bims-mibica 2026-01-11 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–01–11
twenty papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
Nutrient requirements of organ-specific metastasis in breast cancer.
Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.
Therapeutic targeting LRPPRC-Mediated OXPHOS synthesis for cancer intervention.
FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis.
MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.
Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
Dextromethorphan Is a Novel Pharmacological Inhibitor of F1FO-ATPase That Targets the Membrane-Embedded Domain Impairing ATP Synthesis and Hydrolysis.
Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
Mitochondrial control of fuel switching via carnitine biosynthesis.
Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
Mitochondrial citrate transport represents a metabolic liability in MYCN-amplified neuroblastoma.
Inhibition of mitochondrial NADH:ubiquinone oxidoreductase by spinning oscillating magnetic fields causes toxicity in cancer cells.
The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.
Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.
Investigating interspecies mitochondrial transplantation on the malignancy of melanoma cells.
SLC25A39 facilitates Sorafenib resistance in hepatocellular carcinoma by inhibiting mitochondrial oxidative stress-induced ferroptosis.
Single-cell resolution of an open chromatin signature in persister tumor cells.
When heme is low, copper kills cancer.

Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01013-5. [Epub ahead of print]86(1): 6-8

Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.

Yury S Bykov, Johannes M Herrmann.

In this issue of Molecular Cell, Zhu et al.1 show that mitochondria of cancer cells rely on the import of glutamine not only to fuel metabolite synthesis via the tricarboxylic acid cycle but also to charge mt-tRNAGln to allow mitochondrial protein synthesis and respiration.

DOI: https://doi.org/10.1016/j.molcel.2025.12.014
Nature. 2026 Jan 07.

Nutrient requirements of organ-specific metastasis in breast cancer.

Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.

Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.

DOI: https://doi.org/10.1038/s41586-025-09898-9
Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316

Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.

Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.

  Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.

Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102316
bioRxiv. 2025 Dec 26. pii: 2025.12.24.696284. [Epub ahead of print]

CK2 inhibitor, CX-4945, enhances BH3 priming and promotes apoptosis of venetoclax-resistant AML by targeting antiapoptotic proteins.

Muhammad Daniyal, Rajesh Rajaiah, Upendarrao Golla, Marudhu Pandiyan Shanmugam, Koby Duke, Katherine Mercer, Yasin Uzun, Hannah Valensi, Jeremy Hengst, Sinisa Dovat, Yi Qiu, Suming Huang, Chandrika G Behura.

Acute myeloid leukemia (AML), the most common hematologic malignancy, generally has a poor prognosis. Despite initial favorable responses to the BCL2 inhibitor venetoclax (VEN), remission is transient, and AML is eventually fatal. Resistance to VEN is primarily due to the overexpression of anti-apoptotic proteins, including MCL-1, BCL2L1 (BCL-XL), and BCL2A1. Casein kinase II (CK2) is a serine-threonine kinase and a known suppressor of apoptosis. We and others have reported that protein kinase CK2 activity is high in leukemic stem cells (LSCs) and associated with resistance to chemotherapy. We have shown that the selective CK2 inhibitor, CX-4945, suppresses BCL-XL and has a significant anti-tumor effect in AML preclinical models. CK2 expression and activity are high in venetoclax-resistant AML (VR-AML) cell lines. Genetic and pharmacological inhibition of CK2 significantly altered VR-AML gene signature, decreased MCL-1 protein level, increased BH3 priming and sensitized VR-AML cells to apoptosis. More importantly, CX-4945 selectively targeted LSCs (CD34+CD38-) and chemoresistant (CD123+CD47+) subpopulation in VR-AML. CX-4945 combined with VEN decreased leukemia burden and prolonged the survival of VR-AML cell line-derived and patient-derived xenografts compared to either drug alone. The combinatorial treatment was well tolerated in mice without additional myelosuppression or organ toxicity. CX-4945 (silmitasertib) is being tested in several early-phase clinical trials against adult and pediatric cancers. These preclinical results support the use of CX-4945 in combination with VEN to overcome resistance to apoptosis and re-sensitize VR-AML to chemotherapy.

DOI: https://doi.org/10.64898/2025.12.24.696284
Expert Opin Ther Targets. 2026 Jan 05.

Therapeutic targeting LRPPRC-Mediated OXPHOS synthesis for cancer intervention.

