bims-mibica 2025-10-05 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–10–05
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.
Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.
Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia.
Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.
Targeting High-Density Aromatic Peptides to Cardiolipin Optimizes the Mitochondrial Membrane Potential and Inhibits Oxidative Stress.
Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.
Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.
Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.
Engineering Artificial Mitochondria with Self-Amplifying Proton Generation for Autonomous Energy Supply and Metabolic Coupling in Artificial Cells.
Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.
DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.
Regulation of pyruvate dehydrogenase complex: Dancing to different drums in cancer.
Structural insights into chemoresistance mutants of BCL-2 and their targeting by stapled BAD BH3 helices.
Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.
Decoding the Hot-Mitochondrion Paradox.
Factors affecting response and resistance to venetoclax in acute myeloid leukemia.

Cancer Res. 2025 Oct 01. OF1-OF3

Alternatively Spliced Citrate Synthase Supports Colorectal Cancer.

Désirée Schatton, Christian Frezza.

Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3356
Res Sq. 2025 Sep 23. pii: rs.3.rs-7483419. [Epub ahead of print]

Ferritinophagy Loss Drives Mitochondrial Iron Import and Colorectal Tumorigenesis.

Xiang Xue, Hyeoncheol Kim, Luke Villareal, Naiara Santana-Codina, Christian Cabanlong, Lavanya Goodla, Eric Prossnitz, David Martin, Joseph Mancias.

Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory networks linking cellular iron homeostasis to colorectal cancer (CRC) progression remain incompletely understood. Here, we identify nuclear receptor coactivator 4 (NCOA4), a ferritinophagy receptor, as a context-dependent tumor suppressor that coordinates cytosolic and mitochondrial iron handling in CRC. Analysis of human tumors and colon-specific Ncoa4 knockout mice revealed that NCOA4 loss drives tumorigenesis by inducing transferrin receptor-mediated iron uptake and mitochondrial calcium uniporter (MCU)-dependent mitochondrial iron import. This dual iron overload elevates mitochondrial reactive oxygen species, activates STAT3 signaling, and enhances tumor cell proliferation. NCOA4 overexpression reverses these effects, reducing MCU expression and tumor growth. Pharmacological inhibition of MCU, STAT3, or mitochondrial iron transport mitigated tumorigenesis in NCOA4-deficient models. Our findings define an NCOA4-MCU-STAT3 metabolic signaling axis that couples iron metabolism to oncogenic progression and reveal mitochondrial iron handling as a therapeutic vulnerability in CRC.

DOI: https://doi.org/10.21203/rs.3.rs-7483419/v1
Biochim Biophys Acta Mol Basis Dis. 2025 Oct 01. pii: S0925-4439(25)00413-2. [Epub ahead of print] 168065

Metabolic reprogramming represents a targetable mechanism to overcome acquired resistance to venetoclax in acute myeloid leukemia.

Gustavo Nery de Queiroz, Keli Lima, Marcella Cipelli, Victoria Tomaz, Luiz Gustavo Ferreira Cortez, Marina de Franca Basto Silva, Rafael Lucas Muniz Guedes, Paulo Vidal Campregher, Eduardo Magalhães Rego, Niels Olsen Saraiva Câmara, Leticia Veras Costa-Lotufo, João Agostinho Machado-Neto.

  Acute myeloid leukemia (AML) often develops resistance to the BCL2 inhibitor venetoclax through metabolic reprogramming. This study established acquired venetoclax-resistant AML models (MV4-11VR and MOLM-13VR) to explore resistance mechanisms and therapeutic strategies. Cell viability and apoptosis assays revealed robust acquired resistance to venetoclax upon intermittent drug exposure. Metabolic profiling revealed distinct adaptations: MV4-11VR cells favored glycolysis, while MOLM-13VR cells increased oxidative phosphorylation. Proteomic analysis supported these findings, showing pathway enrichment for carbohydrate metabolism in MV4-11VR and aerobic energy production in MOLM-13VR. Despite these differences, both models shared hyperactivation of the PI3K/AKT/mTOR pathway, as shown by RPS6 hyperphosphorylation. Apoptotic regulation also diverged between the cellular models in relation to modulated BCL2-related genes and activation of the MAPK signaling pathway. Targeting these metabolic changes with metformin (a mitochondrial complex I inhibitor) or KPT-9274 (a NAMPT inhibitor) re-sensitized resistant cells to venetoclax. Combination treatments showed strong synergy and near-complete cell elimination. These results highlight metabolic reprogramming as a heterogeneous but targetable resistance mechanism and support combining metabolic inhibitors with BCL2 blockade to treat refractory AML.

