bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2025–09–07
twenty-two papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
  2. PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
  3. MitoTraP: mitochondrial protection for cellular proteostasis.
  4. Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
  5. CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer.
  6. Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
  7. Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
  8. TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
  9. SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
  10. Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.
  11. Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
  12. Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
  13. MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
  14. β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
  15. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
  16. SLC25A40 promotes NSCLC growth by enhancing NADPH-mediated lipid synthesis and suppressing ROS accumulation-induced ferroptosis.
  17. Targeting mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.
  18. The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.
  19. A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
  20. Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
  21. MCL1 may not mediate chemoresistance.
  22. Mitochondria power the nucleus under pressure.
  1. bioRxiv. 2025 Aug 25. pii: 2025.08.21.671546. [Epub ahead of print]
    Quiescent OXPHOS-high triple-negative breast cancer cells that persist after chemotherapy depend on BCL-XL for survival.
    Slawomir Andrzejewski, Marie Winter, Leandro Encarnacao Garcia, Olusiji Akinrinmade, Francisco D M Marques, Emmanouil Zacharioudakis, Anna Skwarska, Julio Aguirre-Ghiso, Marina Konopleva, Guangrong Zheng, Susan Fineberg, Daohong Zhou, Evripidis Gavathiotis, Tao Wang, Eugen Dhimolea.
      The persistent residual tumor cells that survive after chemotherapy are a major cause of treatment failure, but their survival mechanisms remain largely elusive. These cancer cells are typically characterized by a quiescent state with suppressed activity of MYC and MTOR. We observed that the MYC-suppressed persistent triple-negative breast cancer (TNBC) cells are metabolically flexible and can upregulate mitochondrial oxidative phosphorylation (OXPHOS) genes and respiratory function ("OXPHOS-high" cell state) in response to DNA-damaging anthracyclines such as doxorubicin, but not to taxanes. The elevated biomass and respiratory function of mitochondria in OXPHOS-high persistent cancer cells were associated with mitochondrial elongation and remodeling suggestive of increased mitochondrial fusion. A genome-wide CRISPR editing screen in doxorubicin-persistent OXPHOS-high TNBC cells revealed BCL-XL gene as the top survival dependency in these quiescent tumor cells, but not in their untreated proliferating counterparts. Quiescent OXPHOS-high TNBC cells were highly sensitive to BCL-XL inhibitors, but not to inhibitors of BCL2 and MCL1. Interestingly, inhibition of BCL-XL in doxorubicin-persistent OXPHOS-high TNBC cells rapidly abrogated mitochondrial elongation and respiratory function, followed by caspase 3/7 activation and cell death. The platelet-sparing proteolysis targeted chimera (PROTAC) BCL-XL degrader DT2216 enhanced the efficacy of doxorubicin against TNBC xenografts in vivo without induction of thrombocytopenia that is often observed with the first-generation BCL-XL inhibitors, supporting the development of this combinatorial treatment strategy for eliminating dormant tumor cells that persist after treatment with anthracycline-based chemotherapy.
    DOI:  https://doi.org/10.1101/2025.08.21.671546
  2. Autophagy. 2025 Aug 27.
    PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy.
    Soumya Ranjan Mishra, Priyadarshni Mishra, Kewal Kumar Mahapatra, Bishnu Prasad Behera, Gajanan Kendre, Moureq Rashed Alotaibi, Vijay Pandey, Birija Sankar Patro, Daniel J Klionsky, Sujit Kumar Bhutia.
      The inorganic pyrophosphatase PPA2, a matrix-localized protein, maintains mitochondrial function. Here, we identified the role of PPA2 in activating mitochondrial fission signaling. We found that PPA2 overexpression promotes mitochondrial fission by upregulating the mitochondrial translocation of phosphorylated DNM1L S616. Moreover, PPA2 interacts with MTFP1, a mitochondrial inner membrane protein, to induce fission signaling; cells knocked down for MTFP1 and overexpressing PPA2 failed to induce DNM1L activation and subsequent mitochondrial fission. Furthermore, in physiological conditions, PPA2 directed mitochondrial fission at the midzone through MFF-DNM1L, leading to mitochondrial proliferation. Interestingly, during mitochondrial stress following CCCP treatment, PPA2 triggers peripheral fission through FIS1 and DNM1L to segregate parts of damaged mitochondria, which is essential for mitophagy. In addition, PPA2 utilized the C-terminal LC3-interacting region (LIR) of MTFP1 for mitophagy-mediated clearance of damaged mitochondria. In conclusion, PPA2 activates mitochondrial fission signaling through MTFP1-DNM1L and is essential in defining the site of mitochondrial fission, leading to mitochondrial proliferation or mitophagy for maintaining mitochondrial homeostasis.
