bims-mibica 2025-11-23 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2025–11–23
eighteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.
Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia.
Succinate puts the brakes on de novo purine synthesis.
The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.
SLC45A4 encodes a peroxisomal putrescine transporter that promotes GABA de novo synthesis.
Complex II inhibition suppresses RSL3-induced ferroptosis by restoring mitochondrial bioenergetics.
SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation.
Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control.
Mitochondrial NAD+ gradient sustained by membrane potential and transport.
Enzymes of the outer mitochondrial membrane regulating cholesterol and fatty acid metabolism in cancer.
Toward Mitochondrial Targeting of Resistant Triple-Negative Breast Cancer Using Triphenylphosphonium-Conjugated Antimicrobial Peptides.
Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia.
An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.
Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.
Combined Inhibition of telomerase and mitochondria synergistically promote apoptosis in AML cell lines.
Caloric restriction enhances inheritance of wild-type mitochondrial DNA in Saccharomyces cerevisiae.
Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis.
Precision prediction of venetoclax-azacitidine treatment efficacy in acute myeloid leukemia via integrative drug screening and machine learning.

Cancer Res. 2025 Nov 17.

Mitochondrial Transfer Rescues Respiration to Support De Novo Pyrimidine Biosynthesis and Tumor Progression.

Maria Dubisova, Klara Bohacova, Zuzana Nahacka, Daniel Kraus, Jaromir Novak, Sarka Dvorakova, Petra Brisudova, Natalie Danesova, Saba Selvi, Mariia Hrysiuk, Berwini B Endaya, Panagiotis Botsios, Dan-Diem Thi Le, Monika Novotna, Sona Vodenkova, Jaroslav Truksa, Karel Chalupsky, Krystof Klima, Jan Prochazka, Radislav Sedlacek, Francesco Mengarelli, Patrick Orlando, Luca Tiano, Stepana Boukalova, Michael V Berridge, Renata Zobalova, Jiri Neuzil.

Cancer cells with severe defects in mitochondrial DNA (mtDNA) can import mitochondria via horizontal mitochondrial transfer (HMT) to restore respiration. Mitochondrial respiration is necessary for the activity of dihydroorotate dehydrogenase (DHODH), an enzyme of the inner mitochondrial membrane that catalyzes the fourth step of de novo pyrimidine synthesis. Here, we investigated the role of de novo synthesis of pyrimidines in driving tumor growth in mtDNA-deficient (ρ0) cells. While ρ0 cells grafted in mice readily acquired mtDNA, this process was delayed in cells transfected with alternative oxidase (AOX), which combines the functions of mitochondrial respiratory complexes III and IV. The ρ0 AOX cells were glycolytic but maintained normal DHODH activity and pyrimidine production. Deletion of DHODH in a panel of tumor cells completely blocked or delayed tumor growth. The grafted ρ0 cells rapidly recruited tumor-promoting/stabilizing cells of the innate immune system, including pro-tumor M2 macrophages, neutrophils, eosinophils, and mesenchymal stromal cells (MSCs). The ρ0 cells recruited MSCs early after grafting, which were potential mitochondrial donors. Grafting MSCs together with ρ0 cancer cells into mice resulted in mitochondrial transfer from MSCs to cancer cells. Overall, these findings indicate that cancer cells with compromised mitochondrial function readily acquire mtDNA from other cells in the tumor microenvironment to restore DHODH-dependent respiration and de novo pyrimidine synthesis. The inhibition of tumor growth induced by blocking DHODH supports targeting pyrimidine synthesis as a potential widely applicable therapeutic approach.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0737
Cell. 2025 Nov 19. pii: S0092-8674(25)01233-4. [Epub ahead of print]

Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia.