Yuxin Liang, Lina Wang, Ziyan Yang, Wenjia Chen, Ruibin Jiang, Dachi Wang, Wenxi Wang, Wei Zhou, Xiaohong Fang.

   INTRODUCTION: Oxidative phosphorylation (OXPHOS) is essential for the progression of tumors and their resistance to therapy. Conventional inhibitors of OXPHOS that directly targeting the electron transport chain (ETC) activity often lack tumor selectivity and demonstrate limited efficacy. Inhibiting mitochondrial gene expression to block the de novo biogenesis of OXPHOS complexes - rather than inhibiting preexisting OXPHOS complexes - represents a more potent and tumor-selective strategy. This strategy highlights leucine-rich pentatricopeptide repeat-containing (LRPPRC) as a promising anticancer target.
AREAS COVERED: Extensive evidence confirms that LRPPRC is commonly overexpressed in various cancer types and is indispensable for maintaining malignant phenotypes. Mechanistically, LRPPRC binds mitochondrial mRNAs (mt-mRNAs) via its pentatricopeptide repeat (PPR) motif-rich RNA-binding domain. By stabilizing mt-mRNA and enhancing its translational efficiency, LRPPRC facilitates OXPHOS complex biogenesis and OXPHOS in tumors. We have developed the first small molecule screening platform targeting LRPPRC. Using this platform, we identified dual-function compounds that both inhibit LRPPRC's RNA-binding function and trigger its proteolytic degradation. These agents demonstrate potent suppression of OXPHOS and exhibit favorable safety profiles across multiple preclinical models.
EXPERT OPINION: Current LRPPRC inhibitors often suffer from suboptimal specificity and binding affinity. Advancing clinical translation requires co-crystal structures of LRPPRC for rational drug design and novel delivery strategies to enhance mitochondrial enrichment of inhibitors.

Keywords:  LRPPRC; OXPHOS; RNA binding protein; small molecular inhibitors; targeted therapy

DOI:  https://doi.org/10.1080/14728222.2025.2608028
Peptides. 2026 Jan 02. pii: S0196-9781(25)00124-X. [Epub ahead of print]195 171463

FGF9 drives mitochondrial biogenesis in glioblastoma by activating the CREB-PGC-1α axis.

Kun Xue, Junmei Yang, Jia Hu, Lingwei Kong, Xinguo Cui, Yang Kong.

   BACKGROUND: Mitochondrial biogenesis is upregulated in glioblastoma to support tumor growth, invasion, and chemoresistance by meeting the heightened metabolic demands of cancer cells. Fibroblast growth factor 9 (FGF9) is a potent oncogenic driver in various cancers, promoting proliferation, survival, and angiogenesis. However, its role in regulating mitochondrial metabolism in glioblastoma remains unclear.
METHODS: The activation of FGF9/fibroblast growth factor receptor 2 (FGFR2) signaling and expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) were examined in clinical glioblastoma samples and cell lines using real-time PCR, immunohistochemistry, and western blotting. Mitochondrial biogenesis and function in FGF9-treated U-87 cells were evaluated by measuring relative mtDNA/nDNA ratio, mitochondrial mass (MitoTracker), complex activity, membrane potential, and ATP production. The role of cAMP response element-binding protein (CREB) signaling was investigated using the specific inhibitor H89.
RESULTS: We found activated FGF9/FGFR2 signaling in glioblastoma patients, with elevated serum FGF9 and tumor FGFR2. PGC-1α was upregulated in samples and cell lines. FGF9 boosted mitochondrial biogenesis and function in U-87 cells, increasing mtDNA, mass, complex activity, membrane potential, and ATP production. Mechanistically, FGF9 promoted the expression of PGC-1α and mitochondrial transcription factor A (TFAM) via activation of CREB signaling. Inhibition of CREB phosphorylation by H89 abolished FGF9-induced upregulation of PGC-1α/TFAM, mtDNA replication, and ATP production.
CONCLUSION: These findings reveal that FGF9 enhances mitochondrial biogenesis in glioblastoma through the CREB-PGC-1α-TFAM axis, uncovering a novel metabolic mechanism underlying its pro-tumorigenic effects.

Keywords:  CREB; FGF9; Glioblastoma; Mitochondrial biogenesis; PGC-1α

DOI:  https://doi.org/10.1016/j.peptides.2025.171463
Cell Death Dis. 2026 Jan 02.

MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.

Priyadarshika Pradhan, Tanvi Chaudhary, Shivali Mishra, Peter Konik, Eva Durinova, Roman Tuma, Abhijt De, Devanjan Sinha.

Mitochondrial metabolism plays a crucial role in cancer progression and is associated with effective channeling of electrons through Complex I. The ability to adapt this electron flow as per cellular demands is critical for energy homeostasis. Our observations suggest that proliferating cells regulate the electron entry point through alterations in the levels of Methylation-Controlled J-protein (MCJ). Elevated MCJ levels were found to promote aggressive proliferative and migratory phenotypes, leading to increased primary tumor burden. The phenotype was attributed to MCJ-mediated regulation of mitochondrial bioenergetic plasticity, enabling a preferential rerouting of electron flux through succinate dehydrogenase complex (Complex II). Consequently, cells exhibited suppressed glycolysis and a metabolic shift toward lipid-fueled mitochondrial respiration, marked by increased lipid accumulation and its oxidation. Despite Complex I uncoupling, these cells maintained better respiratory output and preserved NADH levels to support an increased redox potential. These findings decouple the reliance on Complex I for effective mitochondrial respiration and underscore the significance of Complex II-driven metabolism in tumor growth, an important consideration for development of future therapeutics, particularly when current strategies predominantly target Complex I-dependent respiration.

DOI: https://doi.org/10.1038/s41419-025-08398-y
PLoS Genet. 2026 Jan 09. 22(1): e1011836

Local mitochondrial physiology defined by mtDNA quality guides purifying selection.

Felix Thoma, Johannes Hagen, Romina Rathberger, Francesco Padovani, David Hörl, Kurt M Schmoller, Christof Osman.

The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellular energy supply, and can cause mitochondrial diseases. These consequences highlight the importance of mtDNA quality control (mtDNA-QC), the process by which cells selectively maintain intact mtDNA to preserve respiratory function. Here, we developed a high-throughput flow cytometry assay for Saccharomyces cerevisiae to track mtDNA segregation in cell populations derived from heteroplasmic zygotes, in which wild-type (WT) mtDNA is fluorescently labeled and mutant mtDNA remains unlabeled. Using this approach, we observe purifying selection against mtDNA lacking subunits of complex III (COB), complex IV (COX2) or the ATP synthase (ATP6), under fermentative conditions that do not require respiratory activity. By integrating cytometric data with growth assays, qPCR-based mtDNA copy-number measurements, and simulations, we find that the decline of mtDNAΔatp6 in populations derived from heteroplasmic zygotes is largely explained by the combination of its reduced mtDNA copy number-biasing zygotes toward higher contributions of intact mtDNA-and the proliferative disadvantage of cells carrying this variant. In contrast, the loss of mtDNAΔcob and mtDNAΔcox2 cannot be explained by growth defects and copy-number asymmetries alone, indicating an additional intracellular selection against these mutant genomes when intact mtDNA is present. In heteroplasmic cells containing both intact and mutant mtDNA, fluorescent reporters revealed local reductions in ATP levels and membrane potential ([Formula: see text]) near mutant genomes, indicating spatial heterogeneity in mitochondrial physiology that reflects local mtDNA quality. Disruption of the respiratory chain by deletion of nuclear-encoded subunits (RIP1, COX4) abolished these physiological gradients and impaired mtDNA-QC, suggesting that local bioenergetic differences are required for selective recognition. Together, our findings support a model in which yeast cells assess local respiratory function as a proxy for mtDNA integrity, enabling intracellular selection for functional mitochondrial genomes.

DOI: https://doi.org/10.1371/journal.pgen.1011836
Biofactors. 2026 Jan-Feb;52(1):52(1): e70076

Dextromethorphan Is a Novel Pharmacological Inhibitor of F1FO-ATPase That Targets the Membrane-Embedded Domain Impairing ATP Synthesis and Hydrolysis.

Cristina Algieri, Antonia Cugliari, Silvia Granata, Patrycja Anna Glogowski, Fabiana Trombetti, Micaela Fabbri, Lucia Scainelli, Salvatore Nesci.