Keywords:  Acute myeloid leukemia; Glycolysis; Metabolic reprogramming; OXPHOS; Targeted therapy; Venetoclax resistance

DOI:  https://doi.org/10.1016/j.bbadis.2025.168065
Pharmacol Res. 2025 Sep 25. pii: S1043-6618(25)00398-6. [Epub ahead of print]221 107973

Imaging of mitochondrial matrix pH dynamics reveals a functional interaction between the ADP/ATP carrier and ATP synthase to regulate H+ distribution.

Bernard Ribalet, Scott John, Madeleine G Milner, Leia Salongo, Ambre M Bertholet.

  In mitochondria, the energy derived from the proton gradient across the mitochondrial inner membrane (IMM) is converted into ATP and heat. For these conversions to occur, H+ is pumped out of the matrix via the electron transport chain (ETC) and then re-enters either via the ATP synthase to produce ATP or via the ADP/ATP carrier (AAC) to release heat. Due to its dual functions of ADP/ATP exchange and H+ transport, AAC may be considered a major regulator of the energy distribution of mitochondria between ATP synthesis and thermogenesis. Using real-time imaging of pH with a fluorescent pH probe targeted to the mitochondrial matrix, we investigated in a myoblast cell model how H+ fluxes across the IMM are regulated by AAC and the ATP synthase. Our data show that activation of AAC-dependent H+ transport by the mitochondrial uncoupler BAM15 causes an acidification of the matrix followed by a re-alkalization phase due to the reversed activity of the ATP synthase. Similar re-alkalization and reversal of ATP synthase activity were observed after acidification caused by inhibition of the electron transport chain. Lastly, the discovery that strong protonophoric activity independent of AAC suppresses the re-alkalization phase and consequently the reverse action of the ATP synthase, suggests the need for strict control of the H+ flux through the IMM by AAC. Thus, real-time imaging of matrix pH reveals a functional interaction between AAC and the ATP synthase for the control of H+ fluxes across the IMM.

Keywords:  ADP/ATP carrier; ATP synthase; BAM15; Electron transport chain; FCCP; Mitochondria; PH sensor; Proton transport; Uncoupling protein

DOI:  https://doi.org/10.1016/j.phrs.2025.107973
FASEB Bioadv. 2025 Oct;7(10): e70052

Targeting High-Density Aromatic Peptides to Cardiolipin Optimizes the Mitochondrial Membrane Potential and Inhibits Oxidative Stress.

Alexander Birk, Sara Arain, Daniele Musumeci, Virginia Garcia-Marin, Margaret A MacNeil.