Alexander C Lewis, Emily Gruber, Rheana Franich, Jessica Armstrong, Madison J Kelly, Carlos M Opazo, Yau C Low, Léa Flippe, Kevin Wijanarko, Caitlin L Rowe, Celeste H Mawal, Alexandra Birrell, Joan So, Srimayee Vaidyanathan, Keziah Ting, Liana N Semcesen, Karena Last, Ching-Seng Ang, Giovanna Pomilio, Fiona C Brown, Andrew H Wei, Jason A Powell, Elizabeth S Ng, Ann E Frazier, Kate McArthur, Najoua Lalaoui, David A Stroud, Kristin K Brown, Ricky W Johnstone, Lev M Kats.

  The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal. Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis.

Keywords:  acute myeloid leukemia; cuproptosis; heme biosynthesis; metabolic vulnerability; metabolism; mitochondrial Complex IV

DOI:  https://doi.org/10.1016/j.cell.2025.10.028
Mol Cell. 2025 Nov 20. pii: S1097-2765(25)00861-5. [Epub ahead of print]85(22): 4109-4110

Succinate puts the brakes on de novo purine synthesis.

Timothy C Kenny, Kıvanç Birsoy.

In this issue of Molecular Cell, Nengroo et al.1 report that the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is essential for de novo purine synthesis, revealing a previously unrecognized metabolic dependency in cancer that can be leveraged therapeutically.

DOI: https://doi.org/10.1016/j.molcel.2025.10.020
Mitochondrion. 2025 Nov 16. pii: S1567-7249(25)00096-0. [Epub ahead of print] 102099

The mitochondrial protein TMEM177 fine-tunes mammalian cytochrome c oxidase assembly.

Jakob D Busch, Thomas Schöndorf, Dusanka Milenkovic, Xinping Li, Rolf Wibom, Joana F Silva-Rodrigues, Roberta Filograna, Camilla Koolmeister, Nils-Göran Larsson, Diana Rubalcava-Gracia.

  The mitochondrial cytochrome c oxidase (COX, complex IV), a multi-subunit protein complex, plays a crucial role in cellular respiration by reducing oxygen to water and simultaneously pumping protons to enable oxidative phosphorylation (OXPHOS). Thus, defects in its assembly can directly affect cellular energy homeostasis. COX20 is an essential chaperone for the core subunit COX2. In human cultured cells, TMEM177 was found to stabilize COX20 and maintain balanced COX2 levels. In mice, TMEM177 was also identified as an interactor of mitochondrial ribosomes. To understand the function of TMEM177 in vivo, we generated Tmem177 knockout mice. Here, we analyze how TMEM177 loss affects mitochondrial gene expression, as well as the activity and assembly of OXPHOS complexes. We found that a small proportion of the knockout mice died perinatally, while surviving knockout mice tended to gain less weight. TMEM177 depletion moderately reduced COX20 levels, but OXPHOS complexes were preserved. Moreover, Tmem177 and Surf1 double knockout mice were born asymptomatic. In conclusion, TMEM177 fine-tunes complex IV assembly by stabilizing COX20 in vivo. Our findings refine the current model of complex IV assembly in mammals.

Keywords:  Cytochrome c oxidase; Mitochondria; Mitoribosomes; OXPHOS; mtDNA

DOI:  https://doi.org/10.1016/j.mito.2025.102099
Nat Commun. 2025 Nov 20. 16(1): 10198

SLC45A4 encodes a peroxisomal putrescine transporter that promotes GABA de novo synthesis.

Cecilia Colson, Yujue Wang, James Atherton, Nisha Rani Dahiya, Davood Kharaghani, Xiaoyang Su.

Solute carriers (SLC) are membrane proteins that facilitate the transportation of ions and metabolites across either the plasma membrane or the membrane of intracellular organelles. With more than 450 human genes annotated as SLCs, many of them are still orphan transporters without known biochemical functions. We develop a metabolomic-transcriptomic association analysis, and we find that the expression of SLC45A4 has a strong positive correlation with the cellular level of γ-aminobutyric acid (GABA). Using mass spectrometry and the stable isotope tracing approach, we demonstrate that SLC45A4 promotes GABA de novo synthesis through the Arginine/Ornithine/Putrescine (AOP) pathway. SLC45A4 functions as a putrescine transporter localized to the peroxisome membrane to facilitate GABA production. Taken together, our results reveal a biochemical mechanism where SLC45A4 controls GABA production.

