bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–11–01
fifteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
  2. Cancer cells have got 'MoVes'.
  3. Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site.
  4. Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.
  5. MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
  6. Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.
  7. Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.
  8. Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
  9. Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain.
  10. Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.
  11. NDUFS1 promotes malignant breast cancer behaviors through enhancement of mitochondrial respiration and PROX1/c-Myc signaling.
  12. Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
  13. Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer.
  14. Stimulated protein degradation to promote mitochondrial function and neuronal survival.
  15. SLC25A39: A key regulator of mitochondrial metabolism and a promising therapeutic target in cancer.
  1. Nat Metab. 2026 Oct 27.
    Respiration-deficient cells require pyruvate carboxylase to suppress asparagine auxotrophy.
    Ruobing Cui, Keun Woo Ryu, Yi Fu, Ziad Bakouny, Dayi Li, Tamar Kavlashvili, Agnel Sfeir, Craig B Thompson.
      Mutations in mitochondrial DNA (mtDNA) impair ETC activity and oxidative phosphorylation, but their phenotypic consequences vary with heteroplasmy levels. Whether increasing mtDNA heteroplasmy creates metabolic dependencies not present in respiratory-competent cells remains unknown. Here, we show that low pyruvate carboxylase (PC) expression creates an asparagine dependency in high-mtDNA-heteroplasmy, respiration-compromised cells. In isogenic cells carrying similar mtDNA deletions, respiration declines linearly with increasing heteroplasmy, whereas redox imbalance emerges only above 50% heteroplasmy. Above 70% heteroplasmy, integrated stress-response-associated translational defects emerge, which can be reversed by either exogenous asparagine or PC overexpression. Asparagine dependence inversely correlates with PC expression across respiration-deficient cells. Consistent with this pattern, patient-derived thyroid tumour cells harbouring a high-heteroplasmy complex I mutation and low PC levels exhibit asparagine auxotrophy and sensitivity to L-asparaginase. Together, these findings demonstrate a role for mitochondrial PC in cellular asparagine synthesis under conditions of compromised respiratory activity.
    DOI:  https://doi.org/10.1038/s42255-026-01651-4
  2. Nat Cell Biol. 2026 Oct 30.
    Cancer cells have got 'MoVes'.
      
    DOI:  https://doi.org/10.1038/s41556-026-02108-2
  3. Nat Commun. 2026 09 28. pii: 11175. [Epub ahead of print]17(1):
    Allosteric inhibition of human mitochondrial ClpP by hijacking the dordaviprone (ONC201) binding site.
    Monica M Goncalves, Adwaith B Uday, Iain D G Watson, Anh M Chau, Shiva Kalhor-Monfared, Benson Wan, Taira Kiyota, S Quinn W Currie, Yulia Jitkova, Yue Feng, Matthew Diamandas, Dakai Ling, Mary Ma, Ross S Mancini, Zhezhou Wang, Matias Casás-Selves, Dhananjay Joshi, Mohammed Mohammed, Ratheesh Subramaniam, Evelyne Lima Fernandes, Yongran Yan, Neil Pomroy, Rose Hurren, Marcela Gronda, Algirdas Velyvis, Andrei K Yudin, Mark A Reed, Gil Prive, Ahmed Aman, Methvin Isaac, Richard Marcellus, David Uehling, Aaron D Schimmer, Natalie Zeytuni, Siavash Vahidi.
      ClpP protease maintains proteostasis in human mitochondria and is overexpressed in cancers such as acute myeloid leukemia (AML). While activators such as dordaviprone (ONC201) have reached the clinic, the development of ClpP inhibitors has been hampered by paradoxical activation upon orthosteric inhibitor binding. Here, we report a series of quinazolinone-based compounds that allosterically inhibit human ClpP with nanomolar potency. Cryo-EM and H/D exchange mass spectrometry reveal that our lead compound binds sub-stoichiometrically to a distal hydrophobic pocket ~30 Å from the active sites, disrupts a conserved inter-subunit cluster, and induces a conformational change that misaligns the catalytic triad, thereby inactivating ClpP. The binding site of our quinazolinone-based inhibitors partially overlaps with that of the activator dordaviprone. In a xenograft mouse model of leukemia, our lead compound significantly reduced tumor burden following short-term oral administration. Our findings identify a regulatory hotspot in human ClpP and a mechanistically distinct inhibition strategy.