  Cardiolipin (CL), a mitochondria-specific non-bilayer phospholipid, plays an essential role in the assembly and structural dynamics of the respiratory chain, affecting the membrane morphology and functional activity of inner mitochondria membrane (IMM)-embedded proteins. CL forms CL-rich domains on the IMM where negative curvature is required to increase the stability of cristae. However, CL constantly transitions between lamellar bilayer and non-bilayer phases, such as inverted CL hexagonal phases and inverted CL micelles. Non-bilayer phases of CL promote mitochondrial fission and fragmentation, transition of CL to the outer mitochondrial membrane (OMM), and mitophagy. In addition, non-bilayer phases of CL can increase proton leakage, which leads to mitochondrial depolarization and decreased mitochondrial ATP synthesis. Thus, therapeutic applications for minimizing non-bilayer CL phases should be able to optimize mitochondrial stability during various stresses. We have developed a novel, high-density aromatic peptide (HDAP2) that targets CL and enhances the stability of CL within the lipid core of bilayers in CL-POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) liposomes. We also demonstrated that HDAP2 interacts with inverted CL micelles, forming HDAP2-CL micelles. This suggests that HDAP2 interacts with the non-bilayer phase of CL, thereby stabilizing CL in the bilayer configuration. Scanning electron microscopy confirmed that HDAP2 assembles into spherical micelles approximately 1-3 μm in diameter. We have also demonstrated that this novel, water-soluble peptide is cell-permeable and targets mitochondria without causing cell toxicity. Furthermore, we used a well-known mitochondrial toxicity model of serum starvation to demonstrate that HDAP2 significantly promoted cell survival in a dose-dependent manner in mitochondria-dependent Madin-Darby bovine kidney (MDBK) cells. Importantly, HDAP2 preserved mitochondrial membrane potential and mitigated oxidative stress during serum deprivation. These protective effects suggest that, through its unique mechanism of action, HDAP2 can enhance cellular homeostasis, which would offer broad therapeutic potential for the prevention, recovery, and reversal of many acute and chronic disease conditions, including neurodegeneration, ischemia-reperfusion injury, and inflammation.

Keywords:  cardiolipin; cell survival; mitochondria; mitochondrial potential; oxidative stress

DOI:  https://doi.org/10.1096/fba.2024-00061
J Med Chem. 2025 Oct 01.

Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.

Zhongli Xu, Dmitry Pokushalov, Md Kabir, Youngeun Lee, Mrittika Chattopadhyay, Edmund C Jenkins, Cessarina Choo, H Ümit Kaniskan, Doris Germain, Jian Jin.

Cancer cells depend on mitochondrial reprogramming for growth, but this raises reactive oxygen species (ROS), increasing reliance on protein quality control (PQC) repair mechanisms. The mitochondrial proteome is maintained through a robust PQC composed of chaperones and proteases, including the mitochondrial matrix protease caseinolytic protease P (ClpP). ClpP has recently emerged as a potential therapeutic target against cancer. Notably, imipridones act as ClpP agonists and have shown potent anticancer activity by inhibiting mitochondrial Electron Transport Chain (ETC) function. In this study, we developed a new generation ClpP agonist, compound 9 (MS6076), which exhibits enhanced ClpP binding, more potent disruption of mitochondrial ETC and lethality in breast cancer models compared to the imipridone ONC212. Furthermore, we show that compound 9 induced cell death in cancer cells resistant to ONC212. The discovery and characterization of compound 9 therefore add to the expanding arsenal of imipridones to target ClpP in cancer.

DOI: https://doi.org/10.1021/acs.jmedchem.5c01315
Nat Commun. 2025 Sep 30. 16(1): 8685

Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.

Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.

Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.

DOI: https://doi.org/10.1038/s41467-025-63813-4
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2506761122

A mouse model of MEPAN demonstrates a role for mitochondrial fatty acid synthesis in iron-sulfur cluster and supercomplex formation.

Deborah G Murdock, Kevin A Janssen, Kierstin Keller, Katherine L Mitchell, Maina Beauplan, William T O'Brien, Lia D'Alessandro, Jeffrey A Haltom, Douglas C Wallace.

  MEPAN (Mitochondrial Enoyl CoA Reductase Protein-Associated Neurodegeneration) is an early-onset movement disorder characterized by ataxia, dysarthria, and optic atrophy. Here, we report the creation of a mouse model of MEPAN with patient-similar compound heterozygous mutations in the Mecr gene. The MEPAN mouse recapitulates the major hallmarks of MEPAN, including a movement disorder, optic neuropathy, defects in protein lipoylation, and reduced mitochondrial oxidative phosphorylation in the brain. MECR catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII), and the mechanism by which loss of mtFASII leads to neurological disease is unknown. LC-MS/MS-based proteomic analysis of Mecr mutant cerebella identified loss of subunits of complex I of oxidative phosphorylation (OXPHOS) and subunits of the iron-sulfur cluster assembly (ISC) complex. Native gels revealed altered OXPHOS complex and supercomplex formation and changes in binding of the acyl carrier protein (ACP) to mitochondrial complexes. These results demonstrate that MECR plays a key role in the acylation of ACP which is necessary for ACP-LYRM-mediated supercomplex modulation and ISC biogenesis and suggest unique pathways for therapeutics.