DOI: https://doi.org/10.1038/s41467-025-62721-x
Biochem Biophys Res Commun. 2025 Nov 14. pii: S0006-291X(25)01686-9. [Epub ahead of print]792 152970

Complex II inhibition suppresses RSL3-induced ferroptosis by restoring mitochondrial bioenergetics.

Sun Chul Lee, Soo Kyung Lee, Hyun Kim, Kyu-Sang Park.

  The mitochondrial electron transport chain (ETC) serves as the main site of cellular energy production and a major source of reactive oxygen species (ROS) generation, which can contribute to the lipid peroxidation associated with ferroptosis. However, the critical roles of mitochondria in ferroptosis are still being debated, and the consequences for cell survival vary depending on different ferroptosis inducers or mitochondrial modulators. In the neuroblastoma clonal cells SH-SY5Y, we demonstrated that inhibition of mitochondrial Complex II by 2-thenoyltrifluoroacetone (TTFA) markedly suppressed RSL3-induced ferroptotic lipid peroxidation and cell death. RSL3, a known inhibitor of glutathione peroxidase 4 (GPX4), significantly increased the mitochondrial membrane potential and superoxide production while reducing ATP-linked oxygen consumption. Co-treatment with TTFA effectively attenuated RSL3-induced mitochondrial hyperpolarization, lowered mitochondrial ROS generation, and restored respiratory activities - particularly enhanced ATP-linked oxygen consumption and reduced proton leak. Consistently, TTFA restored ATP production suppressed by RSL3. In contrast, inhibition of Complex I by rotenone did not suppress superoxide production and lipid peroxidation induced by RSL3, although it provided some protection against RSL3-mediated cytotoxicity. These findings suggest that inhibition of Complex II confers protection against ferroptosis by maintaining mitochondrial redox balance and protecting mitochondrial energy metabolism. In addition, our results uncover a novel mitochondrial mechanism underlying RSL3-induced oxidative stress and ferroptosis that can be modulated through targeted regulation of the ETC.

Keywords:  2-thenoyltrifluoroacetone; ATP-linked respiration; Ferroptosis; Mitochondrial electron transport chain; Mitochondrial superoxide; RSL3

DOI:  https://doi.org/10.1016/j.bbrc.2025.152970
Oncogene. 2025 Nov 18.

SQLE drives bladder cancer progression by boosting mitochondrial oxidative phosphorylation.

Yihong Dong, Xinjian Jiang, Xinxin Yang, Jinfeng Zhang, Qiang Fu, Yunfei Zhou, Xun Yang, Yin Fu, Yunjing Hou, Mujiao Li, Jun Yan, Jianwen Xu, Yujuan Yi, Meijuan Liu, Xiaorui Huo, Jiang Han, Yumeng Wang, Chenxu Guo, Qingxin Zhang, Aodi Wu, Xiaoqing Li, Xiaohan Zhang, Shuyuan Chang, Ayaka Tomii, Lin Jia, Yu Xiao, Xiaoyang Hu, Hongxue Meng, Dabin Liu, Shuijie Li.

Bladder cancer (BCa) remains a prevalent malignancy with limited therapeutic options. Although cholesterol elevation links to BCa progression, the specific role of cholesterol metabolism remains unclear. Here, we demonstrate that squalene epoxidase (SQLE), a key cholesterol biosynthesis enzyme, drives BCa oncogenesis. SQLE is upregulated in BCa patients and correlates with poor survival. Functionally, bladder-specific Sqle transgenic (tg) mice showed accelerated tumorigenesis, while Sqle knockout (ko) demonstrated opposite effects in vivo. Mechanistically, SQLE localizes to mitochondria and directly interacts with Lon peptidase 1 (LONP1) to stabilize mitochondrial transcription factor A (TFAM) by preventing its proteolysis, leading to elevated oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mtROS). Pharmacological clearance of mtROS via Mito-TEMPO suppressed tumor growth in Sqle-overexpressing models. Importantly, the FDA-approved SQLE inhibitor terbinafine significantly suppressed BCa progression in preclinical models. Our findings establish SQLE as a critical regulator of mitochondrial metabolism in BCa, supporting SQLE inhibitors as potential therapeutics. In bladder cancer, overexpression of SQLE impairs LONP1-mediated TFAM degradation through direct interaction with LONP1, thereby leading to increased mitochondrial OXPHOS and the accumulation of mtROS, which ultimately contributes to tumor growth. Treatment with the SQLE inhibitor terbinafine effectively blocks this process, providing a potential therapeutic strategy to inhibit tumor progression. The Graphical Abstract was created using Smart.Servie ( https://smart.servier.com/citation-sharing/ ).

