bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–10–25
seventeen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
  2. Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
  3. BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
  4. TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
  5. Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
  6. Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
  7. Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of "dredging, not repairing".
  8. Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
  9. SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.
  10. Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer.
  11. Mitochondrial transfer between breast cancer cells promotes ROS-dependent proliferation.
  12. HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
  13. BH3 profiling analyses for functional precision medicine.
  14. Elucidating the Molecular Impact of DA29-Induced ClpP Chemoactivation on Mitochondrial Function.
  15. Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
  16. Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
  17. ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.
  1. Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123
    Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
    Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.
      When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.
    Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2613074123
  2. Leukemia. 2026 Oct 23.
    Serine auxotrophy is a targetable vulnerability driven by PSAT1 suppression in AML.
    Ilias Sinanidis, Panagiotis Tsakiroglou, Benjamin Dubner, Rebecca Foertsch, Julia Gondek, InYoung Choi, Bogdan Paun, Teodora Supeanu, Liang Zhao, Gabriel Ghiaur, W Brian Dalton.
      Serine metabolism is of growing biologic and therapeutic interest in cancer. Upregulation of the serine synthesis pathway (SSP) can fuel tumor growth, and cancers with this phenotype are often sensitive to. SSP inhibitors. In parallel, dietary restriction of serine and glycine (SG) can suppress some cancers, but the determinants of sensitivity to. this approach are poorly understood. This is especially true in acute myeloid leukemia (AML), where serine metabolism has been less explored. We report that a subset of human AML cell lines and primary samples are completely dependent on external serine, known as serine auxotrophy. These leukemias consistently suppressed the SSP enzyme PSAT1, failed to. synthesize serine, responded to. SG restriction in vivo, and were rescued by restoring PSAT1. We also found that SG restriction synergized with venetoclax in serine auxotrophic AML, and that MECOM rearrangement was strongly associated with PSAT1 suppression and serine auxotrophy. These findings define a metabolically distinct AML subtype and nominate it for targeting by SG restriction.
    DOI:  https://doi.org/10.1038/s41375-026-03176-x
  3. Science. 2026 Oct 22. 394(6822): eaea2181
    BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
    Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.
      The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.
    DOI:  https://doi.org/10.1126/science.aea2181
  4. Cell Death Dis. 2026 Jul 28. pii: 902. [Epub ahead of print]17(1):
    TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
    Ahmed M Mamdouh, Fizza Iftikhar, Elyse A Olesinski, Fang Qi Lim, Shaista Jasdanwala, Yuhan Wang, Yang Mi, Nicole Si En Lin, Daniel Tan En Liang, Md Al Nayem Chowdhury, Nishtha Chitkara, Leah Hogdal, Coleman R 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 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/10.1038/s41419-026-09087-0
  5. Leukemia. 2026 Oct 19.
    Targeting the mitochondrial complex I subunit NDUFS2 potentiates FLT3 inhibition in acute myeloid leukaemia with FLT3 internal tandem duplication.
    Xiqin Tong, Guopeng Chen, Yuzhe Pan, Yanling Chen, Yuxin Tan, Hongqiang Jiang, Qian Wang, Linlu Ma, Ruihang Li, Yuxing Liang, Xiaoyan Liu, Fuling Zhou.
      Acute myeloid leukaemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) frequently relapses after FLT3 tyrosine kinase inhibitor (TKI) therapy, highlighting the need to define mechanisms of drug tolerance. Here, we identify the mitochondrial complex I core subunit NDUFS2 as a determinant of FLT3 TKI tolerance in FLT3-ITD AML. A metabolism-focused CRISPR-Cas9 sensitiser screen, integrated with transcriptomic profiling of gilteritinib-resistant cells and primary samples, identified NDUFS2 as upregulated in acquired resistance and preferentially expressed in FLT3-ITD AML. NDUFS2 knockdown impaired complex I activity, oxidative phosphorylation, mitochondrial membrane potential and ATP production, thereby promoting apoptosis and sensitising FLT3-ITD AML cells to gilteritinib. Pharmacologic complex I inhibition with IACS-010759 similarly enhanced gilteritinib activity in FLT3-ITD AML cell lines and primary FLT3-ITD samples, activated AMPK-PERK-ATF4-CHOP stress signalling, promoted apoptosis, and reduced leukaemia burden in a patient-derived xenograft model. Genetic NDUFS2 knockdown also prolonged survival in a xenograft model. A preliminary murine safety assessment showed no overt toxicity under the tested short-term dosing schedule. These findings identify NDUFS2-dependent complex I activity as an adaptive metabolic dependency supporting FLT3 inhibitor tolerance and provide mechanistic insight for further preclinical evaluation.