    DOI:  https://doi.org/10.1038/s41467-026-78140-5
  4. Cell Death Discov. 2026 Jul 29. pii: 426. [Epub ahead of print]12(1):
    Stress-induced recruitment of small heat shock protein 1 at the outer mitochondrial membrane underlies resistance to apoptosis.
    Ayesha Kiran Mendes, Stijn L M In 't Groen, Vicky De Winter, Vincent Timmerman.
      Small Heat Shock Protein Family B (HSPB) members are ATP-independent chaperones essential for maintaining cellular proteostasis. Together with chaperones and co-chaperones such as HSP70 and BAG3, they prevent aberrant protein folding and suppress protein aggregation, particularly under proteotoxic stress. HSPBs have also been extensively linked to neurodegenerative disease and in promoting chemoresistance in cancer. We previously showed that members of the HSPB family can reside within the mitochondrial intermembrane space where they contribute to the maintenance of proteostasis, and that acute cytotoxic stress leads to HSPB sequestration to the outer mitochondrial membrane. Here, we further elucidate this mechanism, demonstrating that HSPB1 is selectively enriched within mitochondria under milder thermal stress condition, exhibiting a pronounced association with the outer mitochondrial membrane. We also observed distinct stress-dependent mitochondrial recruitment profiles across HSPB paralogs, revealing a similar behaviour for HSPB8, whereby HSPB1 responded at a comparatively lower stress threshold, indicating functional specialization within the HSPB family. Inducing this mechanism enhances cell survival during hyperthermic stress, preventing Cytochrome c release, and raising the apoptotic activation threshold in our experimental system. These findings indicate that HSPBs, particularly HSPB1 may contribute to mitochondrial stress adaptation prior to Cytochrome c release. This underexplored mechanism may underlie the modulation of stress-related and degenerative disease progression and contribute to the chemoresistance associated with cancer, which have been attributed to HSPBs.
    DOI:  https://doi.org/10.1038/s41420-026-03268-8
  5. Nature. 2026 Oct 28.
    MCT1-dependent mitochondrial lactate import sustains cardiac metabolism.
    Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, James Carrington, Luis Cedeño-Rosario, Giulia C Napoli, Ji Eon Kim, Thirupura S Shankar, Marisa J Brothwell, Rana Hamouche, Álvaro J Narbona-Pérez, Jing Ling, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, David R Eberhardt, Jing Li, Claire E Stanley, Queren A Alcantara, Tarun Yadav, Ryan L Maves, Wojciech I Swiatek, Nicholas A Offei, Bhavya Blaze, Sumangala P Shetty, Dipayan Chaudhuri, Tingting Hong, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Eleni Tseliou, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.
      The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion and injury stressors1. Oxidation of carbohydrate substrates is thought to converge on the cytosolic generation of pyruvate, which is transported by the mitochondrial pyruvate carrier (MPC) for entry into the tricarboxylic acid cycle2. Here we find that glucose-derived carbon is oxidized in mouse myocardium even when the MPC is genetically ablated. Using genetic and pharmacological tools, we demonstrate that lactate monocarboxylate transporter 1 (MCT1, encoded by Slc16a1) is required for the oxidation of glucose carbon by MPC-deficient myocardium. We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes. Together with matrix-localized LDHB, MCT1 enables mitochondrial lactate conversion to pyruvate and NADH, directly fueling the electron transport chain. Loss of MCT1 impairs lactate oxidation, disrupts metabolic flexibility and accelerates the development of heart failure with increased mortality after hyperactivation of the neurohormonal axis or ischemia-reperfusion injury. Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.
    DOI:  https://doi.org/10.1038/s41586-026-11182-3
  6. Cell Rep. 2026 Oct 26. pii: S2211-1247(26)01303-3. [Epub ahead of print]45(11): 118224
    Role of Leu and Val synthesis in sensing mitochondrial nutrient and energy availability.