DOI: https://doi.org/10.1038/s41388-025-03626-3
bioRxiv. 2025 Oct 02. pii: 2025.10.02.678294. [Epub ahead of print]

Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control.

Zachary L Sebo, Ram P Chakrabarty, Rogan A Grant, Karis B D'Alessandro, Alec R Koss, Jenna L E Blum, Shawn M Davidson, Colleen R Reczek, Navdeep S Chandel.

Metformin is a therapeutically versatile biguanide drug primarily prescribed for type II diabetes. Despite its extensive use, the mechanisms underlying many of its clinical effects, including attenuated postprandial glucose excursions, elevated intestinal glucose uptake, and increased production of lactate, Lac-Phe and GDF15, remain unclear. Here, we map these and other clinical effects of metformin to intestine-specific mitochondrial complex I inhibition. Using human metabolomic data and an orthogonal genetics approach in male mice, we demonstrate that metformin suppresses citrulline synthesis, a metabolite generated exclusively by small intestine mitochondria, and increases GDF15 by inhibiting the mitochondrial respiratory chain at complex I. This inhibition co-opts the intestines to function as a glucose sink, driving uptake of excess glucose and converting it to lactate and Lac-Phe. Notably, the glucose-lowering effect of another biguanide, phenformin, and berberine, a structurally unrelated nutraceutical, similarly depends on intestine-specific mitochondrial complex I inhibition, underscoring a shared therapeutic mechanism.

DOI: https://doi.org/10.1101/2025.10.02.678294
Sci Adv. 2025 Nov 21. 11(47): eaea7460

Mitochondrial NAD+ gradient sustained by membrane potential and transport.

Shivansh Goyal, Scott N Lyons, Xiaolu A Cambronne.

SLC25A51 is required for the replenishment of free nicotinamide adenine dinucleotide (oxidized form) (NAD+) into mammalian mitochondria. However, it is not known how SLC25A51 imports this anionic molecule to sustain elevated NAD+ concentrations in the matrix. Understanding this would reveal regulatory mechanisms used to maintain critical bioenergetic gradients for cellular respiration, oxidative mitochondrial reactions, and mitochondrial adenosine triphosphate (ATP) production. In this work, mutational analyses and localized NAD+ biosensors revealed that the mitochondrial membrane potential (ΔΨm) works in concert with charged residues in the carrier's inner pore to enable sustained import of NAD+ against its electrochemical gradient into the matrix. Dissipation of the ΔΨm or mutation of select residues in SLC25A51 led to equilibration of NAD+ from the matrix. Corroborating data were obtained with the structurally distinct mitochondrial NAD+ carrier from Saccharomyces cerevisiae (ScNdt1p) and mitochondrial ATP transport suggesting a shared mechanism of charge compensation and electrogenic transport in these mitochondrial carrier family members.

DOI: https://doi.org/10.1126/sciadv.aea7460
Adv Cancer Res. 2025 ;pii: S0065-230X(25)00017-X. [Epub ahead of print]168 63-97

Enzymes of the outer mitochondrial membrane regulating cholesterol and fatty acid metabolism in cancer.

Leilei Zhang, Milagros Junco, Danyelle M Townsend, Eduardo N Maldonado.