    DOI:  https://doi.org/10.1038/s41375-026-03170-3
  6. Blood Neoplasia. 2026 Nov;3(4): 100296
    Pitavastatin counteracts venetoclax resistance mechanisms including TP53 mutation in acute myeloid leukemia.
    Roberta Buono, Dennis Juarez, Madhuri Paul, Sarah J Skuli, Ian B Wong, Ishita Tarnekar, Zhili Ying, Izabelle Marie F Le, Wen-Pin Chen, Min Zhang, Gerald Wertheim, A'ishah Bakayoko, Marisa Kruidenier, Dequina A Nicholas, Pankaj Gupta, Said M Sebti, Marina Konopleva, Angela G Fleischman, Cholsoon Jang, Martin Carroll, David A Fruman.
      The B-cell lymphoma 2 inhibitor venetoclax has therapeutic activity in several hematological malignancies. In acute myeloid leukemia (AML), venetoclax combined with hypomethylating agents is the standard of care for patients unfit for intensive chemotherapy, but intrinsic and acquired resistance are common. Loss of p53 function is strongly associated with venetoclax resistance, and adding venetoclax to 5-azacitidine provides no overall survival benefit in TP53-mutant AML. Other frequent mechanisms of venetoclax resistance in AML include FLT3 mutations, myeloid cell leukemia 1 (MCL-1) upregulation, and altered mitochondrial metabolism. However, it has been challenging to develop agents that target these mechanisms directly and combinatorially. Here, we report that pitavastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, promotes apoptosis and overcomes several venetoclax resistance mechanisms in human AML cells. At clinically achievable concentrations, pitavastatin treatment has potent cytotoxic activity in cells with mutations in TP53 or FLT3, including primary cells resistant to venetoclax and 5-azacitidine. The apoptotic mechanism involves p53-independent PUMA upregulation and reduced MCL-1 expression. Pitavastatin also suppresses mitochondrial gene expression, oxidative metabolism, and MYC/E2F-driven transcription. These results provide a mechanistic rationale for clinical trials adding pitavastatin to AML regimens to prevent or overcome venetoclax resistance with TP53 mutations and other high-risk features.
    DOI:  https://doi.org/10.1016/j.bneo.2026.100296
  7. Front Pediatr. 2026 ;14 1939961
    Ketogenic diet in treating NADH accumulation caused by complex I dysfunction: the metabolic wisdom of "dredging, not repairing".
    Xiaoying Qiao, Jianxiang Liao.
      Genetic mutations causing Complex I (CI) dysfunction lead to the accumulation of NADH in the mitochondrial matrix due to impaired oxidation. An elevated NADH/NAD⁺ ratio feedback-inhibits key enzymes of the tricarboxylic acid (TCA) cycle, reducing metabolic flux, while concurrent electron transport chain (ETC) blockade exacerbates reactive oxygen species (ROS) generation and oxidative stress. Conventional views propose that the ketogenic diet (KD) bypasses the defective CI to restore downstream ETC electron transfer. However, this perspective harbors an inherent contradiction: CI is the primary entry point for NADH oxidation; bypassing it may sustain some electron flow but fails to consume the accumulated NADH in the matrix, leaving the fate of this critical reducing equivalent inadequately explained. This article proposes the metabolic wisdom of "dredging, not repairing", positing that KD, through metabolic reprogramming, diverts the accumulated NADH into multiple utilizable pathways. These include intra-matrix conversion and consumption (generating NADPH and ketone bodies), pumping malate from the matrix into the cytosol via the reverse malate-aspartate shuttle (rMAS), and further cytosolic malate utilization (gluconeogenesis, NADPH generation, glycerol-3-phosphate shuttle, etc.). This multi-pathway synergy achieves "dredging"rather than "repair". This paper aims to elucidate how KD, via metabolic reprogramming, alleviates the inhibition of the TCA cycle caused by NADH accumulation and restores its flux, thereby offering new insights into metabolic therapeutic strategies for CI-deficient mitochondrial diseases.
    Keywords:  NADH; complex I deficiency; ketogenic diet; metabolic reprogramming; mitochondrial disease
    DOI:  https://doi.org/10.3389/fped.2026.1939961
  8. Nat Chem Biol. 2026 Oct 22.
    Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
    Dina Y Bass, Ekaterina S Potekhina, Alexander V Ivanenko, Aleksandr A Moshchenko, Dmitry A Korzhenevskiy, Alexey M Nesterenko, Evgeny K Shevchenko, Anastasia E Karnaeva, Natalia F Zakirova, Alexander V Ivanov, Liubov E Shimolina, Marina V Shirmanova, Olga V Lyang, Olga I Patsap, Olga M Kudryashova, Guzel R Gazizova, Elena I Shagimardanova, Sofia S Mariasina, Vasiliy A Ivlev, Ivan Bogeski, Oleg A Gusev, Vsevolod V Belousov.
      Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.
    DOI:  https://doi.org/10.1038/s41589-026-02350-7
  9. Cell Death Dis. 2026 Jul 23. pii: 893. [Epub ahead of print]17(1):
    SLC25A20 promotes tumor growth by reprogramming energy metabolism in lung adenocarcinoma.
    Xing Liu, Xiaoyu Song, Cong Gan, Ye Wang, Mingxin Ni, Min Zhang, Shaodi Wen, Yahui Cao, Changhua Yi, Man Tian, Apeng Chen.
      Accumulating evidence has shown that the dysfunction of mitochondria, the multifunctional organelles in various cellular processes, is a pivotal event in the development of various diseases, including human cancers. The molecular alterations in tumors that promote metabolic diversity and distinct targetable dependencies remain poorly defined. The mitochondrial transporter SLC25A20, also known as carnitine-acylcarnitine translocase (CACT), is crucial for fatty acid β-oxidation (FAO) by importing acylcarnitines into the mitochondrial matrix. Here, we demonstrate that SLC25A20 is significantly upregulated in lung adenocarcinoma (LUAD) tissues and cells, and its expression correlates with poor patient survival. Gain- and loss-of-function experiments reveal that SLC25A20 promotes tumor cell proliferation, survival, migration, and invasion by enhancing FAO-associated mitochondrial bioenergetics and suppressing apoptosis. Mechanistically, SLC25A20-mediated FAO maintains mitochondrial function and supports oxidative phosphorylation (OXPHOS), thereby sustaining tumor bioenergetics and redox homeostasis. Pharmacological inhibition or genetic silencing of SLC25A20 impairs tumor growth in vivo. These findings establish SLC25A20 as a key metabolic driver in LUAD and suggest it may be a therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-09119-9
  10. Cell. 2026 Oct 23. pii: S0092-8674(26)01186-4. [Epub ahead of print]
    Cell-state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer.
    Jun W Kim, Christina M Bebber, Yuqin Dai, Sarah Bopp, Anna Edenhofer, Albert M Li, Thomas Rösner, Lena Berning, Ming Yang, Logan B Leak, Jenny Stroh, Bindesh Shrestha, Ali T Abdallah, Dimitrios Prymidis, Hernando J Olivos, Maya Baron, Thuyen Nguyen, Yan Ting Shue, Yoko Nishiga, Alexandros P Drainas, Andrea C Chaikovsky, Krystina Szylo, Yang Li, Yun P Kang, Parvathy Manoj, Alvaro Quintanal Villalonga, Charles M Rudin, Gina M DeNicola, Scott J Dixon, Christian Frezza, Jiangbin Ye, Silvia von Karstedt, Julien Sage.
      Cellular heterogeneity and plasticity are hallmarks of cancer that contribute to tumor growth and therapy resistance. Here, we investigated metabolic heterogeneity in small cell lung cancer (SCLC), an aggressive cancer type with considerable plasticity between neuroendocrine (NE) and non-NE cellular states. Through integrated transcriptomic and metabolomic analyses, we identified a universal dependency on exogenous cysteine/cystine (Cys) across all NE/non-NE SCLC cell states. Notably, NE and non-NE cells with low ASCL1 transcription factor levels underwent ferroptosis upon Cys depletion, whereas ASCL1high cells underwent apoptosis while remaining resistant to ferroptosis. This ferroptosis resistance was driven by the direct transcriptional activation of GCH1 by ASCL1, resulting in increased levels of the antioxidants BH4/BH2. Accordingly, combined Cys depletion and inhibition of BH4/BH2 synthesis reduced tumor growth in patient-derived xenografts. These findings demonstrate that metabolic state influences cell-death susceptibility in SCLC and provide a rationale for therapeutic strategies that exploit these metabolic differences.
    Keywords:  ASCL1; GCH1; SCLC; apoptosis; ferroptosis; heterogeneity; lung cancer; metabolism; neuroendocrine; plasticity
    DOI:  https://doi.org/10.1016/j.cell.2026.09.045
  11. bioRxiv. 2026 Aug 27. pii: 2026.08.26.747325. [Epub ahead of print]
    Mitochondrial transfer between breast cancer cells promotes ROS-dependent proliferation.
    Noah M Bressler, Taylor Z Stevens, Minna Roh-Johnson.
