bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–11–10
fiveteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  2. Mitochondrial elongation impairs breast cancer metastasis.
  3. Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
  4. Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
  5. The combination of venetoclax and quercetin exerts a cytotoxic effect on acute myeloid leukemia.
  6. Mitochondrial respiratory complex II is altered in renal carcinoma.
  7. Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
  8. The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
  9. Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks.
  10. Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.
  11. PHGDH Induction by MAPK is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.
  12. Canine Mammary Tumours (CMTs) exploit mitochondrial cholesterol for aggressive reprogramming.
  13. Surprise finding reveals mitochondrial 'energy factories' come in two different types.
  14. O-GlcNAcylation of hexokinase 2 modulates mitochondrial dynamics and enhances the progression of lung cancer.
  15. PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression.
  1. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  2. Sci Adv. 2024 Nov 08. 10(45): eadm8212
    Mitochondrial elongation impairs breast cancer metastasis.
    Lucía Minarrieta, Matthew G Annis, Yannick Audet-Delage, Hellen Kuasne, Alain Pacis, Catherine St-Louis, Alexander Nowakowski, Marco Biondini, Mireille Khacho, Morag Park, Peter M Siegel, Julie St-Pierre.
      Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm8212
  3. Cell Calcium. 2024 Oct 23. pii: S0143-4160(24)00120-9. [Epub ahead of print]124 102962
    Does a transmembrane sodium gradient control membrane potential in mammalian mitochondria?
    David G Nicholls.
      In a recent publication, Hernansanz-Agusti̒n et al. propose that a sodium gradient across the inner mitochondrial membrane, generated by a Na+/H+ activity integral to Complex I can account for half of the mitochondrial membrane potential. This conflicts with conventional electrophysiological and chemiosmotic understanding.
    Keywords:  Calcium signaling; Goldman equation; Membrane potential; Mitochondria; Sodium proton exchange
    DOI:  https://doi.org/10.1016/j.ceca.2024.102962
  4. Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2414187121
    Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
    Mads M Foged, Emeline Recazens, Sylvain Chollet, Miriam Lisci, George E Allen, Boris Zinshteyn, Doha Boutguetait, Christian Münch, Vamsi K Mootha, Alexis A Jourdain.
      Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.
    Keywords:  OXPHOS; RNA processing; mitochondria; mitochondrial RNA granules; translation
    DOI:  https://doi.org/10.1073/pnas.2414187121
  5. Sci Rep. 2024 11 02. 14(1): 26418
    The combination of venetoclax and quercetin exerts a cytotoxic effect on acute myeloid leukemia.
    Renshi Kawakatsu, Kenjiro Tadagaki, Kenta Yamasaki, Yasumichi Kuwahara, Shinichiro Nakada, Tatsushi Yoshida.
      Venetoclax is a BH3 mimetic that was recently approved for the treatment of acute myeloid leukemia (AML) treatment. However, the effect of venetoclax on AML remains limited, and a novel strategy is required. Here, we demonstrate for the first time that the cytotoxic effect of venetoclax drastically increased when by combined with the naturally occurring flavonoid quercetin. Combined treatment with venetoclax and quercetin caused most of AML KG-1 cells to exhibit a condensed morphology. Cell cycle analysis revealed that the combination strongly induced cell death. Caspase inhibitor blocked this cell death, and the combination induced poly (ADP-ribose) polymerase (PARP) cleavage, indicating that apoptosis was the primary mechanism. These effects were also observed in another AML cell line Kasumi-1 but not in chronic myeloid leukemia (CML) K562 cells. Public data analysis demonstrated that B-cell/CLL lymphoma 2 (Bcl-2) expression is increased in AML cells compared to other malignant tumors, and the survival and the growth of AML cell line depends on Bcl-2. We found that quercetin increased Bcl-2-associated X protein (Bax) expression in KG-1. Our study provides a novel function for quercetin and presents a promising strategy for AML treatment using venetoclax.
    DOI:  https://doi.org/10.1038/s41598-024-78221-9
  6. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 31. pii: S0925-4439(24)00550-7. [Epub ahead of print]1871(1): 167556
    Mitochondrial respiratory complex II is altered in renal carcinoma.
    Sona Miklovicova, Luca Volpini, Ondrej Sanovec, Federica Monaco, Katerina Hadrava Vanova, Jaromir Novak, Stepana Boukalova, Renata Zobalova, Petr Klezl, Marco Tomasetti, Vladimir Bobek, Vojtech Fiala, Josef Vcelak, Lory Santarelli, Zuzana Bielcikova, Katerina Komrskova, Katarina Kolostova, Karel Pacak, Sarka Dvorakova, Jiri Neuzil.