  Mitochondria are major sites of ATP production, also serving as metabolic and biosynthetic hubs. The structure of mitochondria comprises a matrix enclosed by an inner membrane which is separated from the outer mitochondrial membrane (OMM) by the intermembrane space. The OMM is a lipid bilayer that forms an interphase between mitochondria and the surrounding cytosol. While its primary function is to act as a selective barrier, controlling the exchange of molecules between these two cellular compartments, the OMM also plays a crucial role in various metabolic and regulatory processes. It is home to 114 distinct proteins, including transporters, signaling molecules, and structural components. Among these, approximately 30 are enzymes that actively participate in the regulation of lipid metabolism, amino acid processing, calcium homeostasis, and heme biosynthesis. These enzymatic functions highlight the OMM's significance beyond its structural role, positioning it as a key player in cellular energy balance, apoptosis, and intracellular signaling pathways. Here, we focus on OMM proteins involved in the synthesis and utilization of cholesterol and fatty acids. We describe the mechanisms of action, effects, regulation, association with cancer progression, and their potential as pharmacological targets of the steroid acute regulatory protein (StAR), translocator protein (TSPO), acetyl-CoA carboxylase β (ACCβ), acyl-CoA synthetases long chain family member 1 and 6 (ACSL1 and ACSL6), and carnitine palmitoyl transferases 1A and 1B (CPT1A and CPT1B). Overall, we provide a comprehensive view of these OMM enzymes in non-cancerous and cancer cells as well as their potential as targets for developing novel chemotherapies.

Keywords:  Acetyl-CoA carboxylase β; Acyl-CoA synthetases long chain family members 1 and 6; Carnitine palmitoyl transferases 1A and 1B; Cholesterol; Fatty acids; Mitochondria; Outer mitochondrial membrane; Steroid acute regulatory proteins; Translocator protein

DOI:  https://doi.org/10.1016/bs.acr.2025.06.002
ACS Pharmacol Transl Sci. 2025 Nov 14. 8(11): 4159-4171

Toward Mitochondrial Targeting of Resistant Triple-Negative Breast Cancer Using Triphenylphosphonium-Conjugated Antimicrobial Peptides.

Eda Kapan, Cemile Uslu, Haya Arab, Leen Ahmed, Rama Ali, Andrey G Tereshchenkov, Natalia V Sumbatyan, Alex Lyakhovich.

  Metastatic evolution of malignant tumors following standard anticancer therapies and the emergence of resistant cancer cell populations remain major challenges in oncology. One promising strategy is to develop compounds that selectively target mechanisms of therapeutic resistance. Unlike therapy-sensitive malignant cells, which rely primarily on glycolysis for energy, many chemoresistant cells and cancer stem cells (CSCs) preferentially utilize mitochondrial oxidative phosphorylation (OXPHOS). In this study, we employed a triple-negative breast cancer model to demonstrate that short antimicrobial peptides can significantly suppress the metastatic potential of resistant cancer cells and reduce the formation of CSC-like mammospheres by disrupting mitochondrial respiration. This effect was further enhanced by conjugating the peptides to the mitochondrial-targeting cation triphenylphosphonium (TPP). Mechanistic studies revealed that these compounds induce oxidative stress and mitophagy and suppress mitochondrial translation. Collectively, these findings suggest that TPP-conjugated peptides represent a promising therapeutic strategy for targeting OXPHOS-dependent resistance in aggressive solid tumors.

Keywords:  antimicrobial peptides; cancer resistance; cancer stem cells; mitochondria; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.1021/acsptsci.5c00563
Cancer Res. 2025 Nov 21.

Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia.

Johanna Eriksson, Shuyu Zheng, Mihaela Popa, Jie Bao, Jun Dai, Wenyu Wang, Emmet McCormack, Anna Vähärautio, Jing Tang.

