bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–09–08
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
  2. Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells.
  3. Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
  4. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  5. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
  6. TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
  7. Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.
  8. Mitochondrial bioenergetics of breast cancer.
  9. p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.
  10. Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis.
  11. Structure-destabilizing mutations unleash an intrinsic perforation activity of antiapoptotic Bcl-2 in the mitochondrial membrane enabling apoptotic cell death.
  12. Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.
  13. Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
  14. F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
  15. Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells.
  16. MitoAMPK inhibits the Warburg effect by MZF1-SIRT6 with glycosis related genes in NSCLC.
  17. TP53-Mutated Acute Myeloid Leukemia: How Can We Improve Outcomes?
  1. FEBS Lett. 2024 Sep 03.
    Mitochondrial permeability transition mediated by MTCH2 and F-ATP synthase contributes to ferroptosis defense.
    Lishu Guo.
      The opening of the mitochondrial permeability transition pore (PTP), a Ca2+-dependent pore located in the inner mitochondrial membrane, triggers mitochondrial outer membrane permeabilization (MOMP) and induces organelle rupture. However, the underlying mechanism of PTP-induced MOMP remains unclear. Mitochondrial carrier homolog 2 (MTCH2) mediates MOMP process by facilitating the recruitment of tBID to mitochondria. Here, we show that MTCH2 binds to cyclophilin D (CyPD) and promotes the dimerization of F-ATP synthase via interaction with subunit j. The interplay between MTCH2 and subunit j coordinates MOMP and PTP to mediate the occurrence of mitochondrial permeability transition. Knockdown of CyPD, MTCH2 and subunit j markedly sensitizes cells to RSL3-induced ferroptosis, which is prevented by MitoTEMPO, suggesting that mitochondrial permeability transition mediates ferroptosis defense.
    Keywords:  F‐ATP synthase; cyclophilin D; ferroptosis; mitochondrial carrier homolog 2; mitochondrial permeability transition
    DOI:  https://doi.org/10.1002/1873-3468.15008
  2. Commun Biol. 2024 Aug 30. 7(1): 1065
    Cytidine deaminase-dependent mitochondrial biogenesis as a potential vulnerability in pancreatic cancer cells.
    Audrey Frances, Audrey Lumeau, Nicolas Bery, Marion Gayral, Lucille Stuani, Marie Sorbara, Estelle Saland, Delphine Pagan, Naïma Hanoun, Jérôme Torrisani, Anthony Lemarié, Jean-Charles Portais, Louis Buscail, Nelson Dusetti, Jean-Emmanuel Sarry, Pierre Cordelier.
      Cytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine as part of the pyrimidine salvage pathway. Elevated levels of CDA are found in pancreatic tumors and associated with chemoresistance. Recent evidence suggests that CDA has additional functions in cancer cell biology. In this work, we uncover a novel role of CDA in pancreatic cancer cell metabolism. CDA silencing impairs mitochondrial metabolite production, respiration, and ATP production in pancreatic cancer cells, leading to a so-called Pasteur effect metabolic shift towards glycolysis. Conversely, we find that CDA expression promotes mitochondrial biogenesis and oxidative phosphorylation, independently of CDA deaminase activity. Furthermore, we observe that patient primary cells overexpressing CDA are more sensitive to mitochondria-targeting drugs. Collectively, this work shows that CDA plays a non-canonical role in pancreatic cancer biology by promoting mitochondrial function, which could be translated into novel therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1038/s42003-024-06760-y
  3. J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746
    Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
    Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.
      Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
    Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1016/j.jbc.2024.107746
  4. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  5. Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952
    SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
    Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.
      Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
    Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)
    DOI:  https://doi.org/10.1016/j.mito.2024.101952
  6. J Mol Med (Berl). 2024 Aug 29.
    TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
    Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina.
      Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.
    Keywords:  Colorectal cancer; Metabolism; Mitochondrial biogenesis; Peroxisome proliferation-activated receptor gamma coactivator α1-alpha; TNF receptor-associated protein 1; Transcription factor A mitochondrial
    DOI:  https://doi.org/10.1007/s00109-024-02479-9
  7. Cell Rep Med. 2024 Aug 21. pii: S2666-3791(24)00420-8. [Epub ahead of print] 101699
    Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.
    Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy.
      Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.
    Keywords:  alpha-ketoglutarate; fibrolamellar carcinoma; glucose; glutamine; metabolomics; mitochondria; proline; proteomics; pyruvate; serine
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101699
  8. Mitochondrion. 2024 Aug 31. pii: S1567-7249(24)00109-0. [Epub ahead of print]79 101951
    Mitochondrial bioenergetics of breast cancer.