    Keywords:  MTFP1; Mitochondria; PPA2; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2552900
  3. Trends Biochem Sci. 2025 Aug 27. pii: S0968-0004(25)00193-8. [Epub ahead of print]
    MitoTraP: mitochondrial protection for cellular proteostasis.
    Michaela Oborská-Oplová, Michael A Ruoss, Vikram G Panse.
      Cells depend on the efficient import of thousands of nuclear-encoded mitochondrial proteins to maintain mitochondrial function. A new study by Flohr et al. reveals a quality control strategy that traps a subset of mitochondrial precursors in the intermembrane space during energy stress, preventing their toxic accumulation in the cytosol or nucleus.
    Keywords:  mitochondrial import; mitochondrial intermembrane space; mitochondrial quality control; mitochondrial ribosomal proteins (MRPs); mitochondrial stress; proteotoxic stress
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.004
  4. Mol Cancer Ther. 2025 Sep 05. OF1-OF13
    Co-Targeting BCL-xL with MCL-1 Induces Lethal Mitochondrial Dysfunction in Diffuse Mesothelioma.
    Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley.
      Diffuse mesothelioma is a rare but highly aggressive and treatment-resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid cell leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance. We investigated whether B-cell homology domain3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells, and patient-derived xenografts (PDX) by B-cell homology domain-3 profiling; we observed striking consistency which enabled cross-model comparisons. Next, we co-targeted BCL-xl and MCL-1 and noted that the combination synergistically reduced cell viability and increased apoptosis. Mechanistically, BCL-xL inhibition affected the cells through both the canonical and the emerging noncanonical apoptotic pathways. BCL-xL induced mitochondrial depolarization which resulted in MCL-1 cellular dependency, rendering cells highly sensitive to MCL-1 inhibition. Next, we co-targeted BCL-xL and MCL-1 in vivo which induced synthetic lethality in PDX models within hours, implying that this approach is not a safe strategy for clinical development. However, targeting MCL-1, which exerts its antiapoptotic activity without non-apoptotic on-target effects, decreased the mitochondrial threshold for apoptosis and enhanced chemosensitivity without toxicity in PDX models. Our findings suggest that targeting the mitochondria via MCL-1 enhances the efficacy of chemotherapy but co-targeting two proteins in the Bcl-2 pathways results in synergistic lethality. These results will help define a safe clinical strategy to utilize Bcl-2-targeted therapy to undermine therapeutic resistance in patients with diffuse mesothelioma.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0873
  5. Br J Cancer. 2025 Sep 04.
    CDCP1/mitochondrial Src axis increases electron transport chain function to promote metastasis in triple-negative breast cancer.
    Jordan A Woytash, Austin E Y T Lefebvre, Ziang Zhang, Binzhi Xu, Stephanie A Harchenko, Hoa T Le, Andrew R McColloch, Xiaoyu Shi, Michelle A Digman, Olga V Razorenova.
       BACKGROUND: Triple-negative type of breast cancer (TNBC) has limited therapeutic options and frequently metastasizes, leading to low survival rates. Oxidative phosphorylation (OXPHOS) is a driver of TNBC metastasis, but the signaling underlying this metabolic change is poorly understood.
    METHODS: We performed metabolic assays and assessed migratory and metastatic potential in cells with manipulated CDCP1/mitochondrial Src signaling.
    RESULTS: We show that the pro-metastatic cell surface protein CUB-domain containing protein 1 (CDCP1) activates Src kinase localized in mitochondria, which potently induces OXPHOS and TNBC migration. Genetic targeting of either CDCP1 or mitochondrial Src, as well as pharmacological inhibition of Src reduce OXPHOS in vitro. We further show that mitochondrial Src increases OXPHOS by stimulating Complex I activity in the electron transport chain. Importantly, rescuing Complex I activity in cells devoid of CDCP1/mitochondrial Src signaling restores both OXPHOS and migration. We also provide evidence that NAD+ pool generated by Complex I is contributing to the observed migratory phenotype. Lastly, we determined that inhibiting mitochondrial Src reduces metastasis in TNBC cells.
