bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–02–11
twenty-one papers selected by
Kelsey Fisher-Wellman, East Carolina University
  1. Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
  2. Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma.
  3. PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
  4. Spheroid architecture strongly enhances miR-221/222 expression and promotes oxidative phosphorylation in an ovarian cancer cell line through a mechanism that includes restriction of miR-9 expression.
  5. Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
  6. Conformational ensemble of yeast ATP synthase at low pH reveals unique intermediates and plasticity in F1-Fo coupling.
  7. Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
  8. Evaluation of Oxygen Consumption Rates In Situ.
  9. Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
  10. A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
  11. Using the heme peroxidase APEX2 to probe intracellular H2O2 flux and diffusion.
  12. Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma.
  13. Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
  14. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
  15. Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
  16. Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.
  17. mtDNA extramitochondrial replication mediates mitochondrial defect effects.
  18. Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.
  19. Hypermetabolism and energetic constraints in mitochondrial disorders.
  20. Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.
  21. Mitochondrial function in peripheral blood cells across the human lifespan.
  1. Blood Cancer Discov. 2024 Feb 08. OF1-OF3
    Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable?
    David P Steensma.
       SUMMARY: Isocitrate dehydrogenase (IDH)-mutant acute myeloid leukemia (AML) is treatable with inhibitors of mutant IDH and also responds well to combination therapies including venetoclax, but most patients with IDH-mutant AML either never achieve complete remission or relapse because mutant hematopoietic stem cells persist despite treatment. An interesting new study in Blood Cancer Discovery characterizes a specific vulnerability in the mitochondrial oxidative phosphorylation system in preleukemic hematopoietic stem cells from patients with IDH1 mutations that is not present in those with IDH2 mutations; will this susceptibility prove amenable to therapy? See related article by Landberg et al. (10).
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0255
  2. Nat Cancer. 2024 Feb 09.
    Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma.
      
    DOI:  https://doi.org/10.1038/s43018-023-00722-9
  3. bioRxiv. 2024 Jan 25. pii: 2024.01.24.576953. [Epub ahead of print]
    PPTC7 limits mitophagy through proximal and dynamic interactions with BNIP3 and NIX.
    Lianjie Wei, Mehmet Oguz Gok, Jordyn D Svoboda, Merima Forny, Jonathan R Friedman, Natalie M Niemi.
      PPTC7 is a mitochondrial-localized PP2C phosphatase that maintains mitochondrial protein content and metabolic homeostasis. We previously demonstrated that knockout of Pptc7 elevates mitophagy in a BNIP3- and NIX-dependent manner, but the mechanisms by which PPTC7 influences receptor-mediated mitophagy remain ill-defined. Here, we demonstrate that loss of PPTC7 upregulates BNIP3 and NIX post-transcriptionally and independent of HIF-1α stabilization. On a molecular level, loss of PPTC7 prolongs the half-life of BNIP3 and NIX while blunting their accumulation in response to proteasomal inhibition, suggesting that PPTC7 promotes the ubiquitin-mediated turnover of BNIP3 and NIX. Consistently, overexpression of PPTC7 limits the accumulation of BNIP3 and NIX protein levels in response to pseudohypoxia, a well-known inducer of mitophagy. This PPTC7-mediated suppression of BNIP3 and NIX protein expression requires an intact PP2C catalytic motif but is surprisingly independent of its mitochondrial targeting, indicating that PPTC7 influences mitophagy outside of the mitochondrial matrix. We find that PPTC7 exists in at least two distinct states in cells: a longer isoform, which likely represents full length protein, and a shorter isoform, which likely represents an imported, matrix-localized phosphatase pool. Importantly, anchoring PPTC7 to the outer mitochondrial membrane is sufficient to blunt BNIP3 and NIX accumulation, and proximity labeling and fluorescence co-localization experiments suggest that PPTC7 associates with BNIP3 and NIX within the native cellular environment. Importantly, these associations are enhanced in cellular conditions that promote BNIP3 and NIX turnover, demonstrating that PPTC7 is dynamically recruited to BNIP3 and NIX to facilitate their degradation. Collectively, these data reveal that a fraction of PPTC7 dynamically localizes to the outer mitochondrial membrane to promote the proteasomal turnover of BNIP3 and NIX.
    DOI:  https://doi.org/10.1101/2024.01.24.576953
  4. Mol Biol Rep. 2024 Feb 04. 51(1): 275
    Spheroid architecture strongly enhances miR-221/222 expression and promotes oxidative phosphorylation in an ovarian cancer cell line through a mechanism that includes restriction of miR-9 expression.
