bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–06–14
thirteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. ACSL4-driven ferroptosis susceptibility as a targetable vulnerability in monocytic acute myeloid leukemia.
  2. TRAP1 ablation improves mitochondrial cristae and oxidative phosphorylation in pancreatic cancer stem cells.
  3. Activation of c-Myc confers resistance to venetoclax via inhibition of Bim in t(8;21)-positive acute myeloid leukemia.
  4. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  5. Mitochondrial transfer reveals an organellar layer of cancer ecology.
  6. Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.
  7. β3-adrenergic blockade targets fatty acid oxidation to induce ferroptotic vulnerability in pediatric T-ALL.
  8. Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
  9. Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
  10. Mitochondria directly interact with the nuclear pore complex.
  11. Mitochondria-ER contacts function as an iron supply hub.
  12. SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
  13. Hitting AML where it breathes: the peroxisome fat trap.
  1. Front Oncol. 2026 ;16 1837940
    ACSL4-driven ferroptosis susceptibility as a targetable vulnerability in monocytic acute myeloid leukemia.
    Federico De Marchi, Michele Gottardi.
      Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, has emerged as a targetable vulnerability in cancer. ACSL4 is the rate-limiting enzyme that dictates ferroptosis sensitivity by channeling polyunsaturated fatty acids into membrane phospholipids. In acute myeloid leukemia (AML), monocytic subtypes resist BCL2 inhibition with venetoclax, yet their metabolic dependencies remain poorly defined. Here, we integrated PRISM drug-sensitivity data (6,790 compounds) and DepMap CRISPR dependencies (18,435 genes) across 15 adult AML cell lines to map drug-gene co-dependencies. A multi-cohort validation strategy - filtering 50 discovery candidates (29 testable in BeatAML) through ex vivo drug-response data in 476 primary AML specimens and clinical outcomes in 140 adults with de novo AML (TCGA-LAML) - converged on a single axis linking SRC family kinase inhibition to ACSL4 expression. ACSL4-high blasts showed enhanced dasatinib sensitivity (r = -0.25, P = 4.3 x 10-8). A composite SRC/ACSL4 signature stratified overall survival (HR 1.27; 95% CI 1.10-1.47; P = 0.0014), remaining significant after age adjustment. Single-cell atlas projection localized this signature to the monocytic compartment. The SRC/ACSL4-high state displayed a ferroptosis gene expression profile characterized by co-upregulation of ACSL4, HMOX1, and LPCAT3 with failure to upregulate the principal ferroptosis defense axis GPX4/SLC7A11. Conversely, ACSL4-high blasts showed significant ex vivo resistance to venetoclax (r = 0.36, P = 2.5 x 10-12), linking the ferroptosis-primed monocytic state to BCL2 inhibitor failure. These findings nominate ACSL4-driven ferroptosis susceptibility as a lineage-specific vulnerability rendering monocytic AML selectively sensitive to SRC-directed therapy while resistant to BCL2 inhibition.
    Keywords:  ACSL4; SRC kinase; acute myeloid leukemia; dasatinib; ferroptosis; monocytic differentiation; venetoclax resistance
    DOI:  https://doi.org/10.3389/fonc.2026.1837940
  2. Cancer Drug Resist. 2026 ;9 17
    TRAP1 ablation improves mitochondrial cristae and oxidative phosphorylation in pancreatic cancer stem cells.
    Giulia Ambrosini, Elisa Dalla Pozza, Ilaria Cristanini, Sara Vinco, Enrica Cappellozza, Barbara Cisterna, Claudio Laquatra, Andrea Rasola, Emanuela Bottani, Ilaria Dando.