Keywords:  genetics; iron; mitochondrial disease; mitochondrial fatty acid synthesis; mouse model

DOI:  https://doi.org/10.1073/pnas.2506761122
J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]

Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.

Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.

  Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells

DOI:  https://doi.org/10.1172/JCI182480
Cancer Lett. 2025 Sep 26. pii: S0304-3835(25)00640-8. [Epub ahead of print] 218068

MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.

Taylor S Mills, Marlon Arnone, Elsa Görsch, Simone Poeschel, Stefan Winter, Jessica Kuebler, Lucca M Kimmich, Florian A Büttner, Jan Weller, Saskia S Rudat, Lucas Mix, Jan C Schroeder, Anna M Paczulla Stanger, Matthias Schwab, Claudia Lengerke.

  Leukemic stem cells (LSC) are well recognized for their essential roles in acute myeloid leukemia (AML) initiation and relapse. LSC can be distinguished from non-LSC AML cells by the expression of specific cell surface markers, but there is considerable phenotypic heterogeneity among LSC in AML. Here, using primary patient samples, we report that mannose receptor C-type 2 (MRC2) can be used to enrich for LSC across various AML subtypes. When compared to MRC2- AML cells isolated from the same patient samples, MRC2+ leukemic subpopulations show increased in vitro clonogenic capacity, a stemness transcriptomic signature, and enhanced leukemic capacity in mouse xenograft models. Further, we find that MRC2 is functional on AML cells, and enables their robust uptake of collagen, which supports their glycolytic metabolism. In sum these data highlight the use of functional surface markers to distinguish LSC in AML, and how they can yield insight into their unique characteristics.

Keywords:  MRC2; acute myeloid leukemia; glycolysis; leukemia stem cells; mannose receptor c-type2; metabolism

DOI:  https://doi.org/10.1016/j.canlet.2025.218068
Angew Chem Int Ed Engl. 2025 Sep 30. e202514980

Engineering Artificial Mitochondria with Self-Amplifying Proton Generation for Autonomous Energy Supply and Metabolic Coupling in Artificial Cells.

Fangqin Fu, Xuemei Hu, Shijia Tao, Yu Gao, Daniel Crespy, Katharina Landfester, Xiangzhao Mao, Shuai Jiang.

  A continuous and autonomous energy supply is essential for sustaining life-like biochemical processes in artificial cells. Although considerable efforts have been devoted to engineering artificial organelles that emulate mitochondrial energy conversion, the generation of a robust transmembrane proton gradient-essential for driving efficient ATP production-remains a major challenge. Here, we present a mitochondria-mimicking ATP nano-generator constructed through quantitative co-compartmentalization of glucose oxidase and catalase within silica nanocapsules. Enzymes are encapsulated in situ during the formation of core-shell nanocapsules, enabling precise loading, effective protection, and creation of a confined nanoscale reaction chamber that fosters catalytic synergy. Within this microenvironment, catalase rapidly decomposes H2O2 to generate O2, which is in turn utilized by glucose oxidase-thus establishing a self-reinforcing enzymatic cascade that amplifies proton production. After coating the enzyme-loaded nanocapsules with an ATPase-integrated liposome bilayer to construct the artificial mitochondrion, the resulting proton gradient across the membrane efficiently drives ATP synthase rotation, enabling high-yield ATP production. When integrated into giant unilamellar vesicles (GUVs) as synthetic cell models, this system supports autonomous nicotinamide adenine dinucleotide (NADH) biosynthesis and glucose-powered oxidative phosphorylation, mimicking key metabolic features of living mitochondria. This work establishes an effective and versatile platform for engineering energy-autonomous artificial living systems, advancing the state of the art of bottom-up synthetic biology.

Keywords:  Bioenergy; Cascade reactions; Metabolic mimicry; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1002/anie.202514980
bioRxiv. 2025 Sep 23. pii: 2025.09.18.676961. [Epub ahead of print]

Dietary methionine restriction primes T cell metabolism for activation and tumor inhibition and enhances the efficacy of immune checkpoint blockade.

