homeostasis. Knockout of Drp1 resulted in mitochondrial elongation, attenuated ferroptosis-mediated impairment of mitochondrial membrane potential, and stabilized iron trafficking and intracellular iron storage. In addition, Drp1 deficiency exerted metabolic effects, with reduced basal and maximal mitochondrial respiration and a metabolic shift towards glycolysis. These metabolic effects further alleviated the mitochondrial contribution to detrimental ROS production thereby significantly enhancing neural cell resilience against ferroptosis. Taken together, this study highlights the key role of Drp1 in mitochondrial pathways of ferroptosis and expose the regulator of mitochondrial dynamics as a potential therapeutic target in neurological diseases involving oxidative dysregulation.

DOI: https://doi.org/10.1038/s41419-024-07015-8
J Med Chem. 2024 Aug 27.

A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.

Sadhan Jana, Jialin Shang, Jun Young Hong, Michael K Fenwick, Rishi Puri, Xuan Lu, Ari M Melnick, Meng Li, Hening Lin.

Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.

DOI: https://doi.org/10.1021/acs.jmedchem.4c01053
Cancer Lett. 2024 Aug 22. pii: S0304-3835(24)00572-X. [Epub ahead of print]601 217177

6-Phosphogluconate dehydrogenase promotes glycolysis and fatty acid synthesis by inhibiting the AMPK pathway in lung adenocarcinoma cells.

Jun Wu, Yong Chen, Hui Zou, Kaiyue Xu, Jiaqi Hou, Mengmeng Wang, Shuyu Tian, Mingjun Gao, Qinglin Ren, Chao Sun, Shichun Lu, Qiang Wang, Yusheng Shu, Shouyu Wang, Xiaolin Wang.

  Abnormal metabolism has emerged as a prominent hallmark of cancer and plays a pivotal role in carcinogenesis and progression of lung adenocarcinoma (LUAD). In this study, single-cell sequencing revealed that the metabolic enzyme 6-phosphogluconate dehydrogenase (PGD), which is a critical regulator of the pentose phosphate pathway (PPP), is significantly upregulated in the malignant epithelial cell subpopulation during malignant progression. However, the precise functional significance of PGD in LUAD and its underlying mechanisms remain elusive. Through the integration of TCGA database analysis and LUAD tissue microarray data, it was found that PGD expression was significantly upregulated in LUAD and closely correlated with a poor prognosis in LUAD patients. Moreover, in vitro and in vivo analyses demonstrated that PGD knockout and inhibition of its activity mitigated the proliferation, migration, and invasion of LUAD cells. Mechanistically, immunoprecipitation-mass spectrometry (IP-MS) revealed for the first time that IQGAP1 is a robust novel interacting protein of PGD. PGD decreased p-AMPK levels by competitively interacting with the IQ domain of the known AMPKα binding partner IQGAP1, which promoted glycolysis and fatty acid synthesis in LUAD cells. Furthermore, we demonstrated that the combination of Physcion (a PGD-specific inhibitor) and metformin (an AMPK agonist) could inhibit tumor growth more effectively both in vivo and in vitro. Collectively, these findings suggest that PGD is a potential prognostic biomarker and therapeutic target for LUAD.

Keywords:  6-Phosphogluconate dehydrogenase; AMPK pathway; Lung adenocarcinoma; Pentose phosphate pathway; Single-cell sequencing

DOI:  https://doi.org/10.1016/j.canlet.2024.217177
EMBO Rep. 2024 Aug 27.

Drp1 splice variants regulate ovarian cancer mitochondrial dynamics and tumor progression.

Zaineb Javed, Dong Hui Shin, Weihua Pan, Sierra R White, Amal Taher Elhaw, Yeon Soo Kim, Shriya Kamlapurkar, Ya-Yun Cheng, J Cory Benson, Ahmed Emam Abdelnaby, Rébécca Phaëton, Hong-Gang Wang, Shengyu Yang, Mara L G Sullivan, Claudette M St Croix, Simon C Watkins, Steven J Mullett, Stacy L Gelhaus, Nam Lee, Lan G Coffman, Katherine M Aird, Mohamed Trebak, Karthikeyan Mythreye, Vonn Walter, Nadine Hempel.

  Aberrant mitochondrial fission/fusion dynamics are frequently associated with pathologies, including cancer. We show that alternative splice variants of the fission protein Drp1 (DNM1L) contribute to the complexity of mitochondrial fission/fusion regulation in tumor cells. High tumor expression of the Drp1 alternative splice variant lacking exon 16 relative to other transcripts is associated with poor outcome in ovarian cancer patients. Lack of exon 16 results in Drp1 localization to microtubules and decreased association with mitochondrial fission sites, culminating in fused mitochondrial networks, enhanced respiration, changes in metabolism, and enhanced pro-tumorigenic phenotypes in vitro and in vivo. These effects are inhibited by siRNAs designed to specifically target the endogenously expressed transcript lacking exon 16. Moreover, lack of exon 16 abrogates mitochondrial fission in response to pro-apoptotic stimuli and leads to decreased sensitivity to chemotherapeutics. These data emphasize the pathophysiological importance of Drp1 alternative splicing, highlight the divergent functions and consequences of changing the relative expression of Drp1 splice variants in tumor cells, and strongly warrant consideration of alternative splicing in future studies focused on Drp1.

Keywords:   DNM1L ; Alternative Splice Variants; Drp1; Mitochondrial Fission; Ovarian Cancer

DOI:  https://doi.org/10.1038/s44319-024-00232-4
Elife. 2024 Aug 28. pii: RP94438. [Epub ahead of print]13

Insights into metabolic heterogeneity of colorectal cancer gained from fluorescence lifetime imaging.