While FLT3 inhibitors have significantly improved the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), the emergence of resistance remains as a major challenge. Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations. Comparison of the gene expression profiles of these cells revealed transcriptional resistance signatures, including upregulation of GSPT1. Depletion of GSPT1 with CRISPR-Cas9-mediated knockout resulted in increased sensitivity of AML cells to quizartinib treatment. Further, targeting GSPT1 with the small molecule CC-90009 exhibited strong synergistic effects when combined with FLT3 inhibitors in the FLT3-ITD cell lines and primary AML patient samples. In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone. Furthermore, compounds that induced transcriptomic changes opposite to the resistance signatures prompted cells to acquire FLT3 inhibitor-sensitive states. Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3753
Nat Commun. 2025 Nov 20. 16(1): 10222

An inherited mitochondrial DNA mutation remodels inflammatory cytokine responses in macrophages and in vivo in mice.

Eloïse Marques, Stephen P Burr, Alva M Casey, Richard J Stopforth, Chak Shun Yu, Keira Turner, Dane M Wolf, Marisa Dilucca, Vincent Paupe, Suvagata Roy Chowdhury, Victoria J Tyrrell, Robbin Kramer, Yamini M Kanse, Chinmayi Pednekar, Chris A Powell, James B Stewart, Julien Prudent, Michael P Murphy, Michal Minczuk, Valerie B O'Donnell, Clare E Bryant, Patrick F Chinnery, Arthur Kaser, Alexander von Kriegsheim, Dylan G Ryan.

Impaired mitochondrial bioenergetics in macrophages promotes hyperinflammatory cytokine responses, but whether inherited mtDNA mutations drive similar phenotypes is unknown. Here, we profiled macrophages harbouring a heteroplasmic mitochondrial tRNAAla mutation (m.5019A>G) to address this question. These macrophages exhibit combined respiratory chain defects, reduced oxidative phosphorylation, disrupted cristae architecture, and compensatory metabolic adaptations in central carbon metabolism. Upon inflammatory activation, m.5019A>G macrophages produce elevated type I interferon (IFN), while exhibiting reduced pro-inflammatory cytokines and oxylipins. Mechanistically, suppression of pro-IL-1β and COX2 requires autocrine IFN-β signalling. IFN-β induction is biphasic: an early TLR4-IRF3 driven phase, and a later response involving mitochondrial nucleic acids and the cGAS-STING pathway. In vivo, lipopolysaccharide (LPS) challenge of m.5019A>G mice results in elevated type I IFN signalling and exacerbated sickness behaviour. These findings reveal that a pathogenic mtDNA mutation promotes an imbalanced innate immune response, which has potential implications for the progression of pathology in mtDNA disease patients.

DOI: https://doi.org/10.1038/s41467-025-65023-4
Mol Cell Biol. 2025 Nov 18. 1-16

Cholesterol Transport from ER to Outer Mitochondria by ERLIN2 in Steroid Metabolism.

Himangshu S Bose, William E Burak, Randy M Whittal.

  Cholesterol trafficking from the endoplasmic reticulum (ER) through the mitochondria-associated ER membrane (MAM) and finally to mitochondria is essential for mammalian survival. ER lipid raft-associated protein 2 (ERLIN2) scaffolds raft-like microdomains in the trans-Golgi network, endosomes, and plasma membrane. We found that ERLIN2 assists in rolling cholesterol trafficking-associated lipid vesicles by facilitating the intermediate folding of cholesterol trafficker steroidogenic acute regulatory protein (StAR) from the ER to MAM prior to delivery to the outer mitochondrial membrane. Each ERLIN2-StAR interaction is short. The absence of ERLIN2 ablates mitochondrial cholesterol transport. Over time, StAR association with ERLIN2 increases from the ER to MAM, thereby enhancing mitochondrial cholesterol transport. Thus, ERLIN2 is central for regulating mitochondrial cholesterol trafficking required for mitochondrial steroid metabolism.

Keywords:  Steroids; cholesterol; endoplasmic reticulum; mitochondria associated-ER membrane (MAM); pregnenolone; steroidogenic acute regulatory protein (StAR)

DOI:  https://doi.org/10.1080/10985549.2025.2583172
Med Oncol. 2025 Nov 18. 43(1): 5

Combined Inhibition of telomerase and mitochondria synergistically promote apoptosis in AML cell lines.