    Tashvinder Singh, Kangan Sharma, Laxmipriya Jena, Prabhsimran Kaur, Sandeep Singh, Anjana Munshi.
      Breast cancer cells exhibit metabolic heterogeneity based on tumour aggressiveness. Glycolysis and mitochondrial respiration are two major metabolic pathways for ATP production. The oxygen flux, oxygen tension, proton leakage, protonmotive force, inner mitochondrial membrane potential, ECAR and electrochemical proton gradient maintain metabolic homeostasis, ATP production, ROS generation, heat dissipation, and carbon flow and are referred to as "sub-domains" of mitochondrial bioenergetics. Tumour aggressiveness is influenced by these mechanisms, especially when breast cancer cells undergo metastasis. These physiological parameters for healthy mitochondria are as crucial as energy demands for tumour growth and metastasis. The instant energy demands are already elucidated under Warburg effects, while these parameters may have dual functionality to maintain cellular bioenergetics and cellular health. The tumour cell might maintain these mitochondrial parameters for mitochondrial health or avoid apoptosis, while energy production could be a second priority. This review focuses explicitly on the crosstalk between metabolic domains and the utilisation of these parameters by breast cancer cells for their progression. Some major interventions are discussed based on mitochondrial bioenergetics that need further investigation. This review highlights the pathophysiological significance of mitochondrial bioenergetics and the regulation of its sub-domains by breast tumour cells for uncontrolled proliferation.
    Keywords:  Breast Cancer; Electron transport chain; Mitochondrial respiration; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.mito.2024.101951
  9. Bull Math Biol. 2024 Aug 29. 86(10): 124
    p53 Orchestrates Cancer Metabolism: Unveiling Strategies to Reverse the Warburg Effect.
    Roba Abukwaik, Elias Vera-Siguenza, Daniel Tennant, Fabian Spill.
      Cancer cells exhibit significant alterations in their metabolism, characterised by a reduction in oxidative phosphorylation (OXPHOS) and an increased reliance on glycolysis, even in the presence of oxygen. This metabolic shift, known as the Warburg effect, is pivotal in fuelling cancer's uncontrolled growth, invasion, and therapeutic resistance. While dysregulation of many genes contributes to this metabolic shift, the tumour suppressor gene p53 emerges as a master player. Yet, the molecular mechanisms remain elusive. This study introduces a comprehensive mathematical model, integrating essential p53 targets, offering insights into how p53 orchestrates its targets to redirect cancer metabolism towards an OXPHOS-dominant state. Simulation outcomes align closely with experimental data comparing glucose metabolism in colon cancer cells with wild-type and mutated p53. Additionally, our findings reveal the dynamic capability of elevated p53 activation to fully reverse the Warburg effect, highlighting the significance of its activity levels not just in triggering apoptosis (programmed cell death) post-chemotherapy but also in modifying the metabolic pathways implicated in treatment resistance. In scenarios of p53 mutations, our analysis suggests targeting glycolysis-instigating signalling pathways as an alternative strategy, whereas targeting solely synthesis of cytochrome c oxidase 2 (SCO2) does support mitochondrial respiration but may not effectively suppress the glycolysis pathway, potentially boosting the energy production and cancer cell viability.
    Keywords:  Cancer metabolism; Glycolysis; Hypoxia; Mathematical biology; Warburg effect; p53
    DOI:  https://doi.org/10.1007/s11538-024-01346-5
  10. Leuk Lymphoma. 2024 Sep 05. 1-13
    Homoharringtonine sensitized resistant acute myeloid leukemia cells to venetoclax-induced apoptosis.
    Zhao Yin, Ya Gao, Xiaoyin Bu, Junhui Wang, Zurong Yao, Qifa Liu, Yu Zhang, Guopan Yu, Baohong Ping.
      Venetoclax (VEN), a B-cell lymphoma 2 (BCL-2) selective inhibitor, is widely used for treating acute myeloid leukemia (AML) with promising results. However, the anti-leukemic effect of VEN in relapsed/refractory (R/R)- AML requires improvement. In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Basic research indicates that HHT combined with VEN has a highly synergistic effect against both resistant AML cells and primary cells with/without mesenchymal stem cell (MSC) co-culture in vivo, inhibiting proliferation and colony-forming capacity of AML cells associated with concomitant cell cycle arrest. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients.
    Keywords:  Relapsed/refractory; acute myeloid leukemia; fatty acid uptake; homoharringtonine; reactive oxygen species; venetoclax
    DOI:  https://doi.org/10.1080/10428194.2024.2400228
  11. Mitochondrial Commun. 2023 ;1 48-61
    Structure-destabilizing mutations unleash an intrinsic perforation activity of antiapoptotic Bcl-2 in the mitochondrial membrane enabling apoptotic cell death.