    CONCLUSIONS: Both CDCP1 and mitochondrial Src represent potential therapeutic targets to inhibit OXPHOS-mediated TNBC metastasis.
    DOI:  https://doi.org/10.1038/s41416-025-03163-6
  6. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2502483122
    Restoring mitochondrial quantity and quality to reverse the Warburg effect and drive neuroblastoma differentiation.
    Haowen Jiang, Sarah Jane Tiche, Clifford Jiajun He, Junyan Liu, Fuyun Bian, Mohamed Jedoui, Balint Forgo, Md Tauhidul Islam, Meng Zhao, Pamela Emengo, Bo He, Yang Li, Albert M Li, Anh T Truong, Jestine Ho, Cathyrin Simmermaker, Yanan Yang, Meng-Ning Zhou, Zhen Hu, Katrin J Svensson, Daniel J Cuthbertson, Florette K Hazard, Lei Xing, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.
      Reduced mitochondrial quality and quantity in tumors is associated with dedifferentiation and increased malignancy. However, it remains unclear how to restore mitochondrial quantity and quality in tumors and whether mitochondrial restoration can drive tumor differentiation. Our study shows that restoring mitochondrial function using retinoic acid (RA) to boost mitochondrial biogenesis and a mitochondrial uncoupler to enhance respiration synergistically drives neuroblastoma differentiation and inhibits proliferation. U-13C-glucose/glutamine isotope tracing revealed a metabolic shift from the pentose phosphate pathway to oxidative phosphorylation, accelerating the tricarboxylic acid cycle and switching substrate preference from glutamine to glucose. These effects were abolished by electron transport chain (ETC) inhibitors or in ρ0 cells lacking mitochondrial DNA, emphasizing the necessity of mitochondrial function for differentiation. Dietary RA and uncoupler treatment promoted tumor differentiation in an orthotopic neuroblastoma xenograft model, evidenced by neuropil production and Schwann cell recruitment. Single-cell RNA sequencing of xenografts revealed that this strategy effectively eliminated the stem cell population, promoted differentiation, and increased mitochondrial gene signatures along the differentiation trajectory, potentially improving patient outcomes. Collectively, our findings establish a mitochondria-centric therapeutic strategy for inducing tumor differentiation, suggesting that maintaining/driving differentiation in tumor requires not only ATP production but also continuous ATP consumption and sustained ETC activity.
    Keywords:  differentiation; mitochondria; neuroblastoma; retinoic acid; uncoupler
    DOI:  https://doi.org/10.1073/pnas.2502483122
  7. Cancer Res. 2025 Aug 29.
    Loss of SETD8 Impairs Mitochondrial Homeostasis to Suppress Leukemia Stem Cell Function in t(8;21) Acute Myeloid Leukemia.
    Yongwei Su, Shuyi Li, Lei Wang, Yiran Wang, Shujiao He, Xiaotong Li, Jingqiao Qiao, Jingfeng Zhou, Li Yu.
      Leukemic stem cells (LSCs) contribute to relapse and resistance in patients with t(8;21) acute myeloid leukemia (AML). Chromatin accessibility remodeled by epigenetic alterations represents a defining hallmark of LSCs that endows them with enhanced survival and self-renewal capacities, which may offer potential therapeutic opportunities for intervention. Here, we showed that SETD8, a lysine methyltransferase that monomethylates lysine 20 of histone H4 (H4K20me1), is essential for the maintenance of stemness in t(8;21) AML LSCs. Genetic deletion or pharmacological inhibition of SETD8 impaired the survival and self-renewal of LSCs in retroviral AML1-ETO9a-driven t(8;21) AML mice and primary t(8;21) AML CD34+ cells. Mechanistically, SETD8 promoted the expression of the mitochondrial outer membrane protein RHOT1 by increasing chromatin accessibility at the enhancer region, thereby reprogramming mitochondrial homeostasis. These findings improve our understanding of gene regulation through chromatin accessibility remodeling and establish a link between histone lysine methylation and mitochondrial homeostasis, suggesting a potential strategy for eliminating LSCs in t(8;21) AML.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3659
  8. bioRxiv. 2025 Aug 31. pii: 2025.08.28.672283. [Epub ahead of print]
    TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade.