Anastasia D Komarova, Snezhana D Sinyushkina, Ilia D Shchechkin, Irina N Druzhkova, Sofia A Smirnova, Vitaliy M Terekhov, Artem M Mozherov, Nadezhda I Ignatova, Elena E Nikonova, Evgeny A Shirshin, Liubov E Shimolina, Sergey V Gamayunov, Vladislav I Shcheslavskiy, Marina V Shirmanova.

  Heterogeneity of tumor metabolism is an important, but still poorly understood aspect of tumor biology. Present work is focused on the visualization and quantification of cellular metabolic heterogeneity of colorectal cancer using fluorescence lifetime imaging (FLIM) of redox cofactor NAD(P)H. FLIM-microscopy of NAD(P)H was performed in vitro in four cancer cell lines (HT29, HCT116, CaCo2 and CT26), in vivo in the four types of colorectal tumors in mice and ex vivo in patients' tumor samples. The dispersion and bimodality of the decay parameters were evaluated to quantify the intercellular metabolic heterogeneity. Our results demonstrate that patients' colorectal tumors have significantly higher heterogeneity of energy metabolism compared with cultured cells and tumor xenografts, which was displayed as a wider and frequently bimodal distribution of a contribution of a free (glycolytic) fraction of NAD(P)H within a sample. Among patients' tumors, the dispersion was larger in the high-grade and early stage ones, without, however, any association with bimodality. These results indicate that cell-level metabolic heterogeneity assessed from NAD(P)H FLIM has a potential to become a clinical prognostic factor.

Keywords:  NAD(P)H; autofluorescence; cancer biology; colorectal adenocarcinoma; fluorescence lifetime imaging; human; medicine; metabolic heterogeneity; mouse; tumor metabolism

DOI:  https://doi.org/10.7554/eLife.94438
Nat Cancer. 2024 Aug 23.

BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models.

Ulrike Rauh, Guo Wei, Michael Serrano-Wu, Georgios Kosmidis, Stefan Kaulfuss, Franziska Siegel, Kai Thede, James McFarland, Christopher T Lemke, Nicolas Werbeck, Katrin Nowak-Reppel, Sabine Pilari, Stephan Menz, Matthias Ocker, Weiqun Zhang, Kyle Davis, Guillaume Poncet-Montange, Jennifer Roth, Douglas Daniels, Virendar K Kaushik, Brian Hubbard, Karl Ziegelbauer, Todd R Golub.

The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to the current standard of care. Therefore, MCL1 is an attractive anticancer target. Here we describe BRD-810 as a potent and selective MCL1 inhibitor and its key design principle of rapid systemic clearance to potentially minimize area under the curve-driven toxicities associated with MCL1 inhibition. BRD-810 induced rapid cell killing within 4 h in vitro but, in the same 4-h window, had no impact on cell viability or troponin I release in human induced pluripotent stem cell-derived cardiomyocytes, even at suprapharmacologic concentrations. In vivo BRD-810 induced efficacy in xenograft hematological and solid tumor models despite the short residence time of BRD-810 in plasma. In totality, our data support the hypothesis that short-term inhibition of MCL1 with BRD-810 can induce apoptosis in tumor cells while maintaining an acceptable safety profile. We, therefore, intend to advance BRD-810 to clinical trials.

DOI: https://doi.org/10.1038/s43018-024-00814-0
Oncol Lett. 2024 Oct;28(4): 492

MTCH2 promotes the malignant progression of ovarian cancer through the upregulation of AIMP2 expression levels, mitochondrial dysfunction and by mediating energy metabolism.

Guangyu Sun, Yanmin Song, Congxian Li, Bo Sun, Chengcheng Li, Jinbao Sun, Ping Xiao, Zhengmao Zhang.

  Ovarian cancer (OC) is a gynecological malignancy that ranks among the most common female cancers worldwide and notably reduces a patient's quality of life. Mitochondrial carrier homology 2 (MTCH2) is a mitochondrial outer membrane protein that serves a regulatory role in mitochondrial metabolism and cell death. The precise contribution and underlying molecular pathways of MTCH2 in the context of OC development is currently unclear. The present study aimed to investigate the roles of MTCH2 in the energy metabolism, cell proliferation and metastatic potential of OC cells and evaluate the regulatory relationship between MTCH2, aminoacyl transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2) and claudin-3. An analysis of 67 patients with high-grade serous OC demonstrated increased expression levels of MTCH2, AIMP2 and claudin-3 in OC tumor tissue samples compared with in corresponding normal tissues adjacent to OC tissue samples. MTCH2 overexpression was significantly associated with the International Federation of Gynecology and Obstetrics stage and tumor differentiation of the OC tumor samples. In vitro experiments using the SK-OV-3 OC cell line demonstrated that MTCH2 exerts a regulatory effect on the cell proliferation, invasion and migratory capabilities of these cells. Knockdown of MTCH2 reduced ATP production, induced mitochondrial dysfunction and promoted cytoskeleton remodeling and apoptosis in SK-OV-3 OC cells. In addition, MTCH2 knockdown downregulated the expression levels of both claudin-3 and AIMP2 proteins. Knockdown of AIMP2 inhibited the regulatory effect of MTCH2. Co-immunoprecipitation experiments demonstrated that MTCH2 interacts with AIMP2 and claudin-3. The present study provides novel insights into the treatment of OC metastasis, as MTCH2 was demonstrated to serve roles in the progression of OC cells through the regulation of claudin-3 via AIMP2, which could provide novel insights into the treatment of ovarian cancer metastasis.

Keywords:  aminoacyl transfer RNA synthetase-interacting multifunctional protein 2; claudin-3; mitochondrial carrier homology 2; mitochondrial dysfunction; ovarian cancer

DOI:  https://doi.org/10.3892/ol.2024.14625