    Ping Gao, Zhi Zhang, Rui Wang, Li Huang, Hao Wu, Zhenzhen Qiao, Xiaohui Wang, Haijing Jin, Jun Peng, Lei Liu, Quan Chen, Jialing Lin.
      Bcl-2 and Bax share a similar structural fold in solution, yet function oppositely in the mitochondrial outer membrane (MOM) during apoptosis. The proapoptotic Bax forms pores in the MOM to trigger cell death, whereas Bcl-2 inhibits the Bax pore formation to prevent cell death. Intriguingly both proteins can switch to a similar conformation after activation by BH3-only proteins, with multiple regions embedded in the MOM. Here we tested a hypothesis that destabilization of the Bcl-2 structure might convert Bcl-2 to a Bax-like perforator. We discovered that mutations of glutamate 152 which eliminate hydrogen bonds in the protein core and thereby reduce the Bcl-2 structural stability. These Bcl-2 mutants induced apoptosis by releasing cytochrome c from the mitochondria in the cells that lack Bax and Bak, the other proapoptotic perforator. Using liposomal membranes made with typical mitochondrial lipids and reconstituted with purified proteins we revealed this perforation activity was intrinsic to Bcl-2 and could be unleashed by a BH3-only protein, similar to the perforation activity of Bax. Our study thus demonstrated a structural conversion of antiapoptotic Bcl-2 to a proapoptotic perforator through a simple molecular manipulation or interaction that is worthy to explore further for eradicating cancer cells that are resistant to a current Bcl-2-targeting drug.
    Keywords:  Apoptosis; Bcl-2 protein pore; Cytochrome c release; Mitochondrial membrane
    DOI:  https://doi.org/10.1016/j.mitoco.2023.08.001
  12. Cancer Biomark. 2024 Aug 02.
    Glutaminase 1 plays critical roles in myelodysplastic syndrome and acute myeloid leukemia cells.
    Seiichi Okabe, Mitsuru Moriyama, Yuya Arai, Akihiko Gotoh.
       BACKGROUND: Myelodysplastic syndrome (MDS) features bone marrow failure and a heightened risk of evolving into acute myeloid leukemia (AML), increasing with age and reducing overall survival. Given the unfavorable outcomes of MDS, alternative treatments are necessary. Glutamine, the most abundant amino acid in the blood, is metabolized first by the enzyme glutaminase (GLS).
    OBJECTIVES: To investigate whether GLS is involved in the progression of MDS. The efficacy of GLS inhibitors (CB839 or IPN60090) and BCL2 inhibitor venetoclax was also examined.
    METHODS: We employed GLS inhibitors (CB839, IPN60090) and the BCL2 inhibitor venetoclax, prepared as detailed. MDS and AML cell lines were cultured under standard and modified (hypoxic, glutamine-free) conditions. Viability, proliferation, and caspase activity were assessed with commercial kits. RT-PCR quantified gene expression post-shRNA transfection. Mitochondrial potential, ATP levels, proteasome activity, and metabolic functions were evaluated using specific assays. Statistical analyses (t-tests, ANOVA) validated the findings.
    RESULTS: The glutamine-free medium inhibited the growth of MDS cells. GLS1 expression was higher in AML cells than in normal control samples (GSE15061), whereas GLS2 expression was not. Treatment of MDS and AML cells for 72 h was inhibited in a dose-dependent manner by GLS inhibitors. Co-treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax and GLS inhibitors increased potency. Cells transfected with GLS1 short hairpin RNA showed suppressed proliferation under hypoxic conditions and increased sensitivity to venetoclax.
    CONCLUSIONS: Targeting glutaminolysis and BCL2 inhibition enhances the therapeutic efficacy and has been proposed as a novel strategy for treating high-risk MDS and AML.
    Keywords:  AML; BCL-2 inhibitor; GLS inhibitor; Glutaminolysis; MDS; hypoxia
    DOI:  https://doi.org/10.3233/CBM-230454
  13. Pharmacol Res. 2024 Aug 30. pii: S1043-6618(24)00327-X. [Epub ahead of print]208 107382
    Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.
    Veronica Marabitti, Elisabetta Vulpis, Francesca Nazio, Silvia Campello.
      It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.e. the intercellular movement of mitochondria, is recently emerging as a novel process in cancer biology, contributing to tumor growth, metastasis, and resistance to therapy by shaping the metabolic landscape of the tumor microenvironment. This review highlights the influence of transferred mitochondria on cancer bioenergetics, redox balance and apoptotic resistance, which collectively foster aggressive cancer phenotype. Furthermore, the therapeutic implications of mitochondrial transfer are discussed, emphasizing the potential of targeting these pathways to overcome drug resistance and improve treatment efficacy.