  Dextromethorphan (DXM), a widely used antitussive agent, was investigated for its effects on mitochondrial F1FO-ATPase activity and oxidative phosphorylation. Our results demonstrate that DXM inhibited F1FO-ATPase independently of the thiol redox state. Mutual exclusion analysis highlighted an overlapping binding site between DXM and dicyclohexylcarbodiimide (DCCD), indicating a shared or adjacent binding site in the membrane-embedded FO domain of the enzyme. These findings suggested that DXM selectively targeted the proton translocation mechanism of F1FO-ATPase during the ATP hydrolysis and synthesis of ATP. Moreover, kinetic analysis confirmed a high affinity of DXM for the enzyme, with an inhibitory efficiency of 2.37 mM-1⸱s-1. Importantly, DXM did not affect electron transport chain activity but impaired ATP synthesis, as evidenced by altered respiratory control ratios of oxidative phosphorylation. The data obtained offer new insights into its off-target mitochondrial effects and potential implications for bioenergetic regulation.

Keywords:  F1FO‐ATPase; dextromethorphan; enzyme kinetics; mitochondria

DOI:  https://doi.org/10.1002/biof.70076
bioRxiv. 2025 Dec 31. pii: 2025.12.31.697091. [Epub ahead of print]

Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.

Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.

Of the ∼1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B12 chaperone MMADHC and cytosolic B12-dependent methionine synthase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.
Significance Statement: Humans have only two vitamin B12-dependent enzymes - mitochondrial MMUT and cytosolic MTR - and both require a common B12 chaperone MMADHC. We discover that MMADHC is a low abundant, short-lived protein that is continuously imported and degraded by energized mitochondria. Upon collapse of the mitochondrial proton motive force, MMADHC accumulates in the cytosol and increases the levels and activity of MTR, critical for one-carbon metabolism. This PMF-dependent regulation of MMADHC stability and localization is important for understanding cofactor rationing and spatiotemporal compartmentalization of B12 metabolism.

DOI: https://doi.org/10.64898/2025.12.31.697091
Science. 2026 Jan 08. eady5532

Mitochondrial control of fuel switching via carnitine biosynthesis.

Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R P Verkerke, Alexander S Banks, Sheng Hui, Lijun Sun, Shingo Kajimura.

Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.

DOI: https://doi.org/10.1126/science.ady5532
Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00492-6. [Epub ahead of print]89 103979

Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.

William M Curtis, Patrick C Bradshaw.

  The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O2-•), hydrogen peroxide (H2O2), nitric oxide (NO•), peroxynitrite (ONOO-), carbonate radicals (•CO3-), nitrogen dioxide radicals (•NO2), hydroxyl radicals (•OH), oxygen (•O2• or O2), and carbon dioxide (CO2). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O2-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O2-• is mainly produced by the reaction of O2 with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O2-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H2O2. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O2-• readily reacts with NO• to form ONOO-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O2-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.

Keywords:  DJ-1; Mitophagy; NADPH; Nitric oxide synthase; Parkinson's disease; Superoxide sentinel hypothesis

DOI:  https://doi.org/10.1016/j.redox.2025.103979
Mol Ther. 2026 Jan 02. pii: S1525-0016(25)01137-2. [Epub ahead of print]

Mitochondrial citrate transport represents a metabolic liability in MYCN-amplified neuroblastoma.

Chan Chen, Qing Bao, Hao Huang, Liyuan Wang, Jue Jiang, Hudan Liu, Yuan Wang, Guoliang Qing, Yingzhe Fang.

MYCN amplification predicts poor prognosis and resistance to therapy in human neuroblastoma. However, pharmacological strategies that directly antagonize MYCN, the protein encoded by MYCN, remain unsuccessful. Oncogenic MYCN regulates many aspects of cellular metabolism, which in principle provides novel targets for development of effective cancer therapeutics. We herein identified the Solute Carrier Family 25 Member 1 (SLC25A1) mediated mitochondrial citrate export as a metabolic vulnerability in MYCN-amplified neuroblastomas. The citrate efflux from mitochondria is essential for MYCN-amplified neuroblastoma cells to generate the necessary Acetyl-CoA to support histone acetylation and subsequent transcriptional activation of the anti-apoptotic Baculoviral IAP Repeat Containing 3 (BIRC3) gene. Meanwhile, elevated cytosolic Acetyl-CoA sustains the acetylation of non-histone protein Myeloid Cell Leukemia 1 (MCL1), which counteracts its protein degradation by the 26S proteasome. BIRC3 and MCL1 in turn cooperate to inhibit apoptosis in MYCN-amplified neuroblastoma cells. Inhibition of SLC25A1 preferentially induced potent apoptosis in MYCN-amplified neuroblastoma cells, and synergistically potentiated the therapeutic efficacies of BCL2 antagonists. These findings reveal SLC25A1 as an actionable MYCN-driven metabolic liability, and validate SLC25A1 inhibitors, alone or in combination with BCL2 antagonists, as potential effective therapeutics for MYCN-amplified neuroblastomas.

