bims-mibica 2024-12-29 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–12–29
twenty-one papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.
Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
BH3 Mimetics Augment Cytotoxic T Cell Killing of Acute Myeloid Leukemia via Mitochondrial Apoptotic Mechanism.
Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.
Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.
Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.
Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.
Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents.
Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification.
Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.
Mitochondria-targeted antioxidant MitoQ radiosensitizes tumors by decreasing mitochondrial oxygen consumption.
SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8.
A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.
The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.
Single Cell Sequencing Traces Mitochondrial Transfers.
GANT61 surmounts drug resistance of ADR by upregulating lysosome activities and reducing BCL2 expression in HL-60/ADR cells.
Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.
Menin inhibitors in the treatment of acute myeloid leukemia.

bioRxiv. 2024 Nov 22. pii: 2024.11.20.624567. [Epub ahead of print]

Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival.

Monika Komza, Jesminara Khatun, Jesse D Gelles, Andrew P Trotta, Ioana Abraham-Enachescu, Juan Henao, Ahmed Elsaadi, Andriana G Kotini, Cara Clementelli, JoAnn Arandela, Sebastian El Ghaity-Beckley, Agneesh Barua, Yiyang Chen, Bridget K Marcellino, Eirini P Papapetrou, Masha V Poyurovsky, Jerry Edward Chipuk.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

DOI: https://doi.org/10.1101/2024.11.20.624567
J Cell Biol. 2025 Mar 03. pii: e202403140. [Epub ahead of print]224(3):

Functionally conserved inner mitochondrial membrane proteins CCDC51 and Mdm33 demarcate a subset of fission events.

Alia R Edington, Olivia M Connor, Abigail C Love, Madeleine Marlar-Pavey, Jonathan R Friedman.

While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear whether internal mitochondrial proteins in metazoans play a direct role in the process. Previously, the yeast inner membrane protein Mdm33 was shown to be required for normal mitochondrial morphology and has been hypothesized to be involved in mitochondrial fission. However, it is unknown whether Mdm33 plays a direct role, and it is not thought to have a mammalian homolog. Here, we use a bioinformatic approach to identify a structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK), whose depletion phenocopies loss of Mdm33. We find that knockdown of CCDC51 also leads to reduced rates of mitochondrial fission. Further, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 overexpression promotes its spatial association with Drp1 and induces mitochondrial fragmentation, suggesting it is a positive effector of mitochondrial fission. Together, our data reveal that Mdm33 and CCDC51 are functionally conserved and suggest that internal mitochondrial proteins are directly involved in at least a subset of mitochondrial fission events in human cells.

DOI: https://doi.org/10.1083/jcb.202403140
Cell Death Differ. 2024 Dec 21.

Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.

Fleur Jochems, Chrysiida Baltira, Julie A MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards.

Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.

DOI: https://doi.org/10.1038/s41418-024-01439-7
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Res Sq. 2024 Dec 09. pii: rs.3.rs-5307127. [Epub ahead of print]

BH3 Mimetics Augment Cytotoxic T Cell Killing of Acute Myeloid Leukemia via Mitochondrial Apoptotic Mechanism.

Cassian Yee, Kapil Saxena, Esther Ryu, Shao-Hsi Hung, Shailbala Singh, Qi Zhang, Zhihong Zeng, Zhe Wang, Marina Konopleva.

Adoptive cell therapy (ACT) can address an unmet clinical need for patients with relapsed/refractory acute myeloid leukemia (AML), but its effect is often modest in the setting of high tumor burden. In this study, we postulated that strategies to lower the AML apoptotic threshold will augment T cell killing of AML cells. BH3 mimetics, such as venetoclax, are a clinically approved class of compounds that predispose cells to intrinsic apoptosis by inhibiting anti-apoptotic mitochondrial proteins. We explored the anti-leukemic efficacy of BH3 mimetics combined with WT1-specific CD8 + T cells on AML cell lines and primary samples from patients with a diverse array of disease characteristics to evaluate if lowering the cellular apoptotic threshold via inhibition of anti-apoptotic mitochondrial proteins can increase leukemic cell sensitivity to T cell therapy. We found that the combination approach of BH3 mimetic and CD8 + T cells led to significantly increased killing of established AML lines as well as of adverse-risk primary AML leukemic blast cells. In contrast to the hypothesis that enhanced killing would be due to combined activation of the intrinsic and extrinsic apoptotic pathways, we found that CTL-mediated killing of AML cells was accomplished primarily through activation of the intrinsic/mitochondrial apoptotic pathway. This highly effective combinatorial activity due to convergence on the same apoptotic pathway was conserved across multiple AML cell lines and primary samples, suggesting that mitochondrial priming may represent a novel mechanism of optimizing adoptive cell therapy for AML patients.