    Ahmed M Mamdouh, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Nishtha Chitkara, Leah Hogdal, R Coleman Lindsley, Anthony Letai, Koji Itahana, Shruti Bhatt.
      Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy, decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this (post-MOMP brake) is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
    DOI:  https://doi.org/10.1101/2025.08.28.672283
  9. Haematologica. 2025 Sep 04.
    SLC25A1 reprograms mitochondrial and fatty acid metabolism to promote the progression of acute myeloid leukemia.
    Miao Chen, Wenze Li, Yuan Tao, Chenglong Hu, Rui Ge, Sijing Kang, Pengjie Yue, Cheuk Him Man, Lan Wang, Xiaojing Yan.
      Abnormal metabolic reprogramming is a hallmark of acute myeloid leukemia (AML), contributing to leukemia initiation, progression and drug resistance. The key mitochondrial citrate transporter SLC25A1 plays an essential role in regulating cellular energy metabolism and shows to play an important role in lipid metabolism regulation. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in AML remain unexplored. In this study, our analysis of public datasets and patient samples revealed that SLC25A1 expression was markedly elevated in AML and was associated with poor prognosis. Knockdown or pharmacological inhibition of SLC25A1 significantly suppressed AML cell proliferation by inducing apoptosis, without affecting cell cycle progression or differentiation. Moreover, SLC25A1 proved vital for AML tumorigenesis in vivo. Mechanistically, we demonstrated that SLC25A1 inhibition disrupted citrate homeostasis, leading to mitochondrial dysfunction and reduced fatty acid metabolism. Notably, we developed a novel SLC25A1 inhibitor, CTPI3, which effectively inhibits the progression of AML in vivo, and synergizes with venetoclax to kill AML cells by mitochondrial and fatty acid metabolism regulation. In summary, our findings highlight that SLC25A1 plays a vital role of in maintaining AML cell survival and regulating its drug sensitivity, and further developed a more effective novel drug targeting SLC25A1, providing additional therapeutic options for venetoclax-resistant patients and highlighting SLC25A1 as a promising biomarker and therapeutic target for AML.
    DOI:  https://doi.org/10.3324/haematol.2024.287269
  10. Redox Biol. 2025 Aug 26. pii: S2213-2317(25)00358-1. [Epub ahead of print]86 103845
    Metastatic breast cancer cells are vulnerable to fatty acid oxidation inhibition through DDX3-DRP1-mediated mitochondrial plasticity.
    Wen-Jing Hsu, Ming-Chien Hsu, Cheng-Ying Chu, Yu-Cheng Lee, Ching-Chieh Yang, Zei-Wei Liu, Chi-Ching Lee, Yang-Sen Lin, Cheng-Wei Lin.
      Metastatic tumor cells exhibit distinct metabolic flexibility in overcoming different microenvironmental obstacles and thriving in a secondary organ; thus, metabolic vulnerabilities can potentially be targeted. It was reported that mitochondrial biogenesis and dynamics play crucial roles in disseminated tumor cells satisfying their energy demands and metabolic plasticity. However, the detailed molecular mechanism by which mitochondrial dynamics promotes tumor metastasis is still unclear. Herein, we identified that metastatic breast cancer cells exhibited increased lipid contents in mitochondria and promoted a metabolic shift towards fatty acid oxidation (FAO). The increased FAO was accompanied by promotion of mitochondrial fission. Mechanistically, we found that upregulation of DEAD-box polypeptide 3, X-linked (DDX3) promoted mitochondrial fission and facilitated FAO. Suppression of DDX3 diminished FAO and elicited mitochondrial oxidative stress in metastatic tumor cells. Moreover, DDX3 mediated dynamin-related protein 1 (DRP1) phosphorylation at S616 through collaborating with cyclin-dependent kinase 1 (CDK1). Inhibition of the DDX3-DRP1-CDK1 axis reduced cancer stemness properties and tumor metastasis. Our findings indicate that DDX3 modulates mitochondrial plasticity to drive metabolic adaptation in breast tumor metastasis. DDX3 provides a potential diagnostic biomarker and therapeutic vulnerability through which cancer metabolism can be targeted.