DOI: https://doi.org/10.1016/j.ymthe.2025.12.061
FEBS Lett. 2026 Jan 09.

Inhibition of mitochondrial NADH:ubiquinone oxidoreductase by spinning oscillating magnetic fields causes toxicity in cancer cells.

Shashank Hambarde, Arvind Pandey, David S Baskin, Santosh A Helekar.

  A newly developed noninvasive Oncomagnetic device (OMD) causes selective cytotoxicity in glioblastoma and diffuse intrinsic pontine glioma cells, providing a novel, non-toxic approach to anticancer therapy. Here, we report results in cultured glioma cells and in a syngeneic mouse model indicating that the immediate intracellular target mechanism of action of the spinning oscillating magnetic field (sOMF) produced by this device is reactive oxygen species-dependent persistent inhibition of mitochondrial complex I. Steps downstream of this mechanism involve the production of oxidative stress, DNA damage, G1 phase cell cycle arrest, and caspase-dependent apoptosis. We also show that sOMF does not produce these effects in normal human astrocytes and astroglial cells. These data provide a rationale for safe clinical use of OMD.

Keywords:  DNA damage; brain tumor; complex I inhibition; magnetic therapy

DOI:  https://doi.org/10.1002/1873-3468.70271
Cancer Lett. 2026 Jan 07. pii: S0304-3835(26)00008-X. [Epub ahead of print] 218245

The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in MM by modulating mitochondrial metabolism.

Chenggong Tu, Arne Van der Vreken, Sylvia Faict, Gamze Ates, Ann Massie, Kim De Veirman, Elke De Bruyne, Karin Vanderkerken, Eline Menu.

  Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related gene, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.

Keywords:  ISR; bortezomib; metformin; multiple myeloma; pyruvate

DOI:  https://doi.org/10.1016/j.canlet.2026.218245
Neurol Genet. 2026 Feb;12(1): e200343

Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.

Cynthia C Liu, Mangesh Kurade, Anna S Monzel, Catherine Kelly, Robert-Paul Juster, Caroline Trumpff, Michio Hirano, Martin Picard.

Background and Objectives: The aim of this study was to profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how these phenotypes relate to disease manifestations or biomarkers.
Methods: We profiled mitochondrial content and oxidative phosphorylation (OxPhos) enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A > G, n = 23; single, large-scale mitochondrial DNA (mtDNA) deletions, n = 14) and 68 healthy women and men from the Mitochondrial Stress, Brain Imaging, and Epigenetics study.
Results: We first confirmed and quantified robust cell type differences in mitochondrial content; activities of OxPhos complexes I, II, and IV; and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity was consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. MitoD biomarkers growth differentiation factor 15 and fibroblast growth factor 21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state with those in the afternoon/fed state after a stressful experience, we report significant time-dependent changes in mitochondrial biology over hours.
Conclusions: Overall, these results demonstrate that the dynamic and cell type-specific mitochondrial phenotypes are preserved in MitoD and are generally unrelated to symptom severity.

DOI: https://doi.org/10.1212/NXG.0000000000200343
Biosci Biotechnol Biochem. 2026 Jan 07. pii: zbag004. [Epub ahead of print]

Investigating interspecies mitochondrial transplantation on the malignancy of melanoma cells.

Fu-Chen Kuo, Bi-Ling Cheng, Ching-Chung Tsai, Ping-Chen Chen, Wei-Wen Sung, Kuen-Jang Tsai, Hsin-Yi Tsai, Yaw-Bin Huang, Chung-Jung Liu, Deng-Chyang Wu, Ming-Wei Lin, Bin Huang.