    Jasmine Phan, Lincoln Gay, Ladislav Dokládal, Claudio De Virgilio, Leonardo Salcedo, Suprim Tha, Caitlyn Wandvik, Markus Babst.
      How cells integrate nutrient availability to coordinate metabolism and growth remains poorly understood. Here, we identify branched-chain amino acid (BCAA) synthesis as a metabolic sensing system linking mitochondrial activity to translational and transcriptional control. Yeast limits Leu and Val import and instead relies on their synthesis, allowing BCAA production to reflect mitochondrial anabolic capacity. Reduced Val synthesis activates Gcn2, whereas reduced Leu synthesis inhibits TORC1, together decreasing translation efficiency and restricting growth. This response lowers levels of the transcriptional repressor Mig1, suppressing the Warburg/Crabtree effect and promoting alternative carbon source utilization. Remarkably, pharmacological inhibition of Leu/Val synthesis induces this metabolic reprogramming even in nutrient-rich medium, indicating that mitochondrial BCAA synthesis can partially override other nutrient-sensing pathways. Thus, BCAA synthesis couples mitochondrial anabolic capacity to Gcn2 and TORC1 activity and, through translational control of transcription factor abundance, shapes cellular metabolism.
    Keywords:  CP: metabolism; Gcn2; TORC1; Warburg effect; amino acid synthesis; diauxic shift; mitochondria; starvation
    DOI:  https://doi.org/10.1016/j.celrep.2026.118224
  7. Immunity. 2026 Oct 30. pii: S1074-7613(26)00429-2. [Epub ahead of print]
    Mitochondrial DNA abundance is a determinant of immunogenic cell death in cancer.
    Kosuke Tanaka, Yasuki Adachi, Takuma Irie, Tomoko Yamamori-Morita, Kazuhiro Kumagai, Takuya Owari, Genki Okumura, Yoshihisa Kobayashi, Hideaki Bando, Yuichiro Tsukada, Shogo Kumagai, Kota Itahashi, Eri Sugiyama, Hiroki Izumi, Yuji Shibata, Koichi Goto, Akihiro Ohashi, Susumu S Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa.
      Cells experiencing mitochondrial stress can undergo apoptosis or cell death that triggers innate immune activation. We examined the mechanisms determining these distinct outcomes in cancer. Abundant mitochondrial DNA (mtDNA) and high expression of the cGAS-STING pathway were features of KRAS-mutant cancers. In a pharmacological screen, MEK inhibitor (MEKi) effectively induced mtDNA release into the cytosol in KRAS-mutant cancer cells. However, MEKi also induced PRKN-mediated mitophagy, which limited mtDNA release by eliminating damaged mitochondria. Inhibition of mitophagy sustained mtDNA efflux and amplified cGAS-STING signaling. Mechanistically, PRKN-mediated mitophagy restrained mitochondrial outer membrane permeabilization (MOMP) to limit mtDNA efflux. The balance between mtDNA and cytochrome c (cyt.c) release defined two immunologically distinct outcomes: immunogenic cell death (ICD) and apoptosis. In preclinical models, combined inhibition of MEK and mitophagy induced robust dendritic cell (DC) activation and promoted CD8+ T cell-mediated antitumor immunity. Consistently, PRKN expression negatively correlated with immune infiltration in human cancers. Collectively, these findings provide a rationale for combination strategies targeting mitochondrial dynamics to augment antitumor immunity.
    Keywords:  KRAS-mutant cancer; TWINKLE; cGAS-STING; immunogenic cell death; mitochondrial DNA; mitophagy; molecularly targeted therapy; subapoptotic MOMP; type I interferon
    DOI:  https://doi.org/10.1016/j.immuni.2026.10.002
  8. bioRxiv. 2026 Oct 09. pii: 2026.10.08.757705. [Epub ahead of print]
    Random mtDNA mutagenesis maps genotype-phenotype associations across metabolic contexts and lineages.
    Amir Giladi, Ron Baik, Chih-Yao Chung, Minsoo Kim, Josephine Adams, Rahul Saha, Max Land, Ruobing Cui, Emily DeBitetto, Megan E Kelley, Craig B Thompson, Ed Reznik, Roshan Sharma, Ronan Challinge, R Stefan Isaac, Josi Peterson, Alexander van Oudenaarden, Agnel Sfeir.
