bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–01–12
23 papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
  2. The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
  3. ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
  4. α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
  5. Precursor occupancy controls mitochondrial import channel via proteolysis.
  6. SLC7A5 is required for cancer cell growth under arginine-limited conditions.
  7. Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies.
  8. De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.
  9. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  10. Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
  11. Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.
  12. Targeting Mitochondria in Glioma: New Hopes for a Cure.
  13. Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
  14. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  15. Effect of Oral Posaconazole on Venetoclax Plasma Concentration and its Efficacy in Patients with Acute Myeloid Leukemia.
  16. Formation of I2+III2 supercomplex rescues respiratory chain defects.
  17. Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
  18. HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.
  19. Point of No Return-What Is the Threshold of Mitochondria With Permeability Transition in Cells to Trigger Cell Death.
  20. Defects in the Mitochondrial Genome of Dogs with Recurrent Tumours.
  21. Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.
  22. Low-avidity T cells drive endogenous tumor immunity in mice and humans.
  23. To what extent is the association between obesity and colorectal cancer risk mediated by systemic inflammation?
  1. Cancer Res. 2025 Jan 09.
    Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer.
    Steven Tau, Mary D Chamberlin, Huijuan Yang, Jonathan D Marotti, Patricia C Muskus, Alyssa M Roberts, Melissa M Carmichael, Lauren Cressey, Christo Philip C Dragnev, Eugene Demidenko, Riley A Hampsch, Shannon M Soucy, Fred W Kolling, Kimberley S Samkoe, James V Alvarez, Arminja N Kettenbach, Todd W Miller.
      Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1204
  2. Cell Rep. 2025 Jan 09. pii: S2211-1247(24)01505-5. [Epub ahead of print]44(1): 115154
    The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models.
    Jaromir Novak, Zuzana Nahacka, Gabriela L Oliveira, Petra Brisudova, Maria Dubisova, Sarka Dvorakova, Sona Miklovicova, Marketa Dalecka, Verena Puttrich, Lenka Grycova, Silvia Magalhaes-Novais, Catarina Mendes Correia, Jennifer Levoux, Ludek Stepanek, Jan Prochazka, David Svec, David Pajuelo Reguera, Guillermo Lopez-Domenech, Renata Zobalova, Radek Sedlacek, Mikkel G Terp, Payam A Gammage, Zdenek Lansky, Josef Kittler, Paulo J Oliveira, Henrik J Ditzel, Michael V Berridge, Anne-Marie Rodriguez, Stepana Boukalova, Jakub Rohlena, Jiri Neuzil.
      Recent research has shown that mtDNA-deficient cancer cells (ρ0 cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1KO) mice markedly delayed tumor formation after grafting ρ0 cancer cells. Miro1KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ0 cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs.
    Keywords:  CP: Cancer; CP: Cell biology; Miro1; RHOT1; cancer; horizontal transfer of mitochondria; melanoma; mitochondria; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.celrep.2024.115154
  3. J Exp Clin Cancer Res. 2025 Jan 09. 44(1): 10
    ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress.
    Jenna L Carter, Yongwei Su, Eman T Al-Antary, Jianlei Zhao, Xinan Qiao, Guan Wang, Holly Edwards, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Steven A Buck, Maik Hüttemann, Joshua E Allen, Varun V Prabhu, Jay Yang, Jeffrey W Taub, Yubin Ge.
       BACKGROUND: Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells.
    METHODS: Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer.
    RESULTS: ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model.
    CONCLUSIONS: ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.
    Keywords:  Acute myeloid leukemia; Azacitidine; ONC213; Venetoclax
    DOI:  https://doi.org/10.1186/s13046-024-03267-6
  4. Blood. 2024 Dec 27. pii: blood.2024025245. [Epub ahead of print]
    α-Ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia.
    Scott Evan Millman, Almudena Chaves-Perez, Sudha Janaki-Raman, Yu-Jui Ho, John P Morris Iv, Varun Narendra, Chi-Chao Chen, Benjamin T Jackson, Jossie J Yashinskie, Riccardo Mezzadra, Tessa I Devine, Valentin J A Barthet, Michelle Saoi, Timour Baslan, Sha Tian, Zohar Sachs, Lydia Ws Finley, Justin R Cross, Scott W Lowe.
      Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
    DOI:  https://doi.org/10.1182/blood.2024025245
  5. Nat Cell Biol. 2025 Jan 08.
    Precursor occupancy controls mitochondrial import channel via proteolysis.