  Transplanting allogeneic or even interspecies mitochondria to modulate cancer malignancy was investigated herein. Melanoma is a highly metastatic cancer that strongly relies on mitochondrial function. The mitochondrial membrane potential (MMP) and ATP of human (A375) and mouse (B16F10) melanoma cells, and four donor cells, human (HaCaT) and mouse (MPEK-BL6) keratinocytes, human (HUVEC) and mouse (MUVEC) endothelial cells were compared. The mitochondrial transplantations between mouse and human were identified. HUVEC mitochondria could uniquely retard the migration of B16F10. HUVEC mitochondria could be substantially transplanted into B16F10 and were colocalized with endogenous B16F10 mitochondria, in which, the branched mitochondria were converted into globular mitochondria. The reduced DRP1 and LC3 II corresponded to the reduced MMP and ATP. The decreased TGF-β, NANOG, SOX2, SMAD2/3, AKT, ERK, N-cadherin and MMP-9 corresponded to the attenuated invasion, elevated ROS and impaired cell viability. In conclusion, the feasibility of interspecies mitochondrial transplantation was preliminarily validated.

Keywords:  B16F10; HUVEC; Interspecies; Melanoma; Mitochondrial transplantation

DOI:  https://doi.org/10.1093/bbb/zbag004
Cancer Cell Int. 2026 Jan 06.

SLC25A39 facilitates Sorafenib resistance in hepatocellular carcinoma by inhibiting mitochondrial oxidative stress-induced ferroptosis.

Xilin Geng, Jibin Li, Bing Wu, Weifang Wang, Zeyu Li, Sinan Liu, Hui Li, Hulin Chang.



Keywords:  Ferroptosis; Growth; HCC; Mitochondrial ROS; SLC25A39

DOI:  https://doi.org/10.1186/s12935-025-04151-9
Cell Rep. 2026 Jan 02. pii: S2211-1247(25)01480-9. [Epub ahead of print]45(1): 116708

Single-cell resolution of an open chromatin signature in persister tumor cells.

Mihai Gabriel Dumbrava, Wazim Mohammed Ismail, Leticia Sandoval, Amelia Mazzone, Syed Mohammed Musheer Aalam, Megan L Ritting, Xiaonan Hou, Yiwen Xie, Sierra Hamernick, Chunling Hu, Fergus J Couch, Shariska P Harrington, Scott H Kaufmann, Nagarajan Kannan, S John Weroha, Alexandre Gaspar-Maia.

  Cancer can recur when a subset of tumor cells, termed persister cells, survive therapy and re-enter the cell cycle. Through single-nucleus multi-omic profiling (single-nucleus RNA sequencing [snRNA-seq] and single-nucleus assay for transposase-accessible chromatin by sequencing [snATAC-seq]) of (1) non-malignant fallopian tubes and (2) treatment-naive and (3) neoadjuvant-chemotherapy-treated samples from patients with high-grade serous ovarian carcinoma (HGSOC), we identify a persister cell signature defining the chemotherapy-tolerant state. The chromatin features of the signature are detectable in residual tumors after treatment and in treatment-naive tumors from patients who later develop resistance. Further, the signature independently predicts chemotherapy response in metastatic HGSOC and patient-derived xenograft models. Cells enriched in the persister state display a subset of genes primed for expression before treatment, an altered cell cycle, and stress-response programs associated with poor clinical outcomes. These findings suggest that an intrinsic regulatory program primes tumor cells toward chemotherapy tolerance and reveal new vulnerabilities that can be targeted with chromatin-modifying agents to prevent cancer recurrence.

Keywords:  CP: cancer; chemotherapy resistance; chromatin accessibility; high-grade serous ovarian carcinoma; open chromatin; patient-derived xenografts; persister cell signature; single-nucleus multi-omics

DOI:  https://doi.org/10.1016/j.celrep.2025.116708
Cell. 2026 Jan 08. pii: S0092-8674(25)01423-0. [Epub ahead of print]189(1): 3-5

When heme is low, copper kills cancer.

Andreas Linkermann.

Heme carries oxygen and is critical for the control of redox reactions. In this issue of Cell, Lewis and Gruber et al. demonstrate how low concentrations of heme destabilize complex IV of the respiratory chain to release copper and kill acute myeloid leukemia cells by cuproptosis.

DOI: https://doi.org/10.1016/j.cell.2025.12.010