    Avery S Ward, Cody N Hall, Maya O Tree, D Stave Kohtz.
       BACKGROUND: Tumor cell spheroids are organized multicellular structures that form during the expansive growth of carcinoma cells. Spheroids formation is thought to contribute to metastasis by supporting growth and survival of mobile tumor cell populations.
    METHODS AND RESULTS: We investigated how spheroid architecture affects OXPHOS activity, microRNA expression, and intraperitoneal survival of an ovarian carcinoma cell line using high resolution respirometry, quantitative RT-PCR, and a rodent intraperitoneal growth model. Rates of oxidative phosphorylation/respiration per cell of cells growing as spheroids were nearly double those of a variant of the same cell type growing in suspension as loosely aggregated cells. Further, inhibition of spheroid formation by treatment with CDH2 (N-cadherin) siRNA reduced the rate of OXPHOS to that of the non-spheroid forming variant. Cells growing as spheroids showed greatly enhanced expression of miR-221/222, an oncomiR that targets multiple tumor suppressor genes and promotes invasion, and reduced expression of miR-9, which targets mitochondrial tRNA-modification enzymes and inhibits OXPHOS. Consistent with greater efficiency of ATP generation, tumor cells growing as spheroids injected into the nutrient-poor murine peritoneum survived longer than cells growing in suspension as loosely associated aggregates.
    CONCLUSIONS: The data indicate that growth in spheroid form enhances the OXPHOS activity of constituent tumor cells. In addition, spheroid architecture affects expression of microRNA genes involved in growth control and mitochondrial function. During the mobile phase of metastasis, when ovarian tumor cells disperse through nutrient-poor environments such as the peritoneum, enhanced OXPHOS activity afforded by spheroid architecture would enhance survival and metastatic potential.
    Keywords:  Mitochondria; Ovarian cancer; Peritoneal Metastasis; Tumor cell spheroids; miR-221/222; miR-9
    DOI:  https://doi.org/10.1007/s11033-023-09168-9
  5. EMBO J. 2024 Feb 09.
    Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.
    Esmee Vringer, Rosalie Heilig, Joel S Riley, Annabel Black, Catherine Cloix, George Skalka, Alfredo E Montes-Gómez, Aurore Aguado, Sergio Lilla, Henning Walczak, Mads Gyrd-Hansen, Daniel J Murphy, Danny T Huang, Sara Zanivan, Stephen Wg Tait.
      Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.
    Keywords:  Cell Death; Inflammation; Mitochondria; NF-κB; Ubiquitin
    DOI:  https://doi.org/10.1038/s44318-024-00044-1
  6. Nat Struct Mol Biol. 2024 Feb 05.
    Conformational ensemble of yeast ATP synthase at low pH reveals unique intermediates and plasticity in F1-Fo coupling.
    Stuti Sharma, Min Luo, Hiral Patel, David M Mueller, Maofu Liao.
      Mitochondrial adenosine triphosphate (ATP) synthase uses the proton gradient across the inner mitochondrial membrane to synthesize ATP. Structural and single molecule studies conducted mostly at neutral or basic pH have provided details of the reaction mechanism of ATP synthesis. However, pH of the mitochondrial matrix is slightly acidic during hypoxia and pH-dependent conformational changes in the ATP synthase have been reported. Here we use single-particle cryo-EM to analyze the conformational ensemble of the yeast (Saccharomyces cerevisiae) ATP synthase at pH 6. Of the four conformations resolved in this study, three are reaction intermediates. In addition to canonical catalytic dwell and binding dwell structures, we identify two unique conformations with nearly identical positions of the central rotor but different catalytic site conformations. These structures provide new insights into the catalytic mechanism of the ATP synthase and highlight elastic coupling between the catalytic and proton translocating domains.
    DOI:  https://doi.org/10.1038/s41594-024-01219-4
  7. Cell Metab. 2024 Feb 06. pii: S1550-4131(24)00007-X. [Epub ahead of print]36(2): 422-437.e8
    Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding.
    Ashley S Williams, Scott B Crown, Scott P Lyons, Timothy R Koves, Rebecca J Wilson, Jordan M Johnson, Dorothy H Slentz, Daniel P Kelly, Paul A Grimsrud, Guo-Fang Zhang, Deborah M Muoio.
      Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart.
    Keywords:  acylcarnitines; beta-oxidation; fiber type; intermittent fasting; ketones; metabolic flux; mitochondria; proteomics; striated muscles; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.007
  8. Methods Mol Biol. 2024 ;2755 215-226
    Evaluation of Oxygen Consumption Rates In Situ.