DOI: https://doi.org/10.21203/rs.3.rs-5307127/v1
Adv Sci (Weinh). 2024 Dec 23. e2404620

Nuclear Control of Mitochondrial Homeostasis and Venetoclax Efficacy in AML via COX4I1.

Leisi Zhang, Honghai Zhang, Ting-Yu Wang, Mingli Li, Anthony K N Chan, Hyunjun Kang, Lai C Foong, Qiao Liu, Sheela Pangeni Pokharel, Nicole M Mattson, Priyanka Singh, Zeinab Elsayed, Benjamin Kuang, Xueer Wang, Steven T Rosen, Jianjun Chen, Lu Yang, Tsui-Fen Chou, Rui Su, Chun-Wei David Chen.

  Cell signaling pathways are enriched for biological processes crucial for cellular communication, response to external stimuli, and metabolism. Here, a cell signaling-focused CRISPR screen identified cytochrome c oxidase subunit 4 isoform 1 (COX4I1) as a novel vulnerability in acute myeloid leukemia (AML). Depletion of COX4I1 hindered leukemia cell proliferation and impacted in vivo AML progression. Mechanistically, loss of COX4I1 induced mitochondrial stress and ferroptosis, disrupting mitochondrial ultrastructure and oxidative phosphorylation. CRISPR gene tiling scans, coupled with mitochondrial proteomics, dissected critical regions within COX4I1 essential for leukemia cell survival, providing detailed insights into the mitochondrial Complex IV assembly network. Furthermore, COX4I1 depletion or pharmacological inhibition of Complex IV (using chlorpromazine) synergized with venetoclax, providing a promising avenue for improved leukemia therapy. This study highlights COX4I1, a nuclear encoded mitochondrial protein, as a critical mitochondrial checkpoint, offering insights into its functional significance and potential clinical implications in AML.

Keywords:  COX4I1; chlorpromazine; leukemia; mitochondria; venetoclax

DOI:  https://doi.org/10.1002/advs.202404620
Res Sq. 2024 Dec 13. pii: rs.3.rs-5494402. [Epub ahead of print]

Restoring Mitochondrial Quantity and Quality to Reverse Warburg Effect and Drive Tumor Differentiation.

Jiangbin Ye, Haowen Jiang, Sarah Tiche, Clifford He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert Li, Anh Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin Svensson, Daniel Cuthbertson, Florette Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu.

Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors, and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the TCA cycle and switching substrate preference from glutamine to glucose. These effects were reversed by ETC inhibitors or in ρ0 cells lacking mtDNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing analysis of the orthotopic xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, which could potentially significantly improve patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.

DOI: https://doi.org/10.21203/rs.3.rs-5494402/v1
Nat Commun. 2024 Dec 23. 15(1): 10719

Preventing excessive autophagy protects from the pathology of mtDNA mutations in Drosophila melanogaster.

Najla El Fissi, Florian A Rosenberger, Kai Chang, Alissa Wilhalm, Tom Barton-Owen, Fynn M Hansen, Zoe Golder, David Alsina, Anna Wedell, Matthias Mann, Patrick F Chinnery, Christoph Freyer, Anna Wredenberg.

Aberration of mitochondrial function is a shared feature of many human pathologies, characterised by changes in metabolic flux, cellular energetics, morphology, composition, and dynamics of the mitochondrial network. While some of these changes serve as compensatory mechanisms to maintain cellular homeostasis, their chronic activation can permanently affect cellular metabolism and signalling, ultimately impairing cell function. Here, we use a Drosophila melanogaster model expressing a proofreading-deficient mtDNA polymerase (POLγexo-) in a genetic screen to find genes that mitigate the harmful accumulation of mtDNA mutations. We identify critical pathways associated with nutrient sensing, insulin signalling, mitochondrial protein import, and autophagy that can rescue the lethal phenotype of the POLγexo- flies. Rescued flies, hemizygous for dilp1, atg2, tim14 or melted, normalise their autophagic flux and proteasome function and adapt their metabolism. Mutation frequencies remain high with the exception of melted-rescued flies, suggesting that melted may act early in development. Treating POLγexo- larvae with the autophagy activator rapamycin aggravates their lethal phenotype, highlighting that excessive autophagy can significantly contribute to the pathophysiology of mitochondrial diseases. Moreover, we show that the nucleation process of autophagy is a critical target for intervention.