Hossein Kalarestaghi, Khadijeh Dizaji Asl, Zeinab Mazloumi, Mohsen Hemmati-Dinarvand, Abbas Ghotaslou, Majid Nejati, Ali Rafat.

  Despite the significant anti-proliferative effects of telomerase inhibition on acute myeloid leukemia (AML) cells, complementary therapies that promote apoptosis on AML cells have been suggested. This investigation assessed the impact of concurrently targeting telomerase with BIBR1532 and mitochondrial function with Tigecycline on inducing apoptosis in AML cell models. KG-1a and KG-1 AML cells were treated with IC50 concentrations of the telomerase inhibitor BIBR1532 and the mitochondrial inhibitor Tigecycline, both alone and in combination, for 48 h. Cell viability were assessed by MTT assay and Combination Index. Apoptosis was analyzed by Annexin V/7AAD staining using flow cytometry. Gene expression (Bax, Bad, Bcl-2, Bcl-xl, hTERT) was evaluated by quantitative real-time PCR (qRT-PCR), and Bax/Bcl-2 protein levels were measured by ELISA. Telomere length was determined by real-time PCR. Our result showed that, Co-inhibition of telomerase and mitochondria with IC50 values of BIBR1532 and Tigecycline for 48 h synergistically reduced the proliferation rate of AML (KG-1a and KG-1) cells. Besides, telomerase and mitochondria inhibition (TI/MI) synergistically augmented induction of apoptosis coupled with the up-regulation of Bax, Bad genes and down-regulation of Bcl-2, Bcl-xl and hTERT on AML cells. Also, TI/MI significantly changed Bax and Bcl-2 protein levels and reduced telomere length. In conclusion, the combined use of TI/MI induced anti-proliferative effects and induction of apoptosis by down-regulation of anti-apoptotic and up-regulation of pro-apoptotic genes and proteins levels and shortening of telomere length on AML cells.

Keywords:  Acute myeloid leukemia; Apoptosis; Mitochondria; Telomerase

DOI:  https://doi.org/10.1007/s12032-025-03125-1
Sci Rep. 2025 Nov 17. 15(1): 40201

Caloric restriction enhances inheritance of wild-type mitochondrial DNA in Saccharomyces cerevisiae.

Wenjuan Zhu, Minoru Yoshida, Feng Ling.

  In Saccharomyces cerevisiae, an asymmetrical division model, mitochondrial (mt) DNA typically exists in a homoplasmic state, but mutations frequently occur. Rolling-circle replication, mediated by the mtDNA recombinase Mhr1p, forms tandem concatemers that are selectively transmitted to budding cells. In crosses between haploids with wild-type (ρ+) and hypersuppressive (HS) ρ- mtDNA, ρ- progeny are predominantly produced due to the replicative advantage of mtDNA with large deletions. We investigated the effects of caloric restriction (CR; 0.5% glucose medium) on mitochondrial distribution and found that ρ+ mtDNA-mitochondria are pre-selected in zygotes and transmitted into buds prior to mitochondrial fusion. This process, termed ρ+ mtDNA-mitochondrial preselection and transmission (ρ+ mtDNA-MPT), was validated by confocal imaging and flow cytometry analyses. The rate of ρ+ progeny increased under CR conditions compared to glucose-abundant media, suggesting that CR enhances ρ+ mtDNA-MPT and promotes the formation of wild-type mtDNA homoplasmy via an Mhr1p-dependent mechanism, which dominates mtDNA inheritance.

Keywords:  Heteroplasmy; Homoplasmy; Hypersuppresiveness; Mitochondria; Nonmedial budding.; Preselection; mtDNA

DOI:  https://doi.org/10.1038/s41598-025-23888-x
bioRxiv. 2025 Sep 29. pii: 2025.09.28.674326. [Epub ahead of print]

Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis.