      
    DOI:  https://doi.org/10.1038/s41556-024-01575-9
  6. Cell Rep. 2025 Jan 03. pii: S2211-1247(24)01481-5. [Epub ahead of print]44(1): 115130
    SLC7A5 is required for cancer cell growth under arginine-limited conditions.
    Kyle N Dunlap, Austin Bender, Alexis Bowles, Alex J Bott, Joshua Tay, Allie H Grossmann, Jared Rutter, Gregory S Ducker.
      Tumor cells must optimize metabolite acquisition between synthesis and uptake from a microenvironment characterized by hypoxia, lactate accumulation, and depletion of many amino acids, including arginine. We performed a metabolism-focused functional screen using CRISPR-Cas9 to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Using isotope tracing experiments, we show that citrulline uptake and metabolism into arginine are dependent upon expression of SLC7A5. Pharmacological inhibition of SLC7A5 blocks growth under low-arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. We identify a conditionally essential role for SLC7A5 in arginine metabolism, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be effective in the context of arginine limitation.
    Keywords:  CP: Cancer; CP: Metabolism; CRISPR screening; SLC7A5; amino acid transport; arginine; cancer metabolism; citrulline
    DOI:  https://doi.org/10.1016/j.celrep.2024.115130
  7. Cell Death Differ. 2025 Jan 06.
    Apoptotic priming in senescence predicts specific senolysis by quantitative analysis of mitochondrial dependencies.
    Julie A MacDonald, Gary A Bradshaw, Fleur Jochems, René Bernards, Anthony Letai.
      Cellular senescence contributes to a variety of pathologies associated with aging and is implicated as a cellular state in which cancer cells can survive treatment. Reported senolytic drug treatments act through varying molecular mechanisms, but heterogeneous efficacy across the diverse contexts of cellular senescence indicates a need for predictive biomarkers of senolytic activity. Using multi-parametric analyses of commonly reported molecular features of the senescent phenotype, we assayed a variety of models, including malignant and nonmalignant cells, using several triggers of senescence induction and found little univariate predictive power of these traditional senescence markers to identify senolytic drug sensitivity. We sought to identify novel drug targets in senescent cells that were insensitive to frequently implemented senolytic therapies, such as Navitoclax (ABT-263), using quantitative mass spectrometry to measure changes in the senescent proteome, compared to cells which acquire an acute sensitivity to ABT-263 with senescence induction. Inhibition of the antioxidant GPX4 or the Bcl-2 family member MCL-1 using small molecule compounds in combination with ABT-263 significantly increased the induction of apoptosis in some, but not all, previously insensitive senescent cells. We then asked if we could use BH3 profiling to measure differences in mitochondrial apoptotic priming in these models of cellular senescence and predict sensitivity to the senolytics ABT-263 or the combination of dasatinib and quercetin (D + Q). We found, despite being significantly less primed for apoptosis overall, the dependence of senescent mitochondria on BCL-XL was significantly correlated to senescent cell killing by both ABT-263 and D + Q, despite no significant changes in the gene or protein expression of BCL-XL. However, our data caution against broad classification of drugs as globally senolytic and instead provide impetus for context-specific senolytic targets and propose BH3 profiling as an effective predictive biomarker.
    DOI:  https://doi.org/10.1038/s41418-024-01431-1
  8. Redox Biol. 2024 Dec 31. pii: S2213-2317(24)00458-0. [Epub ahead of print]80 103480
    De novo lipogenesis protects dormant breast cancer cells from ferroptosis and promotes metastasis.
    Beatriz Puente-Cobacho, Cintia Esteo, Patricia Altea-Manzano, Jose Luis Garcia-Perez, José L Quiles, Pedro Sanchez-Rovira, María D Martín-Salvago, Lucía Molina-Jiménez, Rafael J Luque, Sarah-Maria Fendt, Laura Vera-Ramirez.
      Dormant disseminated tumor cells (DTCs) remain viable for years to decades before establishing a clinically overt metastatic lesion. DTCs are known to be highly resilient and able to overcome the multiple biological hurdles imposed along the metastatic cascade. However, the specific metabolic adaptations of dormant DTCs remain to be elucidated. Here, we reveal that dormant DTCs upregulate de novo lipogenesis and favor the activation and incorporation of monounsaturated fatty acids (MUFAs) to their cellular membranes through the activation of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3). Pharmacologic inhibition of de novo lipogenesis or genetic knockdown of ACSL3 results in lipid peroxidation and non-apoptotic cell death through ferroptosis. Clinically, ACSL3 was found to be overexpressed in quiescent DTCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Our work provides new insights into the molecular mechanisms enabling the survival of dormant DTCs and supports the use of de novo lipogenesis inhibitors to prevent breast cancer metastasis.