DOI: https://doi.org/10.1038/s41467-024-55559-2
Cell Rep Med. 2024 Dec 11. pii: S2666-3791(24)00649-9. [Epub ahead of print] 101878

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

Marjolein M G Kes, Francisco Morales-Rodriguez, Esther A Zaal, Terezinha de Souza, Natalie Proost, Marieke van de Ven, Marry M van den Heuvel-Eibrink, Jeroen W A Jansen, Celia R Berkers, Jarno Drost.

  Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.

Keywords:  DHODH inhibitor; Methotrexate; cancer metabolism; isotope tracing; malignant rhabdoid tumors; metabolomics; nucleotide synthesis; pediatric kidney cancer

DOI:  https://doi.org/10.1016/j.xcrm.2024.101878
Cell Stem Cell. 2024 Dec 12. pii: S1934-5909(24)00413-2. [Epub ahead of print]

Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.

Salma Merchant, Animesh Paul, Amanda Reyes, Daniel Cassidy, Ashley Leach, Dohun Kim, Sarah Muh, Gerik Grabowski, Gerta Hoxhaj, Zhiyu Zhao, Sean J Morrison.

  Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.

Keywords:  aging; fatty acid; hematopoiesis; high-fat diet; metabolic plasticity; metabolism; mitochondria; β-oxidation

DOI:  https://doi.org/10.1016/j.stem.2024.11.014
Sci Rep. 2024 Dec 28. 14(1): 30767

Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents.

Stephanie Tan, Sujin Kim, Yoosik Kim.

  Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) and endogenous double-stranded RNAs (dsRNAs) that limit tumor growth and trigger apoptosis via viral mimicry. Yet, HMAs show limited effects in many solid tumors despite the strong induction of TSGs and dsRNAs. Here we show that targeting mitochondrial RNAs (mtRNAs) can enhance the HMA-mediated cell death in lung adenocarcinoma cells. We find that HMA treatment accompanies increased mtRNA levels and subsequent enhancement of metabolic activity, resulting in higher ATP production. Compromising the mitochondrial function by downregulating mature mtRNA expression increased cell death by HMAs. We further perform a CRISPR screening on mtRNA processing factors and find that mtRNA polymerase (POLRMT) and ElaC Ribonuclease Z 2 (ELAC2) depleted cells show increased sensitivity to HMAs by suppressing decitabine-triggered enhancement of ATP production. Moreover, we show that a small molecular inhibitor of POLRMT compromises the metabolic activity and synergistically enhances the cytotoxicity of HMAs. Our study unveils the insensitivity to HMAs through the elevation of mtRNAs and suggests mtRNA regulatory factors as potential synergistic targets to improve the therapeutic benefit of HMAs.

Keywords:  Decitabine; Drug response; Hypomethylating agents; Mitochondrial RNA; RNA processing

DOI:  https://doi.org/10.1038/s41598-024-80834-z
Mol Cancer Ther. 2024 Dec 23.

Pan-KRAS inhibitors BI-2493 and BI-2865 display potent anti-tumor activity in tumors with KRAS wild-type allele amplification.

Antonio Tedeschi, Fiorella Schischlik, Francesca Rocchetti, Johannes Popow, Florian Ebner, Daniel Gerlach, Antonia Geyer, Valeria Santoro, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jesse Lipp, Matthias Samwer, Michael Gmachl, Norbert Kraut, Mark Pearson, Dorothea Rudolph.

KRASG12C selective inhibitors, such as sotorasib and adagrasib, have raised hopes of targeting other KRAS mutant alleles in cancer patients. We report that KRAS wild-type amplified tumor models are sensitive to treatment with the small molecule KRAS inhibitors BI-2493 and BI-2865. These pan-KRAS inhibitors directly target the "OFF" state of KRAS and result in potent anti-tumor activity in pre-clinical models of cancers driven by KRAS mutant proteins. Here, we used the high-throughput cellular viability PRISM assay to assess the anti-proliferative activity of BI-2493 in a 900+ cancer cell line panel, expanding on our previous work. KRAS wild-type amplified cancer cell lines, with a copy number >7, were identified as the most sensitive, across cell lines with any KRAS alterations, to our pan-KRAS inhibitors. Importantly, our data suggest that a KRAS "OFF" inhibitor is better suited to treat KRAS wild-type amplified tumors than a KRAS "ON" inhibitor. KRAS wild-type amplification is common in patients with gastroesophageal cancers where it has been shown to act as a unique cancer driver with little overlap to other actionable mutations. The pan-KRAS inhibitors BI-2493 and BI-2865 show potent anti-tumor activity in vitro and in vivo in KRAS wild-type amplified cell lines from this and other tumor types. In conclusion, this is the first study to demonstrate that direct pharmacological inhibition of KRAS shows anti-tumor activity in preclinical models of cancer with KRAS wild-type amplification, suggesting a novel therapeutic concept for patients with cancers bearing this KRAS alteration.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0386
Cancer Metab. 2024 Dec 23. 12(1): 39

Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma.

Fatimah J Al Khazal, Sanjana Mahadev Bhat, Yuxiang Zhu, Cristina M de Araujo Correia, Sherry X Zhou, Brandon A Wilbanks, Clifford D Folmes, Gary C Sieck, Judith Favier, L James Maher.

  Heterozygosity for loss-of-function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts.(281 words).

Keywords:  Complex I; Hypoxia; Paraganglioma; Pheochromocytoma; Succinate dehydrogenase; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1186/s40170-024-00369-9
Cell Death Discov. 2024 Dec 27. 10(1): 514

Mitochondria-targeted antioxidant MitoQ radiosensitizes tumors by decreasing mitochondrial oxygen consumption.

Justin D Rondeau, Sara Lipari, Barbara Mathieu, Claire Beckers, Justine A Van de Velde, Lionel Mignion, Mauricio Da Silva Morais, Marvin Kreuzer, Ilaria Colauzzi, Tania Capeloa, Martin Pruschy, Bernard Gallez, Pierre Sonveaux.

Hypoxic tumors are radioresistant stemming from the fact that oxygen promotes reactive oxygen species (ROS) propagation after water radiolysis and stabilizes irradiation-induced DNA damage. Therefore, an attractive strategy to radiosensitize solid tumors is to increase tumor oxygenation at the time of irradiation, ideally above a partial pressure of 10 mm-Hg at which full radiosensitization can be reached. Historically, the many attempts to increase vascular O2 delivery have had limited efficacy, but mathematical models predicted that inhibiting cancer cell respiration would be more effective. Here, we report that mitochondria-targeted antioxidant MitoQ can radiosensitize human breast tumors in mice. This was not a class effect, as neither MitoTEMPO nor SKQ1 shared this property. At clinically relevant nanomolar concentrations, MitoQ completely abrogated the oxygen consumption of several human cancer cell lines of different origins, which was associated with a glycolytic switch. Using orthotopic breast cancer models in mice, we observed that pretreating hypoxic MDA-MB-231 tumors with MitoQ delayed tumor growth with both single dose irradiation and clinically relevant fractionated radiotherapy. Oxygenated MCF7 tumors were not radiosensitized, suggesting an oxygen enhancement effect of MitoQ. Because MitoQ already successfully passed Phase I clinical trials, our findings foster its clinical evaluation in combination with radiotherapy.

DOI: https://doi.org/10.1038/s41420-024-02277-9
Cell Death Dis. 2024 Dec 20. 15(12): 921

SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8.

Yu Liu, Yan Xu, Qianqian Hao, Luyao Shi, Yufei Chen, Yajun Liu, Mengya Li, Yu Zhang, Tao Li, Yafei Li, Zhongxing Jiang, Yanfang Liu, Chong Wang, Zhilei Bian, Lu Yang, Shujuan Wang.

In recent years, targeting mitochondrial apoptosis has emerged as a promising therapeutic strategy for Acute Myeloid Leukemia (AML). The SLC25 family of mitochondrial carriers plays a critical role in maintaining mitochondrial function and regulating apoptosis. However, the role of SLC25A21, an oxodicarboxylate carrier, in AML progression and its potential as a prognostic biomarker remain underexplored. This study aimed to further investigate the role, molecular mechanism, and potential clinical value of SLC25A21 in AML progression. The transcript levels of SLC25A21 in bone marrow specimens were analyzed using real-time quantitative polymerase chain reaction. The correlation between SLC25A21 expression and the prognosis of AML was assessed through survival analysis. Findings revealed that SLC25A21 was downregulated in adult AML, and the low expression of SLC25A21 was correlated with worse prognosis for AML patients. Furthermore, overexpression of SLC25A21 inhibited cell proliferation and cell cycle progression, and was correlated with apoptosis through mitochondrial apoptosis signaling pathway. C-X-C motif chemokine ligand 8 (CXCL8) was identified as a downstream target of SLC25A21. These functions of SLC25A21 could be rescued by the overexpression of CXCL8. Moreover, SLC25A21 overexpression significantly suppressed the growth of xenograft tumors. In conclusion, the low SLC25A21 expression is correlated with poor clinical outcome. The overexpression of SLC25A21 inhibited the AML cell survival and proliferation by dysregulating the expression of CXCL8. SLC25A21 might be a potential prognostic marker and a treatment target for AML.