      Mitochondrial DNA (mtDNA) mutations cause inherited disease, accumulate with age, and recur in tumors, yet their effects remain unresolved because existing models interrogate one engineered allele at a time. We developed mtDIVE, a random C→T mutagenesis platform for pooled mitochondrial forward genetics in human epithelial cells and zebrafish embryos. mtDIVE generates genotypes ranging from single substitutions to >100 mutations per molecule, impairs respiration, and causes lineage-specific developmental delay. Coupling single-cell transcriptomics with mtDNA genotyping revealed that selection on mutant genomes and their transcriptional consequences depend on metabolic state and developmental lineage. Obligate OXPHOS eliminates highly mutated cells by apoptosis, whereas glycolytic conditions promote their competitive displacement. Individual loci exert modest but non-redundant effects that predict cell state beyond aggregate mutation burden, and cancer-recurrent variants are enriched among mutations linked to reduced mitochondrial transcription. Thus, mtDIVE links mtDNA genotypes to cellular phenotypes, separating the consequences of mutation identity from mutational load.
    DOI:  https://doi.org/10.64898/2026.10.08.757705
  9. Sci Adv. 2026 Oct 30. 12(44): eaed1177
    Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain.
    Andrea Guajardo-Grence, María Fernández-Lamadrid, Greta Moschini, Lidia Marin-Algeciras, Claudia Mesa-Ciller, Rosa Andreu Martínez, Lucía Fernández-Arroyo, Rebeca Vázquez Muñoz, María José Calzada, Noa Beatriz Martín-Cófreces, José Antonio Enríquez, Katrien De Bock, Julián Aragonés.
      Hypoxia-inducible factors (HIFs) are constitutively active in clear cell renal cell carcinoma (ccRCC) cells. Here, we investigated whether these cells could still respond to hypoxia independently of canonical HIF activation. We found that hypoxia provokes a NADH reductive stress that attenuates lactate release when the supply of extracellular pyruvate becomes limited, a response that was restored by the ectopic expression of the cytosolic and mitochondria-targeted NADH oxidase (LbNOX). Suppression of the mitochondrial electron transport chain (mtETC) alone is sufficient to attenuate glycolytic flux when extracellular pyruvate is limited, a situation consistent with metabolomic data from human ccRCCs. Furthermore, this response can be mimicked by pharmacological or genetic inhibition of mitochondrial complex IV (CIV) activity and restored by the mitochondrial-targeted alternative oxidase (AOX). Therefore, our data suggest that cells can respond to low oxygen tension through a mitochondrial-dependent elevation of NADH/NAD+, resulting in the suppression of glycolysis when pyruvate availability is compromised.
    DOI:  https://doi.org/10.1126/sciadv.aed1177
  10. Mol Cancer Ther. 2026 Oct 29.
    Dual targeting of DHODH and SLC29A1 overcomes metabolic resistance and enhances antitumor immune responses in PDAC.
    Rajgopal Govindarajan, Shivam Vij, Arnav Joshi, Sandip M Vibhute, Chengyu Gao, Reena Shakya, Jeffrey Patrick, Chad E Bennett, Christopher C Coss, Meixiao Long, Mitch A Phelps, Shafia Rahman, Fredrik I Thege.