    Keywords:  Breast cancer; Ferroptosis; Lipid metabolism; Lipid peroxidation; Metastasis; Monounsaturated fatty acids activation; Tumor cell dormancy
    DOI:  https://doi.org/10.1016/j.redox.2024.103480
  9. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  10. J Clin Invest. 2025 Jan 09. pii: e184069. [Epub ahead of print]
    Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells.
    Jue Li, Jie Bai, Vincent T Pham, Michihiro Hashimoto, Maiko Sezaki, Qili Shi, Qiushi Jin, Chenhui He, Amy Armstrong, Tian Li, Mingzhe Pan, Shujun Liu, Yu Luan, Hui Zeng, Paul R Andreassen, Gang Huang.
      Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a leads to HSC defects, including loss of HSC quiescence and self-renewal, and increased differentiation. Mechanistically, we find that loss of Cpt1a results in elevated levels of mitochondrial respiratory chain complex components and their activities, as well as increased ATP production, and accumulation of mitochondrial reactive oxygen species (mitoROS) in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate a novel role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.
    Keywords:  Hematology; Hematopoietic stem cells; Metabolism
    DOI:  https://doi.org/10.1172/JCI184069
  11. Antioxidants (Basel). 2024 Dec 19. pii: 1563. [Epub ahead of print]13(12):
    Facts, Dogmas, and Unknowns About Mitochondrial Reactive Oxygen Species in Cancer.
    Milagros Junco, Clara Ventura, Florencia Ximena Santiago Valtierra, Eduardo Nestor Maldonado.
      Cancer metabolism is sustained both by enhanced aerobic glycolysis, characteristic of the Warburg phenotype, and oxidative metabolism. Cell survival and proliferation depends on a dynamic equilibrium between mitochondrial function and glycolysis, which is heterogeneous between tumors and even within the same tumor. During oxidative phosphorylation, electrons from NADH and FADH2 originated in the tricarboxylic acid cycle flow through complexes of the electron transport chain. Single electron leaks at specific complexes of the electron transport chain generate reactive oxygen species (ROS). ROS are a concentration-dependent double-edged sword that plays multifaceted roles in cancer metabolism. ROS serve either as signaling molecules favoring cellular homeostasis and proliferation or damage DNA, protein and lipids, causing cell death. Several aspects of ROS biology still remain unsolved. Among the unknowns are the actual levels at which ROS become cytotoxic and if toxicity depends on specific ROS species or if it is caused by a cumulative effect of all of them. In this review, we describe mechanisms of mitochondrial ROS production, detoxification, ROS-induced cytotoxicity, and the use of antioxidants in cancer treatment. We also provide updated information about critical questions on the biology of ROS on cancer metabolism and discuss dogmas that lack adequate experimental demonstration. Overall, this review brings a comprehensive perspective of ROS as drivers of cancer progression, inducers of cell death, and the potential use of antioxidants as anticancer therapy.
    Keywords:  ROS; VDAC; antioxidants; cancer; lipid peroxidation; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/antiox13121563
  12. Biomedicines. 2024 Nov 28. pii: 2730. [Epub ahead of print]12(12):
    Targeting Mitochondria in Glioma: New Hopes for a Cure.
    Lidia Gatto, Vincenzo Di Nunno, Anna Ghelardini, Alicia Tosoni, Stefania Bartolini, Sofia Asioli, Stefano Ratti, Anna Luisa Di Stefano, Enrico Franceschi.
      Drugs targeting mitochondrial energy metabolism are emerging as promising antitumor therapeutics. Glioma treatment is extremely challenging due to the high complexity of the tumor and the high cellular heterogeneity. From a metabolic perspective, glioma cancer cells can be classified into the oxidative metabolic phenotype (mainly depending on mitochondrial respiration for energy production) and glycolytic phenotype or "Warburg effect" (mainly depending on glycolysis). Herein, we reviewed the function of novel bio-active molecules targeting oxidative phosphorylation (OXPHOS), mitochondrial membrane potential and mitochondrial dynamics. These molecules exhibit intriguing preclinical and clinical results and have been proven to be promising candidates to be further developed for glioma therapy. However, despite these initial encouraging results, it is imperative to rigorously assess the side effects of these metabolic drugs, which have a non-negligible toxicity profile.