DOI: https://doi.org/10.1038/s41419-024-07308-y
Invest New Drugs. 2024 Dec 27.

A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.

Patrick M Boland, Heinz-Josef Lenz, Kristen K Ciombor, Vaia Florou, Michael J Pishvaian, Michael Cusnir, Deirdre Cohen, Jessie Y Guo, Min Tang, Prabhu Rajagopalan, Sandra E Wiley, Richard G Ghalie, Howard S Hochster.

  Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).

Keywords:  Colorectal cancer; ME-344; Metabolic synthetic lethality; Metabolomics; OxPhos inhibition; VEGF

DOI:  https://doi.org/10.1007/s10637-024-01489-1
Am J Physiol Endocrinol Metab. 2024 Dec 23.

The Mitochondrial Lactate Oxidation Complex: endpoint for carbohydrate carbon disposal.

Robert G Leija, Jose A Arevalo, Dianna Xing, José Pablo Vázquez-Medina, George A Brooks.

  The Lactate Shuttle concept has revolutionized our understanding and study of metabolism in physiology, biochemistry, metabolism, nutrition, and medicine. Seminal findings of the Mitochondrial Lactate Oxidation Complex (mLOC) elucidated the architectural structure of its components. Here, we report that the mitochondrial pyruvate carrier (mPC) is an additional member of the mLOC in mouse muscle and C2C12 myoblasts and myotubes. Immunoblots, mass spectrometry, and co-immunoprecipitation experiments of mitochondrial preparations revealed abundant amounts of mitochondrial lactate dehydrogenase (mLDH), monocarboxylate transporter (mMCT), basigin (CD147), cytochrome oxidase (COx), and pyruvate carriers 1 and 2 (mPC1 and 2). Additionally, using confocal laser scanning microscopy (CLSM) and in situ proximity ligation, we also demonstrated planar and 3D colocalization of pyruvate and lactate transporters with COx in fixed skeletal muscle sections, myotubes, and C2C12 myoblasts. This work serves as a landmark for configuring the final pathway of carbohydrate oxidation.

Keywords:  Lactate; Lactate Shuttle; Mitochondral Reticulum; Pyruvate; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpendo.00306.2024
Genomics Proteomics Bioinformatics. 2024 Dec 26. pii: qzae092. [Epub ahead of print]

Single Cell Sequencing Traces Mitochondrial Transfers.

Mengying Wu, Weilin Pu, Zhenglong Gu.

DOI: https://doi.org/10.1093/gpbjnl/qzae092
Cancer Cell Int. 2024 Dec 26. 24(1): 430

GANT61 surmounts drug resistance of ADR by upregulating lysosome activities and reducing BCL2 expression in HL-60/ADR cells.

Cheng Zhou, Liang Zhao, Ming Zhou, Chao Wu, Guanghua Liu, Jiangwen Long, Yuanxiang Shi, Can Liu.