    Keywords:  DDX3; DRP1; FAO; Mitochondrial fission; Tumor metastasis
    DOI:  https://doi.org/10.1016/j.redox.2025.103845
  11. Nat Rev Nephrol. 2025 Aug 29.
    Accumulation of pathogenic mitochondrial DNA mutations in the kidney.
    Ellen F Carney.
      
    DOI:  https://doi.org/10.1038/s41581-025-01002-8
  12. Cell. 2025 Aug 25. pii: S0092-8674(25)00916-X. [Epub ahead of print]
    Proximity-specific ribosome profiling reveals the logic of localized mitochondrial translation.
    Jingchuan Luo, Stuti Khandwala, Jingjie Hu, Song-Yi Lee, Kelsey L Hickey, Zebulon G Levine, J Wade Harper, Alice Y Ting, Jonathan S Weissman.
      Localized translation broadly enables spatiotemporal control of gene expression. Here, we present LOV-domain-controlled ligase for translation localization (LOCL-TL), an optogenetic approach for monitoring translation with codon resolution at any defined subcellular location under physiological conditions. Application of LOCL-TL to mitochondrially localized translation revealed that ∼20% of human nuclear-encoded mitochondrial genes are translated on the outer mitochondrial membrane (OMM). Mitochondrially translated messages form two classes distinguished by encoded protein length, recruitment mechanism, and cellular function. An evolutionarily ancient mechanism allows nascent chains to drive cotranslational recruitment of long proteins via an unanticipated bipartite targeting signal. Conversely, mRNAs of short proteins, especially eukaryotic-origin electron transport chain (ETC) components, are specifically recruited by the OMM protein A-kinase anchoring protein 1 (AKAP1) in a translation-independent manner that depends on mRNA splicing. AKAP1 loss lowers ETC levels. LOCL-TL thus reveals a hierarchical strategy that enables preferential translation of a subset of proteins on the OMM.
    Keywords:  AKAP1; OXPHOS; cis-element analysis; cotranslational targeting; localized translation; mitochondrial bipartite targeting signal; outer mitochondrial membrane; oxidative phosphorylation; translation-independent mRNA targeting
    DOI:  https://doi.org/10.1016/j.cell.2025.08.002
  13. Nat Cancer. 2025 Aug 28.
    MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation.
    Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A Vorholt, Sabine Werner.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.
    DOI:  https://doi.org/10.1038/s43018-025-01038-6
  14. J Biol Chem. 2025 Aug 28. pii: S0021-9258(25)02488-3. [Epub ahead of print] 110636
    β-hydroxybutyrate dehydrogenase promotes pancreatic cancer cell proliferation through regulation of the NAD+/NADH balance and mitochondrial acetylation.
    Xiujuan Wei, Chengkai Zhang, Xiaoguang Zheng, Kexin Pan, Xiaojun Ren, Xiaoting Lou, Zhengquan Yang, Ting Fu, Hezhi Fang, Jianxin Lu.
      Ketone bodies are a key alternative energy source during carbohydrate deficiency. In addition to their metabolic function, they regulate essential cellular processes, including metabolism, signal transduction, and protein post-translational modifications (PTMs). However, the role of ketone body metabolism in tumorigenesis remains poorly understood. Here, we demonstrate that ketone body synthesis metabolism is activated in pancreatic cancer, while exogenous ketone supplementation does not affect PDAC cell proliferation. Moreover, we observe a significant upregulation of β-Hydroxybutyrate dehydrogenase (BDH1), a key enzyme in ketone body metabolism, in human pancreatic ductal adenocarcinoma (PDAC) tissues compared to adjacent normal pancreatic tissues. BDH1 promotes PDAC cell proliferation by maintaining mitochondrial acetylation levels through regulation of the intracellular NAD+/NADH ratio. These findings underscore the importance of ketone body metabolism in pancreatic cancer progression and highlight the regulatory role of BDH1 in maintaining cellular NAD+/NADH balance and mitochondrial acetylation.