      Aim: Cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) display high metabolic plasticity, supporting tumor aggressiveness and therapeutic resistance. Here, we investigated the role of the mitochondrial chaperone TRAP1 in regulating mitochondrial architecture, metabolism, and adhesion in CSCs. Methods: We studied an in vitro model of CSCs using Panc1 cells and the corresponding stable TRAP1-knockout cells (TRAP1-KO). Molecular techniques used were quantitative polymerase chain reaction (qPCR), Western blot, transmission electron microscopy, and Seahorse technology. Results: CSCs showed increased TRAP1 expression after 2 weeks of culture, reflecting a preferential metabolic shift toward glycolysis. TRAP1 deletion impaired the ability of CSCs to form compact spheroids without altering canonical CSC traits, such as reduced proliferation, increased stem marker expression, and enhanced chemoresistance. We demonstrate that TRAP1 deletion increases CDH1, an effect that was reversed by succinate supplementation, indicating that the TRAP1-succinate-CDH1 axis controls adhesion-related properties. Ultrastructural analyses revealed profound mitochondrial remodeling in the absence of TRAP1: parental cells displayed enlarged, elongated mitochondria with wider cristae, whereas CSCs developed fragmented mitochondria with thinner cristae and tighter crista junctions. These alterations were closely associated with the differential regulation of mitochondrial fission factor (MFF). Functionally, loss of TRAP1 enhanced oxidative phosphorylation, leading to increased mitochondrial adenosine triphosphate (ATP) production, elevated maximal respiration, and reduced proton leak. Conclusion: Collectively, these findings identify TRAP1 as a critical regulator of mitochondrial organization, respiratory efficiency, and CDH1-mediated adhesion in PDAC CSCs, highlighting metabolic and structural vulnerabilities that may be exploited therapeutically to destabilize CSC homeostasis and enhance treatment response.
    Keywords:  CDH1; Cancer stem cells; TRAP1; mitochondria; oxidative phosphorylation; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.20517/cdr.2025.229
  3. Cell Commun Signal. 2026 Jun 11.
    Activation of c-Myc confers resistance to venetoclax via inhibition of Bim in t(8;21)-positive acute myeloid leukemia.
    Zhao Yin, Zurong Yao, DanDan Chen, Dan Xu, Li Xuan, Qifa Liu, Baohong Ping, Guopan Yu.
       BACKGROUND AND PURPOSE: Venetoclax (VEN), a selective BCL-2 inhibitor, has improved outcomes in acute myeloid leukemia (AML). However, patients carrying the t(8;21)(q22;q22) translocation often show limited sensitivity to VEN-based therapy. This study aimed to elucidate the molecular mechanism of VEN resistance and explore rational combination strategies.
    EXPERIMENTAL APPROACH: Molecular and functional analyses were performed in t(8;21) AML models to examine the role of c-Myc activation in VEN response. Pharmacologic inhibition, genetic knockdown, and xenograft studies were used to assess the effects of c-Myc and its downstream effector Bim. The efficacy of VEN combined with homoharringtonine (HHT) was further evaluated.
    KEY RESULTS: VEN induced c-Myc expression in a dose-dependent manner, which was not suppressed by azacitidine. Inhibition or knockdown of c-Myc enhanced VEN-induced apoptosis. Mechanistically, c-Myc repressed the pro-apoptotic BH3-only protein Bim, reducing mitochondrial priming and conferring VEN resistance. HHT downregulated c-Myc and restored Bim expression, leading to synergistic anti-leukemic activity with VEN in vitro and in vivo.
    CONCLUSIONS AND IMPLICATIONS: c-Myc activation is a key driver of VEN resistance in t(8;21) AML. HHT acts as a mechanistically complementary agent, restoring VEN sensitivity. These results provide a preclinical rationale for clinical evaluation of VEN-HHT combination therapy in genetically defined AML subsets.
    Keywords:  Acute myeloid leukemia; Bim; Homoharringtonine; Venetoclax; c-Myc
    DOI:  https://doi.org/10.1186/s12964-026-02994-x
  4. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  5. Trends Cancer. 2026 Jun 11. pii: S2405-8033(26)00113-5. [Epub ahead of print]
    Mitochondrial transfer reveals an organellar layer of cancer ecology.
    Derick Okwan-Duodu, Bo Li, Edgar Engleman.