    Keywords:  IACS-010759; ONC201; OXPHOS; Warburg; metformin; mitochondria
    DOI:  https://doi.org/10.3390/biomedicines12122730
  13. Commun Biol. 2025 Jan 09. 8(1): 24
    Mapping mitochondrial morphology and function: COX-SBFSEM reveals patterns in mitochondrial disease.
    Julie Faitg, Tracey Davey, Ross Laws, Conor Lawless, Helen Tuppen, Eric Fitton, Doug Turnbull, Amy E Vincent.
      Mitochondria play a crucial role in maintaining cellular health. It is interesting that the shape of mitochondria can vary depending on the type of cell, mitochondrial function, and other cellular conditions. However, there are limited studies that link functional assessment with mitochondrial morphology evaluation at high magnification, even fewer that do so in situ and none in human muscle biopsies. Therefore, we have developed a method which combines functional assessment of mitochondria through Cytochrome c Oxidase (COX) histochemistry, with a 3D electron microscopy (EM) technique, serial block-face scanning electron microscopy (SBFSEM). Here we apply COX-SBFSEM to muscle samples from patients with single, large-scale mtDNA deletions, a cause of mitochondrial disease. These deletions cause oxidative phosphorylation deficiency, which can be observed through changes in COX activity. One of the main advantages of combining 3D-EM with the COX reaction is the ability to look at how per-mitochondrion oxidative phosphorylation status is spatially distributed within muscle fibres. Here we show a robust spatial pattern in COX-positive and intermediate-fibres and that the spatial pattern is less clear in COX-deficient fibres.
    DOI:  https://doi.org/10.1038/s42003-024-07389-7
  14. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
  15. Recent Pat Anticancer Drug Discov. 2025 Jan 08.
    Effect of Oral Posaconazole on Venetoclax Plasma Concentration and its Efficacy in Patients with Acute Myeloid Leukemia.
    Mengqi Guo, Yingzhi He, Jingwen Du, Dezhi Qiu, Yinjie Qin, Yuxian Huang.
       BACKGROUND: BCL-2 was the first gene identified to have antiapoptotic effects, and venetoclax is an oral selective BCL-2 inhibitor, which has great potential in the treatment of patients with acute myeloid leukemia (AML) who are not candidates for intensive therapy. Notably, posaconazole, an oral antifungal drug, is also a strong factor that can affect blood venetoclax concentrations. To the best of our knowledge, the relationship between BCL-2 expression, posaconazole, and venetoclax, as well as their influence on treatment efficacy and the prognosis of patients with AML, has not been reported.
    OBJECTIVES: In this single-center retrospective study, the relationship between BCL-2 expression and blood venetoclax concentration was analyzed in 35 patients with AML. After that, we explored the differences in curative effect, adverse reactions, and outcomes between patients with different BCL-2 expression levels and patients with different venetoclax concentration levels, respectively.
    METHODS: BCL-2 mRNA expression levels were examined by reverse transcription quantitative PCR. Blood venetoclax concentrations were measured using high-performance liquid chromatography- tandem mass spectrometry.
    RESULTS: The results revealed that among patients with AML, those with lower primary BCL-2 expression had a higher complete remission (CR) rate (p =0.005), overall response (OR) rate (p <0.0001), and progression-free survival time (p =0.04). Posaconazole was revealed to be a strong factor that was able to increase blood venetoclax concentration (p <0.001) and CR rate in the venetoclax plus posaconazole group compared to that in the venetoclax monotherapy group (p =0.002); however, no significant difference was identified in the occurrence of adverse reactions between these groups. Among low and high-blood venetoclax concentration groups, the event-free survival of the former group was significantly higher (p =0.013).
    CONCLUSION: Higher levels of BCL-2 expression at initial diagnosis may have adverse effects on the efficacy and prognosis of patients, and higher levels of venetoclax concentration may advance the time of adverse reactions in patients, thus adversely affecting event-free survival (EFS).
    Keywords:  Acute myeloid leukemia; BCL-2 expression; BCL-2 inhibitor; posaconazole.; venetoclax
    DOI:  https://doi.org/10.2174/0115748928330206241104161111
  16. Cell Metab. 2025 Jan 08. pii: S1550-4131(24)00457-1. [Epub ahead of print]
    Formation of I2+III2 supercomplex rescues respiratory chain defects.