    Keywords:  BDH1; Ketone body; NAD(+)/NADH; Pancreatic Cancer; mitochondrial acetylation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110636
  15. Science. 2025 Sep 04. eadk7978
    Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
    Huihui Huang, Yi Wang, Zsuzsanna K Zsengeller, Joshua M Gorham, Vamsidhara Vemireddy, Amanda J Clark, Hui Pan, Jonathan M Dreyfuss, Vasantha Jotwani, Michael G Shlipak, Mark J Sarnak, Chirag R Parikh, Heather Thiessen-Philbrook, Ronit Katz, Sushrut S Waikar, Nicole J Lake, Monkol Lek, Wen Shi, Daniela Puiu, Yun Soo Hong, Jonathan G Seidman, Dan E Arking, Samir M Parikh.
      Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored ATP generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (p < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
    DOI:  https://doi.org/10.1126/science.adk7978
  16. Exp Cell Res. 2025 Aug 26. pii: S0014-4827(25)00327-1. [Epub ahead of print]452(1): 114727
    SLC25A40 promotes NSCLC growth by enhancing NADPH-mediated lipid synthesis and suppressing ROS accumulation-induced ferroptosis.
    Peini Xue, Xian Guo, Boru Zhang, Xin Yang, Jiaying Gao, Feng Zhou, Jiangang Ma, Faguang Jin.
      Mitochondria serve as vital organelles that play critical roles in regulating cell metabolism and maintaining redox homeostasis. Their dysfunctions are closely associated with the progression of multiple human malignancies. SLC25A40 has been predicted as a mitochondrial carrier required for glutathione import into mitochondria. However, the role of SLC25A40 in human cancers, especially in non-small cell lung cancer (NSCLC), remains poorly understood. Here, we found that SLC25A40 expression was elevated in NSCLC. This upregulation was associated with poor prognosis. Silencing SLC25A40 suppressed NSCLC growth by inhibiting cell proliferation and inducing ferroptosis, whereas its overexpression promoted NSCLC growth. Mechanistically, SLC25A40 promotes cell proliferation by increasing NADPH-mediated lipid synthesis and suppresses ferroptosis by decreasing mitochondrial ROS accumulation. Furthermore, we demonstrated that the elevation of SLC25A40 expression in NSCLC cells was primarily due to decreased miR-4299. This research highlights the pivotal role of SLC25A40 in NSCLC progression by modulating both cell proliferation and ferroptosis, suggesting it as a promising therapeutic target in the management of NSCLC.
    Keywords:  Ferroptosis; Lipid synthesis; NSCLC; ROS; SLC25A40
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114727
  17. Cell Commun Signal. 2025 Sep 03. 23(1): 393
    Targeting mitochondrial proteases CLPP and LONP1 via disruption of mitochondrial redox homeostasis induces proteotoxic stress and suppresses tumor progression.
    Shivani R Nandha, R S Patwardhan, Deepak Sharma, Santosh K Sandur, Rahul Checker.
       BACKGROUND: Cancer cells, which rely heavily on mitochondria for their energy demands and oncometabolites, have a high mitochondrial load, often associated with an aggressive, invasive, and metastatic phenotype. Mitochondrial ROS (mtROS), which play a causal role in cancer, represent the Achilles' heel of cancer since excessive mtROS causes protein misfolding/aggregation, resulting in cell death via proteotoxic stress. Furthermore, the detailed underlying mechanism(s) of mitochondrial oxidative stress-induced cell death remain obscure.
    METHODS: Cell growth was estimated by MTT assay, clonogenic assay, live-cell imaging and flow cytometry. Intracellular ROS, mtROS, glutathione and antioxidant levels were studied by spectrophotometry. RNAseq and Western blotting were performed to elucidate the underlying mechanism(s). In vivo efficacy was evaluated using a syngeneic mouse model.
    RESULTS: We employed a mitochondria-targeted agent to disrupt the mitochondrial redox balance. Among tumors of different origins, such as lung, breast, prostate, bone, skin, cervical and liver, triple-negative breast cancer (TNBC) exhibited the highest sensitivity to mitochondrial oxidative stress. Compared with the parent compound, mitochondria-targeted agent showed 39-fold more effectiveness in killing TNBCs. We observed a possible correlation between the mitochondrial load in different cancer cell lines and their sensitivity to mitochondrial oxidative stress. Transcriptomic analysis revealed an enrichment of biological response to unfolded and/or misfolded proteins, which are regulated by two key proteases, Lon peptidase 1 (LONP1) and Caseinolytic protease P (CLPP), that control mitochondrial proteostasis. Bioinformatics analyses revealed enhanced expression and a strong positive correlation between these proteases in breast cancer patients, with highest expression observed in TNBC. Additionally, an early relapse was observed in breast cancer patients over-expressing both LONP1 and CLPP. Mitochondrial oxidative stress triggered a decrease in the native functional forms and an increase in the aggregated forms of LONP1 and CLPP, thereby disrupting mitochondrial proteostasis. Interestingly, no such changes were observed in normal cells. Mechanistically, excess mtROS induced proteotoxic stress and mitochondrial dysfunction, culminating in growth inhibition both in vitro and in vivo.