      Tumors are ecological systems shaped by continuous exchange with surrounding cells. The transfer of functional mitochondria, which reprograms malignant behavior, introduces a distinct layer to this ecology. Cancer evolution may proceed not solely through mutation and selection but also through the horizontal assimilation of organellar traits acquired from neighboring cells.
    Keywords:  cancer hallmarks; metabolism; metastasis; mitochondrial transfer; organellar ecology
    DOI:  https://doi.org/10.1016/j.trecan.2026.05.006
  6. J Clin Invest. 2026 Jun 09. pii: e203835. [Epub ahead of print]
    Epigenetic and oncogenic inhibitors converge to drive a metabolic catastrophe in castration-resistant prostate cancer.
    Rhea Sahu, Miriam Enos, Swastika Sharma, Amy E Schade, Alycia Gardner, Akiko Yoshinaga, Alexandra Indeglia, Eleanor Minogue, Songhua Hu, Kiran Kurmi, Shakchhi Joshi, Daniel R Schmidt, Samkyu Yaffe, Van Tm Nguyen, Fang Xie, Steven P Balk, Matthew G Vander Heiden, Kristian Helin, Marcia C Haigis, Karen Cichowski.
      Men with advanced prostate cancer are typically treated with androgen deprivation therapy, but most ultimately develop resistance and incurable disease (e.g. castration-resistant prostate cancer (CRPC)). The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing two targetable pathways outside of AR. Here we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation prior to cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting two key regulators of metabolism, MYC and HIF-1A, while concomitantly derepressing a pro-apoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by co-targeting upstream oncogenic nodes that converge on this important process.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology; Signal transduction; Therapeutics
    DOI:  https://doi.org/10.1172/JCI203835
  7. Biol Direct. 2026 Jun 11.
    β3-adrenergic blockade targets fatty acid oxidation to induce ferroptotic vulnerability in pediatric T-ALL.
    Cristina Banella, Serena Travaglini, Francesco Carrozzo, Agnese Roveta, Francesco Pegoraro, Gianluca Mattei, Rachele Amato, Maria Ascone, Federica De Luca, Aurora Chinnici, Cinzia Marchi, Elena Chiocca, Annalisa Tondo, Marinella Veltroni, Maura Calvani.
      Pediatric T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of childhood ALL. It is associated with a high risk of relapse, with ~25% of patients failing conventional therapy. Resistance is driven by pro-survival signaling, impaired apoptosis, and metabolic adaptations that sustain leukemic proliferation under stress. Herein, we investigate the role of β3-adrenergic receptor (β3-AR) antagonist SR59230A signaling in the metabolic reprogramming and therapeutic vulnerability of pediatric T-ALL. β3-AR expression and transcriptomic profiling following SR59230A exposure were assessed in T-ALL cell lines by RNA sequencing, followed by gene set enrichment analysis of Gene Ontology and Hallmark pathways. Metabolic alterations were validated by Seahorse analyses of mitochondrial respiration, glycolysis, fatty acid oxidation (FAO), and fuel dependency. Systemic iron metabolism was evaluated by ferritin and free iron quantification using COBAS8000. β3-AR was markedly upregulated in T-ALL cells compared with normal hematopoietic counterparts, identifying a selective metabolic vulnerability. Pharmacologic inhibition of β3-AR with SR59230A affected mitochondrial oxidative phosphorylation, predominantly complex I, and suppressed FAO. The metabolic collapse disrupted bioenergetic flexibility and triggered ferroptotic cell death. This was accompanied by modulation of ferritin and transferrin levels, suggesting their potential role as biomarkers of metabolic response. Importantly, β3-AR blockade sensitized T-ALL cells to oxidative phosphorylation inhibition, resulting in synergistic cytotoxicity in refractory models. Collectively, these findings identify β3-AR as a central regulator of metabolic plasticity in pediatric T-ALL highlighting metabolic and iron-dependent vulnerabilities as potential combined targets for high-risk disease.
    Keywords:  Acute lymphoblastic leukemia; Adrenergic receptor; Fatty acid oxidation; Ferroptosis; Metabolism
    DOI:  https://doi.org/10.1186/s13062-026-00850-z
  8. bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]
    Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
    Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.
      Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.
    DOI:  https://doi.org/10.64898/2026.06.04.730191
  9. J Cell Biol. 2026 Aug 03. pii: e202507174. [Epub ahead of print]225(8):
    Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
    Marjana Ndoci, Sharanya Bhattacharya, Ishita Agrawal, Yvonne Hinze, Kathrin Lemke, Anna-Lena Schumacher, Esther Uijttewaal, Ulrich Elling, Steffen Lawo, Patrick Giavalisco, Thomas Langer, Soni Deshwal.
      Coenzyme Q (CoQ) is a hydrophobic lipid primarily synthesized in the mitochondria, though it is also present in non-mitochondrial membranes. However, the metabolic pathways that regulate intracellular CoQ distribution are unknown. This study identifies a key role for the mevalonate pathway in regulating CoQ distribution. The mevalonate pathway synthesizes isopentenyl pyrophosphate (IPP) as the precursor metabolite for both CoQ and cholesterol. We show that CoQ synthesis remains stable regardless of whether the mevalonate pathway is upregulated or downregulated. Upregulation of HMG-CoA reductase (HMGCR), indicative of increased mevalonate flux, enhances cholesterol ester synthesis without altering CoQ levels. When the pathway is downregulated, cholesterol synthesis declines, yet mitochondrial CoQ levels are preserved. Under these limiting conditions, mitochondria reduce CoQ export to maintain their internal CoQ pool. While this adaptation sustains mitochondrial respiration, it diminishes extramitochondrial CoQ availability and sensitizes cells to ferroptosis. These findings uncover a mitochondria-driven mechanism that preserves respiratory function by prioritizing CoQ retention during metabolic stress.
    DOI:  https://doi.org/10.1083/jcb.202507174
  10. Nature. 2026 Jun 10.
    Mitochondria directly interact with the nuclear pore complex.
    Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.
      Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.
    DOI:  https://doi.org/10.1038/s41586-026-10588-3
  11. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  12. Free Radic Biol Med. 2026 Jun 11. pii: S0891-5849(26)00876-2. [Epub ahead of print]
    SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative stress-associated ferroptosis vulnerability.
    Tiange Wang, Jun Tu, Xiangyun Wei, Zi Liang, Rong Cai, Qiuju Fan, Jianli He, Tianshi Wang, Jinke Cheng.
      Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated vulnerability remains incompletely defined. Here, we identify PRDX3 as a candidate SIRT3-regulated effector of mitochondrial peroxide control. In AML12 cells, oxidative stress reduced mitochondrial SENP1, increased SIRT3 SUMOylation and elevated mitochondrial protein acetylation. Mitochondrial acetylome profiling identified PRDX3 K92 as a SIRT3-responsive acetylation site. Genetic activation of SIRT3 reduced PRDX3 acetylation and was associated with enhanced PRDX3 dimerization, improved peroxide clearance and reduced mitochondrial H2O2, lipid peroxidation, iron accumulation and other ferroptosis-associated changes. Conversely, an acetylation-mimetic PRDX3 mutant impaired peroxide clearance and attenuated the protective phenotype associated with SIRT3 activation, whereas a deacetylation-mimetic mutant improved redox balance and cell viability under oxidative stress. In vivo, activation of the SIRT3-PRDX3 axis mitigated paraquat-induced liver injury. Collectively, these data support a model in which SIRT3-dependent regulation of PRDX3 acetylation helps sustain mitochondrial peroxide detoxification and limits oxidative injury during stress.
    Keywords:  PRDX3; SIRT3; ferroptosis; lysine acetylation; mitochondrial peroxide detoxification; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.021
  13. Blood. 2026 Jun 11. 147(24): 2856-2857
    Hitting AML where it breathes: the peroxisome fat trap.
    Fabienne Brenet, Jean-Emmanuel Sarry.
      
    DOI:  https://doi.org/10.1182/blood.2026033659
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 2:09.