      Previously, we showed that macrophages transfer mitochondria to breast cancer cells, promoting proliferation in acceptor cancer cells. Transferred mitochondria were depolarized and accumulated reactive oxygen species (ROS), and the mitochondrial transfer-induced proliferation was dependent upon ROS signaling (Kidwell et al. 2023). Our unexpected findings supported a model in which transferred mitochondria act as a signal for proliferation in acceptor cancer cells rather than a direct source of increased bioenergetics. It remains unclear whether this unexpected signaling mechanism is unique to macrophages as the donor cell, or whether this mechanism applies to mitochondrial transfer between other cells within the tumor microenvironment. Here, we show that highly metastatic cancer cells transfer mitochondria to weakly metastatic cancer cells. These transferred mitochondria are depolarized, accumulate ROS, and promote ROS-dependent proliferation in acceptor cancer cells. Furthermore, we specifically attribute this proliferative phenotype to the transfer of mitochondria, as when we isolate mitochondria from highly metastatic cells and apply these purified mitochondria directly to weakly metastatic cells in culture, acceptor cancer cells that internalize the purified mitochondria exhibit increased proliferation in a ROS-dependent manner. These findings support mitochondrial transfer within the breast tumor microenvironment as a signaling axis for proliferation, regardless of donor cell identity.
    DOI:  https://doi.org/10.64898/2026.08.26.747325
  12. FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):
    HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
    Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.
      Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.
    Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria
    DOI:  https://doi.org/10.1096/fj.202603280R
  13. Oncogenesis. 2026 Jul 25. pii: 54. [Epub ahead of print]15(1):
    BH3 profiling analyses for functional precision medicine.
    Paula Morales-Sánchez, Joan Montero.
      Evasion of apoptosis is a central hallmark of cancer and a major driver of therapeutic resistance. While genomic and transcriptomic profiling have reshaped our understanding of cancer, they often fail to predict whether a cell will die when treated. BH3 profiling and its variants solve this by directly interrogating mitochondrial apoptotic priming and its reliance on anti-apoptotic dependencies by directly exposing cells to defined BH3-only peptides. Over the past decade, researchers have successfully applied these assays across a wide range of hematologic malignancies, solid tumors, and resistant cancer models. This functional assay predicts treatment response, identifies rational drug combinations, and reveals mechanisms of both intrinsic and acquired resistance to apoptosis. In hematologic malignancies, functional dependence on BCL-2 measured by BH3 profiling strongly correlates with sensitivity to venetoclax, while reduced mitochondrial priming underlies resistance. In solid tumors, these analyses have uncovered previously unappreciated reliance on BCL-xL and MCL-1, enabling the design of effective combination strategies despite limited single-agent activity of BH3 mimetics. Recent methodological advances, including high-throughput and dynamic BH3 profiling, further highlight the changing and heterogeneous nature of apoptotic regulation within tumors. This review evaluates the preclinical and early clinical evidence for BH3 profiling in precision oncology. Beyond assessing its current performance, we examine the methodological requirements for its transition into clinical settings and its potential to address the limitations of current personalized cancer therapies.
    DOI:  https://doi.org/10.1038/s41389-026-00647-9
  14. FASEB J. 2026 Oct 31. 40(20): e72384
    Elucidating the Molecular Impact of DA29-Induced ClpP Chemoactivation on Mitochondrial Function.
    Francesca Rizzo, Morena Miciaccia, Maria Grazia Perrone, Antonio Scilimati, Paola Loguercio Polosa, Francesco Bruni.
      Cellular function relies on tightly regulated mitochondrial proteolysis, which controls organelle protein quality and specific mitochondrial functions, including gene expression and oxidative phosphorylation. In human mitochondria, one of the main proteolytic machineries is the soluble ClpXP complex, consisting of the protease ClpP and its chaperone ClpX, which degrades misfolded or aggregated proteins to preserve organelle function and integrity. As hyperactivation of ClpP has been shown to inhibit tumor cell growth in various types of cancer, this protease has become an important target for the development of small-molecule therapeutics. A piperazine-based compound, DA29, has proven effective in inducing cytotoxicity in diffuse intrinsic pontine glioma (DIPG) patient-derived cells and organoids, causing mitochondrial dysfunction and ROS accumulation. In this study, we employed in cellulo systems to conduct molecular and mechanistic analyses of ClpP hyperactivation mediated by DA29. Our data show that DA29 impairs mitochondrial function by specifically activating ClpP. Interestingly, degradation of ClpP itself is promoted when its proteolytic activity exceeds a certain threshold or is sustained for prolonged periods, suggesting a complex regulatory network that tunes protease levels within mitochondria.