    Anqi Li, Yuan Qin, Ying Zhang, Xiaoqun Zhen, Guohua Gong.
      An analysis of the mitochondrial respiration function represented by the oxygen consumption rate is necessary to assess mitochondrial bioenergetics and redox function. This protocol describes two alternative techniques to evaluate mitochondrial respiration function in situ: (1) measure oxygen consumption rates via an electrode; (2) measure oxygen consumption rates via a seahorse instrument. These in situ approaches provide more physiological access to mitochondria to evaluate mitochondrial respiration function in a relatively integrated cellular system.
    Keywords:  ATP; Mitochondria; Mitochondrial stress test; Oxidative phosphorylation; Oxygen consumption
    DOI:  https://doi.org/10.1007/978-1-0716-3633-6_16
  9. FEBS Lett. 2024 Feb 04.
    Remodelling of mitochondrial function by import of specific lipids at multiple membrane-contact sites.
    Aksel J Saukko-Paavola, Robin W Klemm.
      Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods.
    Keywords:  autophagy; endoplasmic reticulum (ER); lipid droplets (LDs); membrane contact sites; metabolic adaptation; mitochondria; mitochondrial shape; organelle-network; starvation
    DOI:  https://doi.org/10.1002/1873-3468.14813
  10. Cancer Res. 2024 Feb 08.
    A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
    Matthew J Bernard, Andrew S Goldstein.
      Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and towards fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic-epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0460
  11. Nat Commun. 2024 Feb 09. 15(1): 1239
    Using the heme peroxidase APEX2 to probe intracellular H2O2 flux and diffusion.
    Mohammad Eid, Uladzimir Barayeu, Kateřina Sulková, Carla Aranda-Vallejo, Tobias P Dick.
      Currently available genetically encoded H2O2 probes report on the thiol redox state of the probe, which means that they reflect the balance between probe thiol oxidation and reduction. Here we introduce the use of the engineered heme peroxidase APEX2 as a thiol-independent chemogenetic H2O2 probe that directly and irreversibly converts H2O2 molecules into either fluorescent or luminescent signals. We demonstrate sensitivity, specificity, and the ability to quantitate endogenous H2O2 turnover. We show how the probe can be used to detect changes in endogenous H2O2 generation and to assess the roles and relative contributions of endogenous H2O2 scavengers. Furthermore, APEX2 can be used to study H2O2 diffusion inside the cytosol. Finally, APEX2 reveals the impact of commonly used alkylating agents and cell lysis protocols on cellular H2O2 generation.
    DOI:  https://doi.org/10.1038/s41467-024-45511-9
  12. NAR Cancer. 2024 Mar;6(1): zcae004
    Rewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma.
    Christina M Fitzsimmons, Mariana D Mandler, Judith C Lunger, Dalen Chan, Siddhardha S Maligireddy, Alexandra C Schmiechen, Supuni Thalalla Gamage, Courtney Link, Lisa M Jenkins, King Chan, Thorkell Andresson, Daniel R Crooks, Jordan L Meier, W Marston Linehan, Pedro J Batista.
      Metabolic reprogramming is a hallmark of cancer that facilitates changes in many adaptive biological processes. Mutations in the tricarboxylic acid cycle enzyme fumarate hydratase (FH) lead to fumarate accumulation and cause hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is a rare, inherited disease characterized by the development of non-cancerous smooth muscle tumors of the uterus and skin, and an increased risk of an aggressive form of kidney cancer. Fumarate has been shown to inhibit 2-oxoglutarate-dependent dioxygenases (2OGDDs) involved in the hydroxylation of HIF1α, as well as in DNA and histone demethylation. However, the link between fumarate accumulation and changes in RNA post-transcriptional modifications has not been defined. Here, we determine the consequences of fumarate accumulation on the activity of different members of the 2OGDD family targeting RNA modifications. By evaluating multiple RNA modifications in patient-derived HLRCC cell lines, we show that mutation of FH selectively affects the levels of N6-methyladenosine (m6A), while the levels of 5-formylcytosine (f5C) in mitochondrial tRNA are unaffected. This supports the hypothesis of a differential impact of fumarate accumulation on distinct RNA demethylases. The observation that metabolites modulate specific subsets of RNA-modifying enzymes offers new insights into the intersection between metabolism and the epitranscriptome.
    DOI:  https://doi.org/10.1093/narcan/zcae004
  13. Cancer Lett. 2024 Feb 06. pii: S0304-3835(24)00089-2. [Epub ahead of print] 216696
    Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
    Luojun Chen, Xiaoke Xing, Yue Zhu, Yali Chen, Huadong Pei, Qibin Song, Juanjuan Li, Pingfeng Zhang.