Vasileios Chortis, Kleiton Silva Borges, Cong-Hui Yao, Claudio Ribeiro, Luis Fernando Nagano, Mesut Berber, Alessandro Prete, Lukáš Najdekr, Michail E Klontzas, Andris Jankevics, Pedro Vendramini, Jean Lucas Kremer, Liam Kelley, Sathuwarman Raveenthiraraj, Stylianos Tsagarakis, Magdalena Macech, Ivana D Pupovac, Thomas G Papathomas, Betul Haykir, Catherine Winder, Marcus Quinkler, M Conall Dennedy, Grethe Å Ueland, Felix Beuschlein, Antoine Tabarin, Martin Fassnacht, Angela E Taylor, Darko Kastelan, Urszula Ambroziak, Dimitra A Vassiliadi, Katja Kiseljak-Vassiliades, Irina Bancos, Diana L Carlone, Warwick B Dunn, Wiebke Arlt, Marcia C Haigis, David T Breault.

Dysregulation of cellular metabolism is a hallmark of cancer, which remains poorly understood in adrenocortical carcinoma (ACC). Here, we dissected ACC metabolism by integrating transcriptional profiling from human and mouse ACC, targeted tissue metabolomics from a mouse ACC model, and untargeted serum metabolomics from a large patient cohort, providing cross-species validation of metabolic rewiring in ACC. This study revealed global metabolic dysregulation, involving glutamine-dependent pathways such as non-essential amino-acid and hexosamine biosynthesis, nucleotide metabolism, and glutathione biosynthesis, suggesting glutamine catabolism is a critical metabolic vulnerability in ACC. Treatment with glutamine antagonists 6-Diazo-5-Oxo-L-Norleucine (DON) and JHU-083 elicited robust anti-tumor responses. Mechanistic studies revealed DON's anti-tumor effect was primarily driven by selective inhibition of glutamine-fueled de novo nucleotide biosynthesis. Additionally, DON led to DNA damage, which yielded potent synergism with inhibition of the DNA damage response pathway. Collectively, this work highlights glutamine metabolism as a central metabolic dependency and therapeutic target in ACC.

DOI: https://doi.org/10.1101/2025.09.28.674326
Cell Rep Med. 2025 Nov 19. pii: S2666-3791(25)00534-8. [Epub ahead of print] 102461

Precision prediction of venetoclax-azacitidine treatment efficacy in acute myeloid leukemia via integrative drug screening and machine learning.

Peng Jin, Dan Wang, Jie Shen, Qiqi Jin, Hao Zhang, Xiaxin Liu, Mengke He, Wen Jin, Yixuan Li, Fangyi Dong, Fengbo Jin, Yanli Yang, Ruiji Zheng, Shaoyuan Wang, Jianxin Guo, Shuangyue Li, Debin Liu, Zhiling Yan, Chenghao Jin, Bing Xu, Weiming Guo, Hongming Zhu, Yunxiang Zhang, Zhen Jin, Kankan Wang.

  Venetoclax-azacitidine (VEN/AZA) has transformed acute myeloid leukemia (AML) therapy, yet reliable predictors of response remain lacking. We employ a multidisciplinary strategy combining ex vivo drug sensitivity testing, transcriptomic profiling, functional assays, and clinical data to identify determinants of VEN/AZA response. Core genes consistently associated with responsiveness are validated through CRISPR-Cas9 screening, with silencing of BCL2L1 and PINK1 preferentially enhancing drug sensitivity. Building on these insights, we develop and validate an eight-gene random forest model (RF8) that achieves high accuracy across four independent cohorts (n = 498). RF8 distills the downstream effects of genetic alterations to assist in predicting treatment response and outperforms existing genetic mutation-based signatures. Moreover, RF8 scores show a nearly monotonic relationship with clinical response probabilities and survival outcomes, enabling precise patient stratification. These findings demonstrate the feasibility of integrating transcriptomic and drug-response data to guide VEN/AZA therapy, representing an advance toward personalized therapeutic strategies.

Keywords:  acute myeloid leukemia; ex vivo drug sensitivity testing; machine learning; random forest model; treatment response prediction; venetoclax-azacitidine

DOI:  https://doi.org/10.1016/j.xcrm.2025.102461