    Keywords:  ClpP; ClpX; DA29; DIPG; ONC201; mitochondria; molecular therapy; piperazine; protein quality control
    DOI:  https://doi.org/10.1096/fj.202603398RR
  15. Pharmacol Res. 2026 Oct 19. pii: S1043-6618(26)01611-7. [Epub ahead of print]233 109696
    Should mitochondrial membrane potential be reconsidered as a criterion of cell death?
    Petr Mlejnek.
      
    Keywords:  Cell death; Cell death criteria; Cell viability; Flow cytometry; Mitochondrial membrane potential; Plasma membrane permeabilization
    DOI:  https://doi.org/10.1016/j.phrs.2026.109696
  16. Cell. 2026 Oct 23. pii: S0092-8674(26)01208-0. [Epub ahead of print]
    Perforin triggers iron-induced mitochondrial damage to drive ferroptosis and anti-tumor immunity.
    Hannah N Bell, Kavya Nair, Kole Tison, Peng Liao, Hongwei Lei, Marwa O El-Derany, Ayijiang Yisimayi, Haiwei Zhang, Ryan Rebernick, Weichao Wang, Yoshitaka Adachi, Cristina Castillo, Nupur K Das, Jinsu An, Vivien R Sutton, Xun Lin, Heng Lin, Xinghao Wang, Yunfei Li, Linda Vatan, Amr Aboud, Shuang Wei, Miguel Gijon, Samantha Goodwin, Yatrik M Shah, Ilona Kryczek, Joseph A Trapani, Margarida Barroso, Judy Lieberman, Weiping Zou.
      Cytotoxic CD8+ T cells and natural killer cells are critical effectors of anti-tumor immunity. Cytotoxic lymphocytes eliminate tumor cells by releasing perforin (Prf1), a pore-forming protein that enables granzymes (Gzms) to enter target cells and trigger both caspase-dependent and -independent cell death. Here, we uncover a previously unrecognized, Gzm-independent function of Prf1. We find that Prf1 directly induces tumoral ferroptosis, an iron- and lipid-dependent form of cell death. Mechanistically, Prf1-mediated pore formation drives endocytosis of the transferrin receptor, which increases cellular iron uptake. Prf1 promotes the formation of endosomal-mitochondrial contacts, which leads to mitochondrial iron accumulation, mitochondrial dysfunction, and tumor cell ferroptosis. Dietary iron supplementation suppresses tumor progression in murine tumor models in a Prf1-dependent manner. Higher Prf1 expression correlates with improved survival and enhanced response to immune checkpoint blockade in patients with cancer. These findings define a Gzm-independent function of Prf1 as a direct executioner of cancer cell death through ferroptosis.
    Keywords:  NK cell; T cell; ferroptosis; granzyme; immune checkpoint blockade; iron; mitochondria; perforin
    DOI:  https://doi.org/10.1016/j.cell.2026.09.062
  17. Cell Rep. 2026 Oct 22. pii: S2211-1247(26)01272-6. [Epub ahead of print]45(11): 118193
    ALKBH8 promotes acute myeloid leukemia progression by coupling codon-dependent translation elongation to mRNA stability.
    Songyu Li, Yunguang Hong, Songze Deng, Xiang Wu, Zhirong Jia, Yan Liu, Ya Liu, Guocai Wu, Yinhui Chen, Aibing Wu, Xiangwei Gao, Zhanghui Chen.
      Dysregulated mRNA translation is a critical driver of acute myeloid leukemia (AML) progression. While translation initiation is extensively studied, mechanisms governing translation elongation in AML remain unclear. Here, we show that the RNA methyltransferase ALKBH8 is overexpressed in patients with AML and correlates with poor prognosis. ALKBH8 is required for the proliferation and leukemogenic capacity of human and murine AML cells in vitro and in vivo. Mechanistically, ALKBH8 promotes translation-coupled mRNA stabilization via its methyltransferase domain. Loss of ALKBH8 induces ribosome pausing and preferentially destabilizes transcripts enriched in adenine-ending codons. Specifically, ALKBH8 regulates the expression of the DNA repair gene BRCA1 in a codon-dependent manner, supporting homologous recombination and cell survival. Moreover, ALKBH8 depletion sensitizes AML cells to the PARP inhibitor olaparib. Collectively, our study reveals a codon-specific mechanism of ALKBH8-mediated translation, highlighting the ALKBH8-BRCA1 axis as a potential target for therapeutic intervention.
    Keywords:  ALKBH8; AML; BRCA1; CP: cancer; CP: molecular biology; tRNA modification; translation elongation
    DOI:  https://doi.org/10.1016/j.celrep.2026.118193
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