      Lactate dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its enzyme activity, lactate production, and reduces reactive oxygen species (ROS) generation. Replacement of endogenous LDHA with a palmitoylation-deficient mutant leads to reduced pancreatic cancer cell proliferation, increased T-cell infiltration, and limited tumor growth; it also affects pancreatic cancer cell response to chemotherapy. Moreover, LDHA palmitoylation is upregulated in gemcitabine resistant pancreatic cancer cells. Clinically, ZDHHC9 is upregulated in pancreatic cancer and correlated with poor prognoses for patients. Overall, our findings identify ZDHHC9-mediated palmitoylation as a positive regulator of LDHA, with potentially significant implications for cancer etiology and targeted therapy for pancreatic cancer.
    Keywords:  Gemcitabine; LDHA; Palmitoylation; Pancreatic cancer; ZDHHC9
    DOI:  https://doi.org/10.1016/j.canlet.2024.216696
  14. Nat Cell Biol. 2024 Feb 08.
    Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
    Laura E Newman, Sammy Weiser Novak, Gladys R Rojas, Nimesha Tadepalle, Cara R Schiavon, Danielle A Grotjahn, Christina G Towers, Marie-Ève Tremblay, Matthew P Donnelly, Sagnika Ghosh, Michaela Medina, Sienna Rocha, Ricardo Rodriguez-Enriquez, Joshua A Chevez, Ian Lemersal, Uri Manor, Gerald S Shadel.
      Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA-protein complexes) and activation of cGAS-STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS-STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS-STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria-endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.
    DOI:  https://doi.org/10.1038/s41556-023-01343-1
  15. FASEB J. 2024 Feb 15. 38(3): e23454
    Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation-induced autophagy through calcium signaling.
    Vitor M Ramos, Julian D C Serna, Eloisa A Vilas-Boas, João Victor Cabral-Costa, Fernanda M Cunha, Tetsushi Kataura, Viktor I Korolchuk, Alicia J Kowaltowski.
      Mitochondria shape intracellular Ca2+ signaling through the concerted activity of Ca2+ uptake via mitochondrial calcium uniporters and efflux by Na+ /Ca2+ exchangers (NCLX). Here, we describe a novel relationship among NCLX, intracellular Ca2+ , and autophagic activity. Conditions that stimulate autophagy in vivo and in vitro, such as caloric restriction and nutrient deprivation, upregulate NCLX expression in hepatic tissue and cells. Conversely, knockdown of NCLX impairs basal and starvation-induced autophagy. Similarly, acute inhibition of NCLX activity by CGP 37157 affects bulk and endoplasmic reticulum autophagy (ER-phagy) without significant impacts on mitophagy. Mechanistically, CGP 37157 inhibited the formation of FIP200 puncta and downstream autophagosome biogenesis. Inhibition of NCLX caused decreased cytosolic Ca2+ levels, and intracellular Ca2+ chelation similarly suppressed autophagy. Furthermore, chelation did not exhibit an additive effect on NCLX inhibition of autophagy, demonstrating that mitochondrial Ca2+ efflux regulates autophagy through the modulation of Ca2+ signaling. Collectively, our results show that the mitochondrial Ca2+ extrusion pathway through NCLX is an important regulatory node linking nutrient restriction and autophagy regulation.
    Keywords:  NCLX; autophagy regulation; calcium transport; caloric restriction; hepatocytes; mitochondria
    DOI:  https://doi.org/10.1096/fj.202301368RR
  16. Cancer Med. 2024 Jan;13(2): e6987
    Mitochondrial dynamics as a novel treatment strategy for triple-negative breast cancer.
    Yuechen Wang, Narumi Harada-Shoji, Narufumi Kitamura, Yuto Yamazaki, Akiko Ebata, Masakazu Amari, Mika Watanabe, Minoru Miyashita, Hiroshi Tada, Takaaki Abe, Takashi Suzuki, Kohsuke Gonda, Takanori Ishida.
       INTRODUCTION: Triple-negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.
    METHODS: The Wst-8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA-MB-231 (TNBC), and MCF-7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin-related protein-1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC).
    RESULTS: MDA-MB-231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)-based metabolism. HCC38, a doxorubicin-sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor-negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence-free survival.
    CONCLUSION: Our findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.
    Keywords:  breast cancer; drug resistance; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/cam4.6987
  17. iScience. 2024 Feb 16. 27(2): 108970
    mtDNA extramitochondrial replication mediates mitochondrial defect effects.