    CONCLUSION: Our studies, for the first time, show that the mitochondrial load and induction of mtROS for concomitant inhibition of LONP1 and CLPP to induce proteotoxic stress, could be novel therapeutic targets for cancer.
    Keywords:  Mitochondria; Mitochondrial proteases; Oxidative stress; Proteotoxic stress; Unfolded protein response
    DOI:  https://doi.org/10.1186/s12964-025-02127-w
  18. Leuk Res Rep. 2025 ;24 100537
    The synergistic effect of 2-deoxy-D-glucose and cytarabine on mitochondria of stem-like cells derived from KG1-a.
    Sona Rezaei, Mohammad Mohammadzadeh-Vardin, Keyvan Amirshahrokhi, Mojtaba Amani.
      Acute myeloid leukemia (AML) often relapses post-chemotherapy due to leukemia stem cells (LSCs), which rely on mitochondria for energy, ROS regulation, and apoptosis. Targeting mitochondrial pathways may overcome LSC resistance. This study evaluated Cytarabine (Ara-C), 2-Deoxy-d-Glucose (2-DG), and their combination on AML-derived KG1-a cells using MTT assays, showing reduced viability with combined treatment. The Magnetic sorting isolated CD34+ (stem-like) and CD34- cells. Flow cytometry revealed increased ROS and decreased mitochondrial membrane potential (MMP) in KG1-a and CD34+ cells with 2-DG and Ara-C, suggesting a promising strategy to target resistant LSCs in AML therapy.
    Keywords:  CD34+ stem-like cells; Cytarabine, 2-deoxy-D-glucose; Mitochondrial membrane potential; Reactive oxygen specious
    DOI:  https://doi.org/10.1016/j.lrr.2025.100537
  19. Cancer Res. 2025 Sep 03.
    A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.
    Justin Chak Ting Cheung, Lok Wan Ng, Zhongxu Zhu, Bonan Chen, Stephen Li, Mingjing Xu, Xiaofan Ding, Dandan Pu, Yi Hu, Yuqing Ren, Wei Kang, Ming Li, Jason Wing Hon Wong, Xin Wang, Yuen Kit Cheng, Wei Shen Aik, Ka Leung Wong, Simon Siu Man Ng, Nathalie Wong, Yujuan Dong.
      Metabolic reprogramming, notably alterations in the tricarboxylic acid (TCA) cycle, has emerged as a hallmark of cancer that supports tumor growth and metastasis. Despite the TCA cycle being a classical central metabolic pathway, further exploration is needed to fully elucidate the intricate manifestations and contributory mechanisms of TCA cycle rewiring in colorectal carcinogenesis. Herein, we identified a splicing isoform of citrate synthase (CS), CS-ΔEx4, and unveiled its role in TCA cycle dysregulation in colorectal cancer (CRC). CS-ΔEx4 was distinctly upregulated in CRC tumors compared with the canonical full-length (CS-FL) isoform. Clinical analyses established a strong correlation between elevated CS-ΔEx4 expression and cancer recurrence as well as inferior survival outcomes in patients with CRC. Functional experiments revealed the active contribution of CS-ΔEx4 to the aggressive phenotype of CRC cells both in vitro and in vivo. Mechanistically, CS-ΔEx4 formed a heterocomplex with CS-FL within the mitochondria that influenced the enzymatic function of canonical CS and accelerated TCA cycle flux, thereby promoting accumulation of the oncometabolite 2-hydroxyglutarate. The CS-ΔEx4-mediated metabolic alterations engendered epigenomic modulations that drove the upregulation of oncogenic gene signatures. In silico screening identified a small molecule with potent anti-proliferative effects in CRC cell line and organoid models that selectively antagonized the CS-ΔEx4 and CS-FL heterocomplex activity while sparing the CS-FL homodimers. Together, this study discovered the presence of a spliced CS isoform that promotes CRC progression and identified a molecule that holds potential for targeting the CS-ΔEx4 and CS-FL heterocomplex.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2355
  20. Drug Resist Updat. 2025 Aug 20. pii: S1368-7646(25)00097-4. [Epub ahead of print]83 101294
    Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.