       BACKGROUND: Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients.
    METHODS: We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients.
    RESULTS: ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue.
    CONCLUSIONS: Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.
    Keywords:  Complex II; Metabolism; Mitochondria; Organoids; Renal cell carcinoma; Succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167556
  7. Cold Spring Harb Perspect Med. 2024 Nov 05. pii: a041814. [Epub ahead of print]
    Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
    Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis.
      Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041814
  8. Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977
    The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
    Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.
      Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.
    Keywords:  EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.mito.2024.101977
  9. Nat Commun. 2024 Nov 01. 15(1): 9438
    Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks.
    Jinchun Wu, Yang Liu, Liqiong Ou, Tingting Gan, Zhengrong Zhangding, Shaopeng Yuan, Xinyi Liu, Mengzhu Liu, Jiasheng Li, Jianhang Yin, Changchang Xin, Ye Tian, Jiazhi Hu.
      Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.
    DOI:  https://doi.org/10.1038/s41467-024-53806-0
  10. Br J Dermatol. 2024 Nov 07. pii: ljae432. [Epub ahead of print]
    Exploration of the mutational landscape of cutaneous leiomyoma confirms FH as a driver gene and identifies targeting purine metabolism as a potential therapeutic strategy.
    Louise van der Weyden, Martin Del Castillo Velasco-Herrera, Saamin Cheema, Kim Wong, Jacqueline M Boccacino, Ian Vermes, Victoria Offord, Alastair Droop, David R A Jones, Elizabeth Anderson, Claire Hardy, Nicolas de Saint Aubain, Peter M Ferguson, Carolin Mogler, Neil Rajan, Derek Frew, Paul W Harms, Steven D Billings, Désirée Schatton, Marc Segarra-Mondejar, Mark J Arends, Ingrid Ferreira, Thomas Brenn, Christian Frezza, David J Adams.
      
    DOI:  https://doi.org/10.1093/bjd/ljae432
  11. Cancer Res. 2024 Nov 04.
    PHGDH Induction by MAPK is Essential for Melanoma Formation and Creates an Actionable Metabolic Vulnerability.
    Neel Jasani, Xiaonan Xu, Benjamin Posorske, Yumi Kim, Kaizhen Wang, Olga Vera, Kenneth Y Tsai, Gina M DeNicola, Florian A Karreth.
      Overexpression of PHGDH, the rate-limiting enzyme in the serine synthesis pathway, promotes melanomagenesis, melanoma cell proliferation, and survival of metastases in serine-low environments such as the brain. Here, we found that PHGDH is universally increased in melanoma cells and required for melanomagenesis. While PHGDH amplification explained PHGDH overexpression in a subset of melanomas, oncogenic BRAFV600E also promoted PHGDH transcription through mTORC1-mediated translation of ATF4. Importantly, depletion of PHGDH in genetic mouse melanoma models blocked tumor formation. In addition to BRAFV600E-mediated upregulation, PHGDH was further induced by exogenous serine restriction. Surprisingly, BRAFV600E inhibition diminished serine restriction-mediated PHGDH expression by preventing ATF4 induction. Consequently, melanoma cells could be specifically starved of serine by combining BRAFV600E inhibition with exogenous serine restriction, which promoted cell death in vitro and attenuated melanoma growth in vivo. In summary, this study identified that PHGDH is essential for melanomagenesis and regulated by BRAFV600E, revealing a targetable vulnerability in BRAFV600E-mutant melanoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2471
  12. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 30. pii: S0925-4439(24)00540-4. [Epub ahead of print] 167546
    Canine Mammary Tumours (CMTs) exploit mitochondrial cholesterol for aggressive reprogramming.
    Liana Hardy, Brindha Kannan, Manuel Rigon, Genevieve Benton-Hawthorn, Renato L Previdelli, Iris M Reichler, Franco Guscetti, Mariusz P Kowalewski, Michelangelo Campanella.
      In human breast cancer the mitochondrial translocator protein (TSPO) aids pro-survival cellular response by facilitating the formation of mitochondrial contact sites with the nucleus termed Nucleus Associated Mitochondria (NAM). Here, we show that TSPO positively associates with the aggressiveness of tissues and cells isolated from Canine Mammary Tumours (CMTs). TSPO is also readily upregulated in reprogrammed mammary tumour cells following long-term deprivation of oestrogen or exposure to the endocrine chemotherapeutic (ET) agent Tamoxifen. The latter triggers mitochondrial handling of cholesterol which is facilitated by TSPO whose upregulation reduces susceptibility to Tamoxifen. TSPO binding ligands boost, on the other hand, the efficacy of Tamoxifen and Chemotherapy agents. In aggressive canine mammary tumour cells, TSPO repression impairs the NF-kB pattern thus confirming the pro-survival role of the NAM uncovered in the human counterpart. Mitochondrial cholesterol handling via TSPO emerges therefore as a signature in the aggressive reprogramming of CMTs thus advancing our understanding of the molecular mechanisms underpinning this pathology. A novel target mechanism to improve bio-marking and therapeutic protocols is here proposed.