    Zhaoliang Shan, Shengnan Li, Yuxue Gao, Chunhua Jian, Xiuxiu Ti, Hui Zuo, Ying Wang, Guochun Zhao, Yan Wang, Qing Zhang.
      A high ratio of severe mitochondrial defects causes multiple human mitochondrial diseases. However, until now, the in vivo rescue signal of such mitochondrial defect effects has not been clear. Here, we built fly mitochondrial defect models by knocking down the essential mitochondrial genes dMterf4 and dMrps23. Following genome-wide RNAi screens, we found that knockdown of Med8/Tfb4/mtSSB/PolG2/mtDNA-helicase rescued dMterf4/dMrps23 RNAi-mediated mitochondrial defect effects. Extremely surprisingly, they drove mtDNA replication outside mitochondria through the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis to amplify cytosolic mtDNA, leading to activation of the cGAS-Sting-like IMD pathway to partially mediate dMterf4/dMrps23 RNAi-triggered effects. Moreover, we found that the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis also mediated other fly mitochondrial gene defect-triggered dysfunctions and Drosophila aging. Overall, our study demarcates the Med8/Tfb4-mtSSB/PolG2/mtDNA-helicase axis as a candidate mechanism to mediate mitochondrial defect effects through driving mtDNA extramitochondrial replication; dysfunction of this axis might be used for potential treatments for many mitochondrial and age-related diseases.
    Keywords:  Biological sciences; Molecular biology; Molecular genetics; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.108970
  18. Nat Commun. 2024 Feb 08. 15(1): 1163
    Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses.
    Seong Eun Lee, Seongyeol Park, Shinae Yi, Na Rae Choi, Mi Ae Lim, Jae Won Chang, Ho-Ryun Won, Je Ryong Kim, Hye Mi Ko, Eun-Jae Chung, Young Joo Park, Sun Wook Cho, Hyeong Won Yu, June Young Choi, Min-Kyung Yeo, Boram Yi, Kijong Yi, Joonoh Lim, Jun-Young Koh, Min Jeong Lee, Jun Young Heo, Sang Jun Yoon, Sung Won Kwon, Jong-Lyul Park, In Sun Chu, Jin Man Kim, Seon-Young Kim, Yujuan Shan, Lihua Liu, Sung-A Hong, Dong Wook Choi, Junyoung O Park, Young Seok Ju, Minho Shong, Seon-Kyu Kim, Bon Seok Koo, Yea Eun Kang.
      The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-024-45366-0
  19. Nat Metab. 2024 Feb 09.
    Hypermetabolism and energetic constraints in mitochondrial disorders.
    Alexander J Sercel, Gabriel Sturm, Dympna Gallagher, Marie-Pierre St-Onge, Christopher P Kempes, Herman Pontzer, Michio Hirano, Martin Picard.
      
    DOI:  https://doi.org/10.1038/s42255-023-00968-8
  20. Life Sci Alliance. 2024 Apr;pii: e202302353. [Epub ahead of print]7(4):
    Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.
    Ling Yin, Xiaoding Hu, Guangsheng Pei, Mengfan Tang, You Zhou, Huimin Zhang, Min Huang, Siting Li, Jie Zhang, Citu Citu, Zhongming Zhao, Bisrat G Debeb, Xu Feng, Junjie Chen.
      Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.
    DOI:  https://doi.org/10.26508/lsa.202302353
  21. NPJ Aging. 2024 Feb 07. 10(1): 10
    Mitochondrial function in peripheral blood cells across the human lifespan.
    Johannes K Ehinger, Emil Westerlund, Eleonor Åsander Frostner, Michael Karlsson, Gesine Paul, Fredrik Sjövall, Eskil Elmér.
      Mitochondrial dysfunction is considered a hallmark of aging. Up to now, a gradual decline of mitochondrial respiration with advancing age has mainly been demonstrated in human muscle tissue. A handful of studies have examined age-related mitochondrial dysfunction in human blood cells, and only with small sample sizes and mainly in platelets. In this study, we analyzed mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and platelets from 308 individuals across the human lifespan (0-86 years). In regression analyses, with adjustment for false discovery rate (FDR), we found age-related changes in respiratory measurements to be either small or absent. The main significant changes were an age-related relative decline in complex I-linked respiration and a corresponding rise of complex II-linked respiration in PBMCs. These results add to the understanding of mitochondrial dysfunction in aging and to its possible role in immune cell and platelet senescence.
    DOI:  https://doi.org/10.1038/s41514-023-00130-4
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