   BACKGROUND: Drug resistance remains a significant obstacle to Acute myeloid leukemia (AML) successful treatment, often leading to therapeutic failure. Our previous studies demonstrated that Glioma-associated oncogene-1 (GLI1) reduces chemotherapy sensitivity and promotes cell proliferation in AML cells. GANT61, an inhibitor of GLI1, emerges as a promising candidate in AML treatment. This study aims to explore the effects of the combination of GANT61 and Adriamycin (ADR) on AML cells resistance and elucidate the mechanisms through which GANT61 may potentiate the sensitivity of AML cells to ADR.
METHODS: AML cell lines and AML primary cells were studied to evaluate effects and mechanisms of GANT61. Flow cytometry assays were used to verify apoptosis. Cell Counting Kit-8 (CCK-8) and EDU+ staining were used to observe changes in cell viability and the cytotoxic effect to different drugs. The transcriptomic profiles of HL-60/ADR cells with or without GANT61 treatment were compared via RNA-Seq analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and Gene Set Enrichment Analysis (GSEA) were performed for differentially expressed genes (DEGs) to reveal the underlying mechanisms of GANT61 in AML cells. GLI1, BCL2, Bax protein and mRNA expression levels were assessed by Western blot and Real-time polymerase chain reaction (RT-PCR).
RESULTS: Our studies found that the combination of GANT61 and ADR synergistically inhibits proliferation while enhancing apoptosis in HL-60/ADR cells, and does not significantly exacerbate myelosuppression. Mechanistically, GSEA revealed enrichment of the gene set associated with the KEGG term "Apoptosis" and "Lysosome" in GANT61 treated cells. Meanwhile, "Apoptosis" was identified as the third most relevant pathway enriched by lysosomal DEGs, and BCL2 expression showed a negative correlation with these lysosomal DEGs in AML patients. RT-PCR and Western blot analysis disclosed that GANT61 significantly restrained BCL2 expression in AML cells. Lastly, we proved that venetoclax, a BCL2 inhibitor, co-treatment with GANT61 improved ADR sensitivity in HL-60/ADR cells.
CONCLUSIONS: GANT61 effectively reversed ADR resistance in HL-60/ADR cells by upregulating lysosome activities and downgrading BCL2 expression, providing a new treatment strategy with acceptable toxicity for AML-resistant patients.

Keywords:  Acute myeloid leukemia; Adriamycin; BCL2; GANT61; Lysosome; Resensitisation; Resistance

DOI:  https://doi.org/10.1186/s12935-024-03626-5
Metabolites. 2024 Dec 13. pii: 703. [Epub ahead of print]14(12):

Influence of the Microbial Metabolite Acetyl Phosphate on Mitochondrial Functions Under Conditions of Exogenous Acetylation and Alkalization.

Natalia V Beloborodova, Nadezhda I Fedotcheva.

   BACKGROUND: Acetyl phosphate (AcP) is a microbial intermediate involved in the central bacterial metabolism. In bacteria, it also functions as a donor of acetyl and phosphoryl groups in the nonenzymatic protein acetylation and signal transduction. In host, AcP was detected as an intermediate of the pyruvate dehydrogenase complex, and its appearance in the blood was considered as an indication of mitochondrial breakdown. In vitro experiments showed that AcP is a powerful agent of nonenzymatic acetylation of proteins. The influence of AcP on isolated mitochondria has not been previously studied.
METHODS: In this work, we tested the influence of AcP on the opening of the mitochondrial permeability transition pore (mPTP), respiration, and succinate dehydrogenase (SDH) activity under neutral and alkaline conditions stimulating the nonenzymatic acetylation using polarographic, cation-selective, and spectrophotometric methods.
RESULTS: It was found that AcP slowed down the opening of the mPTP by calcium ions and decreased the efficiency of oxidative phosphorylation and the activity of SDH. These effects were observed only at neutral pH, whereas alkaline pH by itself caused a decrease in these functions to a much greater extent than AcP. AcP at a concentration of 0.5-1 mM decreased the respiratory control and the swelling rate by 20-30%, while alkalization decreased them twofold, thereby masking the effect of AcP. Presumably, the acetylation of adenine nucleotide translocase involved in both the opening of mPTP and oxidative phosphorylation underlies these changes. The intermediate electron carrier phenazine methosulfate (PMS), removing SDH inhibition at the ubiquinone-binding site, strongly activated SDH under alkaline conditions and, partially, in the presence of AcP. It can be assumed that AcP weakly inhibits the oxidation of succinate, while alkalization slows down the electron transfer from the substrate to the acceptor.
CONCLUSIONS: The results show that both AcP and alkalization, by promoting nonmetabolic and nonenzymatic acetylation from the outside, retard mitochondrial functions.

Keywords:  acetyl phosphate; adenine nucleotide translocase; alkalization; mitochondrial permeability transition pore; nonenzymatic acetylation; respiration; succinate dehydrogenase

DOI:  https://doi.org/10.3390/metabo14120703
Blood. 2024 Dec 24. pii: blood.2024026232. [Epub ahead of print]

Menin inhibitors in the treatment of acute myeloid leukemia.

Gerwin A Huls, Carolien M Woolthuis, Jan Jacob Schuringa.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML such as KMT2A rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

DOI: https://doi.org/10.1182/blood.2024026232