    Keywords:  Canine Mammary Tumours (CMTs); Cholesterol; Mitochondria; TSPO; Tamoxifene
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167546
  13. Nature. 2024 Nov 06.
    Surprise finding reveals mitochondrial 'energy factories' come in two different types.
    Benjamin Thompson, Emily Bates.
      
    Keywords:  Chemistry; Microbiology; Plant sciences; Psychology
    DOI:  https://doi.org/10.1038/d41586-024-03646-1
  14. Mol Cell Biochem. 2024 Nov 04.
    O-GlcNAcylation of hexokinase 2 modulates mitochondrial dynamics and enhances the progression of lung cancer.
    S I Panpan, G E Wei, W U Kaiming, Renquan Zhang.
      Non-small cell lung cancer (NSCLC) stands as the prevailing manifestation of lung cancer, with current therapeutic modalities linked to a dismal prognosis, necessitating further advancements. Hexokinase 2 (HK2), a critical enzyme positioned on the mitochondrial membrane, exerts control over diverse biological pathways, thereby regulating cancer. Nevertheless, the precise role and mechanism of HK2 in NSCLC remain inadequately elucidated, warranting comprehensive investigation. HK2 expression in NSCLC tissues and cell lines was detected through immunohistochemistry and western blot analysis. Concurrently, shRNA assays were applied to scrutinize the impact of HK2 on cell proliferation, apoptosis, migration, and invasion processes in NSCLC cell lines, utilizing CCK8, flow cytometry, wound-healing assay, and transwell techniques. The involvement of HK2 in mitochondrial dynamics was probed through western blot analysis, mitochondrial membrane potential assay, and assessment of ROS generation. Next, the functional role of HK2 was assessed by examining its influence on xenograft tumor growth in nude mice in vivo. Further research has demonstrated that HK2 played a role in NSCLC through its O-GlcNAcylation process. The results of the study revealed that HK2 O-GlcNAcylation promoted the proliferation, migration, and invasive characteristics of NSCLC cells, while alleviating mitochondrial damage, whereas O-GlcNAcylation inactivation yielded the opposite effect. Furthermore, in vivo experiments in nude mice illustrated that HK2 O-GlcNAcylation could stimulate tumor growth in NSCLC. These results suggested that HK2 may impact mitochondrial dynamics in NSCLC through its O-GlcNAcylation, thereby contributing to the progression of NSCLC.
    Keywords:   O-GlcNAcylation; Hexokinase 2; Mitochondrial dynamics; NSCLC
    DOI:  https://doi.org/10.1007/s11010-024-05146-2
  15. Cancer Res. 2024 Nov 04.
    PRDM16 Induces Methylation of FLT3 to Promote FLT3-ITD Signaling and Leukemia Progression.
    Fengxian Zhai, Guozheng Pan, Lei Xue, Can Cheng, Jiabei Wang, Yao Liu, Lianxin Liu.
      Internal tandem duplication (ITD) in the FMS-like receptor tyrosine kinase-3 (FLT3) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with poor prognosis. FLT3-ITD mutations result in endoplasmic reticulum (ER) retention and constitutive autophosphorylation of FLT3. The PR/SET domain 16 (PRDM16) is highly expressed in FLT3-ITD+ AML patients, suggesting it might play a role in leukemogenesis. Here, we revealed that genetic and pharmacological suppression of PRDM16 greatly slowed the progression of FLT3-ITD-driven leukemia, sensitized leukemic cells to tyrosine kinase inhibitors (TKIs), and extended the survival of leukemic mice. PRDM16 enhanced activation of oncogenic FLT3-ITD and ligand-dependent activation of wild-type FLT3 in leukemic cells. Mechanistically, PRDM16 mediated monomethylation of FLT3-ITD at lysine 614 and promoted its ER localization, resulting in enhanced FLT3 signaling in leukemia cells. Moreover, pharmacological suppression of FLT3-ITD methylation in combination with TKIs increased the elimination of FLT3-ITD+ AML cells. Altogether, these results suggest that PRDM16 boosts oncogenic FLT3 signaling in leukemic cells by prompting FLT3-ITD methylation. Therefore, PRDM16 may serve as a therapeutic target for AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0577
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