    Ling Li, Yangyang Feng, Jingbo Zhou, Fangyuan Shao, Yuzhong Peng, Sitian Zang, Josh Haipeng Lei, Heng Sun, Dongyang Tang, Shiqi Lin, Jinghong Chen, Hanghang Li, Xiangpeng Chu, Yunfeng Qiao, Xinyu Guo, Kakun Wu, Xiaoling Xu, Chu-Xia Deng.
      Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome-mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1-Parkin independent but ROS-BNIP3-mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.
    Keywords:  MDR; cell death; lysosome membrane permeabilization; mitochondrial protein import; mitophagy; proteasome activity; protein damage
    DOI:  https://doi.org/10.1016/j.drup.2025.101294
  21. bioRxiv. 2025 Aug 27. pii: 2025.08.22.671824. [Epub ahead of print]
    MCL1 may not mediate chemoresistance.
    Kylin A Emhoff, Kunho Chung, Dongmei Zhang, Belinda Willard, Timothy Chan, Babal Kant Jha, Shaun R Stauffer, Jesse A Coker, Jan Joseph Melenhorst.
      The anti-apoptotic BCL2 family member MCL1 is overexpressed in many cancers and has been linked to chemoresistance. Unlike other BCL2 family members, MCL1 displays both well-defined mitochondrial anti-apoptotic activities and also emerging nuclear functions. Prior reports suggest that MCL1 enters the nucleus during chemotherapy and promotes chemoresistance by influencing cell cycle progression and DNA repair. These nuclear roles of MCL1, however, remain poorly characterized. Using a newly validated monoclonal antibody across several cell lines and treatments, we find no evidence that MCL1 enhances chemoresistance or preferentially accumulates in the nucleus after drug exposure. Proximity biotinylation identified novel nuclear MCL1 interactors but did not recover previously reported DNA repair or cell cycle partners. Thus, while MCL1 does reach the nucleus and interact with nuclear proteins, our data do not support a role for MCL1 in chemoresistance. Further work is needed to clarify the functional significance of nuclear MCL1.
    SIGNFIGANCE: Previous studies have implicated MCL1 in promoting chemoresistance via interactions with DNA repair machinery in the nucleus. Using a validated, monoclonal anti-MCL1 antibody, we were unable to replicate these data. We report that MCL1 neither confers chemoresistance, translocates to the nucleus during chemotherapy treatment, nor interacts with DNA repair proteins in live cancer cells.
    DOI:  https://doi.org/10.1101/2025.08.22.671824
  22. Mechanobiol Med. 2025 Sep;3(3): 100146
    Mitochondria power the nucleus under pressure.
    Meng Yao, Yao Zong, Junjie Gao.
      Mechanical confinement of cells, as occurs during processes like tumor cell invasion or immune cell trafficking, poses a pressure that can threaten nuclear integrity and cell viability. Recent findings illuminate a rapid adaptive mechanism by which cells under acute compressive stress rearrange their internal architecture to preserve nuclear functions. Upon confinement, mitochondria swiftly relocate to cluster around the nucleus (forming nuclear-associated mitochondria, NAM), entrapped by a web of endoplasmic reticulum (ER) and actin filaments. This proximity provides a localized surge of ATP within the nucleus, fueling energy-intensive nuclear processes, notably maintaining an open chromatin state and facilitating efficient DNA damage repair. This targeted energy delivery maintains nuclear chromatin accessibility, supports DNA repair mechanisms, and ensures sustained cell proliferation despite physical constraints. Here we provide a commentary on these findings, discussing the biological significance of mitochondria-nucleus repositioning, the role of nuclear ATP in safeguarding chromatin, and the broader implications for cellular fitness in development and disease.
    Keywords:  Mechanical confinement; Mitochondrial dynamics; Nuclear ATP
    DOI:  https://doi.org/10.1016/j.mbm.2025.100146
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