    Keywords:  Mitochondria transfer; cancer therapy; metabolic alterations; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2024.107382
  14. Pharmacol Res. 2024 Sep 02. pii: S1043-6618(24)00338-4. [Epub ahead of print]208 107393
    F-ATP synthase inhibitory factor 1 and mitochondria-organelle interactions: New insight and implications.
    Lishu Guo.
      Mitochondria are metabolic hub, and act as primary sites for reactive oxygen species (ROS) and metabolites generation. Mitochondrial Ca2+ uptake contributes to Ca2+ storage. Mitochondria-organelle interactions are important for cellular metabolic adaptation, biosynthesis, redox balance, cell fate. Organelle communications are mediated by Ca2+/ROS signals, vesicle transport and membrane contact sites. The permeability transition pore (PTP) is an unselective channel that provides a release pathway for Ca2+/ROS, mtDNA and metabolites. F-ATP synthase inhibitory factor 1 (IF1) participates in regulation of PTP opening and is required for the translocation of transcriptional factors c-Myc/PGC1α to mitochondria to stimulate metabolic switch. IF1, a mitochondrial specific protein, has been suggested to regulate other organelles including nucleus, endoplasmic reticulum and lysosomes. IF1 may be able to mediate mitochondria-organelle interactions and cellular physiology through regulation of PTP activity.
    Keywords:  Ca(2+); F-ATP synthase inhibitory factor 1; Metabolites; Mitochondria; Mitochondria-organelle interactions; Permeability transition; ROS
    DOI:  https://doi.org/10.1016/j.phrs.2024.107393
  15. PLoS One. 2024 ;19(9): e0304939
    Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells.
    Jingyu Tan, Xinlin Dong, Haiwen Liu.
      Cellular oxidative stress mediated by intrinsic and/or extrinsic reactive oxygen species (ROS) is associated with disease pathogenesis. Oxidative DNA damage can naturally be substituted by mitochondrial DNA (mtDNA), leading to base lesion/strand break formation, copy number changes, and mutations. In this study, we devised a single test for the sensitive quantification of acute mtDNA damage, repair, and copy number changes using supercoiling-sensitive quantitative PCR (ss-qPCR) and examined how oxidative stress-related mtDNA damage responses occur in oral cancer cells. We observed that exogenous hydrogen peroxide (H2O2) induced dynamic mtDNA damage responses, as reflected by early structural DNA damage, followed by DNA repair if damage did not exceed a particular threshold. However, high oxidative stress levels induced persistent mtDNA damage and caused a 5-30-fold depletion in mtDNA copy numbers over late responses. This dramatic depletion was associated with significant growth arrest and apoptosis, suggesting persistent functional consequences. Moreover, oral cancer cells responded differentially to oxidative injury when compared with normal cells, and different ROS species triggered different biological consequences under stress conditions. In conclusion, we developed a new method for the sensitive detection of mtDNA damage and copy number changes, with exogenous H2O2 inducing dynamic mtDNA damage responses associated with functional changes in stressed cancer cells. Finally, our method can help characterize oxidative DNA damage in cancer and other human diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0304939
  16. J Cell Mol Med. 2024 Sep;28(17): e70053
    MitoAMPK inhibits the Warburg effect by MZF1-SIRT6 with glycosis related genes in NSCLC.
    Shangyu Li, Jinyao He, Lijie Zhang, Qiaojiajie Zhao, Shuqi Zhao, Shanshan Jiang.
      MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non-small-cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK-8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis-related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP-qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1-SIRT6 complex.
    Keywords:  MZF1; SIRT6; Warburg effect; glycolysis; mitochondrial AMPK; non‐small‐cell lung cancer
    DOI:  https://doi.org/10.1111/jcmm.70053
  17. Blood. 2024 Sep 05. pii: blood.2024024245. [Epub ahead of print]
    TP53-Mutated Acute Myeloid Leukemia: How Can We Improve Outcomes?
    David A Sallman, Maximilian Stahl.
      Despite advances in the treatment paradigm of patients with acute myeloid leukemia (AML), TP53 mutated AML represents a molecular subgroup that has failed to improve with an overall survival around 6 months that is independent of age and fitness. Notably, there has been significant elucidation in understanding the biology of the disease and key advancements in the classification and prognostication of these patients. International collaborative efforts of novel clinical interventions are urgently needed to change the standard of care.
    DOI:  https://doi.org/10.1182/blood.2024024245
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