Xiaoqing Qing, Binita Chakraborty, Panpan Liu, Sandeep Artham, Patrick K Juras, Dongyin Guan, Kristen E Pauken, Ching-Yi Chang, Xia Gao.

The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.

DOI: https://doi.org/10.1101/2025.09.18.676961
Nat Metab. 2025 Sep 30.

DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.

Saber H Saber, Nyakuoy Yak, Xuan Ling Hilary Yong, Yih Tyng Bong, Hannah Leeson, Chuan-Yang Dai, Tobias Binder, Siyuan Lu, Reshinthine Purushothaman, An-Sofie Lenaerts, Leonardo Almeida-Souza, Lidiia Koludarova, Safak Er, Irena Hlushchuk, Arnaud Gaudin, Sachin Singh, Tuula A Nyman, Jeffrey R Harmer, Steven Zuryn, Ernst Wolvetang, Gert Hoy Talbo, Mikko Airavaara, Brendan J Battersby, Ashley J van Waardenberg, Victor Anggono, Giuseppe Balistreri, Merja Joensuu.

Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.

DOI: https://doi.org/10.1038/s42255-025-01367-x
Int J Cancer. 2025 Oct 04.

Regulation of pyruvate dehydrogenase complex: Dancing to different drums in cancer.

Mulchand S Patel, Todd C Rideout.

  Mechanisms governing the regulation of pyruvate dehydrogenase complex (PDC) are markedly modified in cancer cells compared to normal cells. PDC activity in normal cells is controlled by the reversible phosphorylation of three serine residues by dedicated kinases and phosphatases. Recent advances in metabolic reprogramming of glucose in cancer cells show that new and expanded mechanisms operate to regulate PDC. This comprehensive review presents several post-translational modifications of PDC proteins such as phosphorylation, acetylation, lactylation, methylation, and others (at least 12). Transcriptional regulation of PDC-specific kinase and phosphatase genes amplifies cancer-specific regulation of PDC. In some cancer cells, to enhance the mitochondrial oxidative metabolism to meet increased energy requirements, PDC is maintained in its active state by employing yet another novel mechanism involving AMPK-mediated phosphorylation of two different serine residues. Interestingly, impairment in PDC function as a major supplier of mitochondrial acetyl-CoA to the nuclear pool of acetyl-CoA is circumvented by the translocation of the PDC to the nucleus for histone acetylation. These cancer-specific PDC regulatory mechanisms represent an incredible advancement in our understanding of the reprogramming of cellular metabolism in cancer cells and could contribute to the development of new therapeutic strategies.

Keywords:  aerobic glycolysis; cancer; nuclear translocation; posttranslational modifications; pyruvate dehydrogenase complex

DOI:  https://doi.org/10.1002/ijc.70189
Nat Commun. 2025 Sep 29. 16(1): 8623

Structural insights into chemoresistance mutants of BCL-2 and their targeting by stapled BAD BH3 helices.

Thomas M DeAngelo, Utsarga Adhikary, Kyle J Korshavn, Hyuk-Soo Seo, Clara R Brotzen-Smith, Christina M Camara, Sirano Dhe-Paganon, Gregory H Bird, Thomas E Wales, Loren D Walensky.

BCL-2 is a central regulator of apoptosis and inhibits cell death by sequestering pro-apoptotic BH3 alpha-helices within a hydrophobic surface groove. While venetoclax, a BH3-mimetic drug, has transformed the treatment of BCL-2-driven malignancies, its efficacy is increasingly limited by acquired resistance mutations that disrupt small-molecule binding yet preserve anti-apoptotic function-reflecting a remarkable structural adaptation. Here, we employ hydrocarbon-stapled alpha-helices derived from the BAD BH3 motif as conformation-sensitive molecular probes to investigate this therapeutic challenge. The stapled peptides not only retain high-affinity binding to all BCL-2 variants but also show enhanced potency to select venetoclax-resistant mutants. Structural analyses, including X-ray crystallography and hydrogen-deuterium exchange mass spectrometry (HDX MS), demonstrate that these stapled helices restore native BH3 engagement by reversing the conformational consequences of resistance mutations. Notably, we identify a serendipitous interaction between the α3-α4 region of BCL-2 and hydrocarbon staple, which further compensates for altered groove conformation and contributes to mutant binding affinity. Together, these findings offer mechanistic insights into BCL-2 drug resistance and reveal a blueprint for designing next-generation inhibitors that overcome this clinically significant barrier to durable treatment responses.