    Chao Liang, Abhilash Padavannil, Shan Zhang, Sheryl Beh, David R L Robinson, Jana Meisterknecht, Alfredo Cabrera-Orefice, Timothy R Koves, Chika Watanabe, Miyuki Watanabe, María Illescas, Radiance Lim, Jordan M Johnson, Shuxun Ren, Ya-Jun Wu, Dennis Kappei, Anna Maria Ghelli, Katsuhiko Funai, Hitoshi Osaka, Deborah Muoio, Cristina Ugalde, Ilka Wittig, David A Stroud, James A Letts, Lena Ho.
      Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I2+III2, resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction.
    Keywords:  complex I; complex III; complex III ROS; cryo-EM structure; electron transport chain; ischemia reperfusion injury; mitohormesis; respirasome; reverse electron transport; supercomplex
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.011
  17. Cell Metab. 2025 Jan 07. pii: S1550-4131(24)00487-X. [Epub ahead of print]37(1): 5-6
    Divide and conquer, mitochondrial edition: Subpopulations direct cellular energy and nutrient supply.
    Sijie Tan, Nora Kory.
      Mitochondria produce energy and building blocks essential for cell growth. How these competing processes are balanced and sustained during nutrient scarcity remains unclear. Ryu et al. uncover distinct mitochondrial subpopulations, one dedicated to ATP production and another to macromolecule synthesis, enabling cell growth and proliferation under nutrient-limiting conditions.
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.006
  18. Cell Signal. 2025 Jan 03. pii: S0898-6568(24)00559-X. [Epub ahead of print]127 111583
    HDAC inhibitor enhances ferroptosis susceptibility of AML cells by stimulating iron metabolism.
    Ruipeng Bian, Yingying Shang, Nahua Xu, Baiping Liu, Yanni Ma, Hui Li, Jieping Chen, Qi Yao.
      Acute Myeloid Leukemia (AML) are challenging blood cancers with limited long-term survival rates, necessitating novel therapeutic strategies. This study explored the role of Histone deacetylase (HDAC) inhibitors in enhancing ferroptosis in AML cells by modulating iron metabolism. We demonstrated that HDAC inhibitors (Entinostat and Vorinostat) sensitize AML cells to ferroptosis both in vitro and in vivo. Mechanistically, we show that HDAC inhibitor treatment upregulated the expression of iron metabolism genes that lead to increased labile iron pool. Notably, NCOA4, a ferritin degradation mediator, and HMOX1/2 proteins, involved in heme breakdown, were identified as critical contributors to this process. The functional role of these genes was confirmed through CRISPR-Cas9 mediated knockouts, which significantly rescued cells from HDAC-induced ferroptosis sensitivity. Our results suggest a novel therapeutic approach for AML, where combining HDAC inhibitors with ferroptosis inducers could exploit the disrupted iron metabolism in AML cells. This study highlights the potential of HDAC inhibitors to modulate iron metabolism pathways, offering new insights into the treatment of these malignancies.
    Keywords:  AML; Ferroptosis; HDAC inhibitors; Iron metabolism
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111583
  19. J Cell Physiol. 2025 Jan;240(1): e31521
    Point of No Return-What Is the Threshold of Mitochondria With Permeability Transition in Cells to Trigger Cell Death.
    Kristina A Kritskaya, Olga A Stelmashchuk, Andrey Y Abramov.
      Programmed cell death (apoptosis) is essential part of the process of tissue regeneration that also plays role in the mechanism of pathology. The phenomenon of fast and transient permeability of mitochondrial membranes by various triggers, known as permeability transition pore (mPTP) leads to the release of proapoptotic proteins and acts as an initial step in initiation of apoptosis. However, a role for mPTP was also suggested for physiology and it is unclear if there is a threshold in number of mitochondria with mPTP which induces cell death and how this mechanism is regulated in different tissues. Using simultaneous measurements of mitochondrial membrane potential and a fluorescent marker for caspase-3 activation we studied the number of mitochondria with calcium-induced mPTP opening necessary for induction of apoptosis in rat primary cortical neurons, astrocytes, fibroblasts, and cancer (BT-474) cells. The induction of apoptosis was correlated with 80%-90% mitochondrial signal loss in neural cells but only 35% in fibroblasts, and in BT-474 cancer cells over 90% of mitochondria opens mPTP before apoptosis becomes obvious. The number of mitochondria with mPTP which induce cell death did not correlate with total expression levels of proapoptotic proteins but was consistent with the Bax/Bcl-2 ratio in these cells. Calcium-induced mPTP opening increased levels of necrosis which was higher in fibroblasts compared to neurons, astrocytes and BT-474 cells. Thus, different tissues require specific numbers of mitochondria with PTP opening to induce apoptosis and it correlates to the proapoptotic/antiapoptotic proteins expression ratio in them.
    Keywords:  apoptosis; astrocytes; caspase‐3; fibroblasts; mPTP; mitochondria; necrosis; neurons
    DOI:  https://doi.org/10.1002/jcp.31521
  20. Int J Mol Sci. 2024 Dec 14. pii: 13414. [Epub ahead of print]25(24):
    Defects in the Mitochondrial Genome of Dogs with Recurrent Tumours.
    Krzysztof Kowal, Kaja Ziółkowska-Twarowska, Angelika Tkaczyk-Wlizło, Ludmiła Grzybowska-Szatkowska, Brygida Ślaska.
      This study presents a comprehensive analysis of mitochondrial DNA (mtDNA) variations in dogs diagnosed with primary and recurrent tumours, employing Oxford Nanopore Technologies (ONT) for sequencing. Our investigation focused on mtDNA extracted from blood and tumour tissues of three dogs, aiming to pinpoint polymorphisms, mutations, and heteroplasmy levels that could influence mitochondrial function in cancer pathogenesis. Notably, we observed the presence of mutations in the D-loop region, especially in the VNTR region, which may be crucial for mitochondrial replication, transcription, and genome stability, suggesting its potential role in cancer progression. The study is pioneering in its use of long-read sequencing to explore the mutational landscape of mtDNA in canine tumours, revealing that while the overall mutational load did not differ between primary and recurrent tumours, specific changes in m.16168A/G, m.16188G/A, and m.16298A/G are linked with tumour tissues. Interestingly, the heteroplasmy outside the D-loop region was not specific to tumour tissues and did not provoke any malignant damage in protein-coding sequences, which in turn may be a tolerant effect of the reactive oxygen species (ROS) cellular stress mechanism.
    Keywords:  Oxford Nanopore Sequencing; cancers; dog; mtDNA
    DOI:  https://doi.org/10.3390/ijms252413414
  21. Nat Metab. 2025 Jan 09.
    Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.
    Michael Nshanian, Joshua J Gruber, Benjamin S Geller, Faye Chleilat, Samuel M Lancaster, Shannon M White, Ludmila Alexandrova, Jeannie M Camarillo, Neil L Kelleher, Yingming Zhao, Michael P Snyder.
      The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate bind and act as promoters of genes involved in growth, differentiation and ion transport. We propose a mechanism involving direct modification of specific genomic regions by SCFAs resulting in increased chromatin accessibility and, in the case of butyrate, opposing effects on the proliferation of normal versus CRC cells.
    DOI:  https://doi.org/10.1038/s42255-024-01191-9
  22. Nat Immunol. 2025 Jan 09.
    Low-avidity T cells drive endogenous tumor immunity in mice and humans.
    Summit Singhaviranon, Joseph P Dempsey, Adam T Hagymasi, Ion I Mandoiu, Pramod K Srivastava.
      T cells recognize neoepitope peptide-major histocompatibility complex class I on cancer cells. The strength (or avidity) of the T cell receptor-peptide-major histocompatibility complex class I interaction is a critical variable in immune control of cancers. Here, we analyze neoepitope-specific CD8 cells of distinct avidities and show that low-avidity T cells are the sole mediators of cancer control in mice and are solely responsive to checkpoint blockade in mice and humans. High-avidity T cells are ineffective and immune-suppressive. The mechanistic basis of these differences lies in the higher exhaustion status of high-avidity cells. High-avidity T cells have a distinct transcriptomic profile that is used here to calculate an 'avidity score', which we then use for in silico identification of low-avidity and high-avidity T cells in mice and humans. Surprisingly, CD8+ T cells with identical T cell receptors exhibit wide variation in avidities, suggesting an additional level of regulation of T cell activity. Aside from providing a better understanding of endogenous T cell responses to cancer, these findings might instruct future immunotherapy strategies.
    DOI:  https://doi.org/10.1038/s41590-024-02044-z
  23. Cancer Commun (Lond). 2025 Jan 10.
    To what extent is the association between obesity and colorectal cancer risk mediated by systemic inflammation?
    Fatemeh Safizadeh, Marko Mandic, Michael Hoffmeister, Hermann Brenner.
      
    DOI:  https://doi.org/10.1002/cac2.12659
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