DOI: https://doi.org/10.1038/s41467-025-63657-y
Nature. 2025 Oct 01.

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22.

Fangtao Chi, Qiming Zhang, Jessica E S Shay, Shixun Han, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Samuel Block, Sumeet Solanki, Yatrik M Shah, Matthew G Vander Heiden, Judith Agudo, Ömer H Yilmaz.

A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

DOI: https://doi.org/10.1038/s41586-025-09589-5
ArXiv. 2025 Jul 04. pii: arXiv:2507.16824v1. [Epub ahead of print]

Decoding the Hot-Mitochondrion Paradox.

Peyman Fahimi, Michael Lynch, Cherif F Matta.

In a 2018 paper and a subsequent article published in 2023, researchers reported that mitochondria maintain temperatures 10-15 degrees higher than the surrounding cytoplasm - a finding that deviates by 5 to 6 orders of magnitude from theoretical predictions based on Fourier s law of heat conduction. In 2022, we proposed a solution to this apparent paradox. In the present perspective, we build upon that framework and introduce new ideas to further unravel how a biological membrane - whether of an organelle or a whole cell - can become significantly warmer than its environment. We propose that proteins embedded in the inner mitochondrial membrane (IMM) can be modeled as ratchet engines, introducing a novel, previously overlooked mode of heat transfer. This mechanism, coupled with localized heat release during the cyclical dehydration-translocation-hydration of ions through membrane proteins, may generate transient but substantial temperature spikes. In the case of protons, the cycle additionally includes deprotonation before translocation and protonation after. The cumulative effect of these microscopic events across the three-dimensional surface of the IMM can account for the elevated temperatures detected by molecular probes. We also offer a hypothesis based on quantum chemical calculations on how such probes might detect these fleeting thermal signatures.
Front Oncol. 2025 ;15 1577908

Factors affecting response and resistance to venetoclax in acute myeloid leukemia.

Michael D Diamantidis.

  The use of the BCL2 inhibitor venetoclax in combination with hypomethylating agents (HMA) is a revolution for the treatment of frail and elderly acute myeloid leukemia (AML) patients. This effective treatment strategy is increasingly more and more applicable for other subsets of AML patients and is currently being tested in numerous clinical trials in combination with other drugs in all treatment lines. In particular, venetoclax combinations can also serve as a definitive therapy or as an effective bridge to allogeneic hematopoietic stem cell transplantation (HSCT). However, the factors affecting response to venetoclax in the abovementioned AML patients are not completely clear and understood until today. The aim of this review is to describe the molecular and clinical patterns of response and durable remission of venetoclax-based combinations in AML patients. Hence, mutations in IDH1, IDH2, ASXL1, NPM1, DDX41, chromatin-cohesin complex and splicing-factor genes predict superior response to venetoclax, while inferior response to the drug has been observed for FLT3-ITD, KRAS, NRAS and TP53 gene mutations. Intriguingly, the achievement of measurable residual disease (MRD) negativity in the first four cycles of venetoclax administration characterizes a subgroup of NPM1-mutated AML patients with a more favorable outcome. Even though focus will be given on factors influencing response to the drug in this review, the main mechanisms of resistance to venetoclax in AML patients will also be discussed.

Keywords:  BCL2 (B-cell lymphoma 2) inhibition; MCL1 (myeloid cell leukemia sequence 1) overexpression; acute myeloid leukemia (AML); azacitidine (AZA); hypomethylating agents (HMAs); resistance; response; venetoclax (VEN)

DOI:  https://doi.org/10.3389/fonc.2025.1577908