      Pancreatic ductal adenocarcinoma (PDAC) displays profound metabolic plasticity that sustains rapid proliferation through heightened demands for nucleotide biosynthesis. Here, we characterize HOSU-53 (JBZ-001), a dihydroorotate dehydrogenase (DHODH) inhibitor demonstrating potent antitumor activity in preclinical PDAC models and define the metabolic determinants of sensitivity and resistance. In HOSU-53-sensitive PDAC cells, DHODH inhibition induces G₂/M cell cycle arrest and triggers apoptotic and ferroptotic cell death. In contrast, resistant cells evade metabolic stress by activating compensatory nucleoside transport and macropinocytosis pathways. Integrated functional and genetic analyses reveal that nucleoside salvage via the equilibrative nucleoside transporter SLC29A1 constitutes a dominant resistance mechanism, enabling uptake of extracellular nucleosides to bypass de novo pyrimidine synthesis. Unbiased metabolomic profiling demonstrates that combined inhibition of DHODH and SLC29A1 precipitates mitochondrial dysfunction, oxidative stress, lipid remodeling, and amino acid depletion, culminating in metabolic collapse and energetic failure. Consistent with these findings, dual inhibition markedly suppresses tumor growth and metastatic burden in xenograft and syngeneic orthotopic PDAC models while reprogramming the tumor microenvironment toward a pro inflammatory, immune activated state. Furthermore, co targeting DHODH and SLC29A1 synergizes with anti-PD 1 immune checkpoint blockade, enhancing immunotherapeutic efficacy. Together, these results establish dual targeting of de novo and salvage nucleotide metabolism as a compelling strategy to overcome metabolic resistance, remodel tumor-immune interactions and potentiate therapeutic responses in PDAC.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-26-0461
  11. iScience. 2026 Nov 20. 29(11): 117942
    NDUFS1 promotes malignant breast cancer behaviors through enhancement of mitochondrial respiration and PROX1/c-Myc signaling.
    Yen-Yun Wang, Pang-Yu Chen, Lester Uy Vinzons, Chih-Huang Tseng, Yuk-Kwan Chen, Stephen Chu-Sung Hu, Steven Lo, Ming-Feng Hou, Ching-Hu Wu, Yu-Chieh Chen, Shyng-Shiou F Yuan.
      Cancer cells exploit oxidative phosphorylation (OXPHOS) for growth and metastasis. NDUFS1, the largest subunit of the electron transport chain complex I, is a promising therapeutic target in cancer but has a context-dependent role. Here, we elucidate the function of NDUFS1 in breast cancer. Elevated NDUFS1 expression was associated with advanced breast cancer stage and poor survival outcomes. In vitro experiments showed that NDUFS1 knockdown inhibited breast cancer cell proliferation, invasion, and stemness-associated properties, whereas NDUFS1 overexpression enhanced these phenotypes. Moreover, NDUFS1 directly regulated mitochondrial respiratory function in breast cancer cells and increased c-Myc expression via PROX1. In a mouse model of breast cancer, NDUFS1 knockdown in injected mammary carcinoma cells or OXPHOS inhibition decreased tumor growth and PROX1 and c-Myc expression. Our study highlights the role of the NDUFS1-PROX1-c-Myc axis in breast cancer progression, paving the way for new therapies targeting breast cancer mitochondrial OXPHOS.
    Keywords:  NDUFS1; breast cancer; c-Myc; mitochondrial respiration; prox1
    DOI:  https://doi.org/10.1016/j.isci.2026.117942
  12. Cancer Res. 2026 Oct 27.
    Targeting Branched-Chain Amino Acid Transamination Sensitizes Clear Cell Renal Cell Carcinoma to Glutaminase Inhibition.
    Nathan J Coffey, Sara M Demczyszyn, Yizheng Xue, Zian Zhang, Nicolas Skuli, Nicholas P Lesner, Romain Riscal, Yanqing Jiang, Xu Han, Madeleine Carens, Morgan Brown, Laura C Kim, Brian Keith, Zoltan Arany, M Celeste Simon.
      Metabolic reprogramming is a well-described hallmark of clear cell renal cell carcinoma (ccRCC). Gene copy number variation and altered gene expression data suggest enhanced branched-chain amino acid (BCAA) transamination and reduced BCAA oxidation are highly selected traits in ccRCC. Surprisingly, we found that genetic modulation of BCAA oxidation had little effect on experimental ccRCC cell growth in vitro and in vivo. In contrast, BCAA transamination in ccRCC cells was essential for the generation of glutamate-derived glutathione and cell viability when glutamine was limiting. Thus, BCAA transamination conferred resistance to states of low glutamine or treatment with the glutaminase inhibitor CB-839 by providing glutathione independent of glutamine breakdown. Targeting BCAA transamination in vitro and in vivo sensitized ccRCC to CB-839 mediated glutaminase inhibition by decreasing glutathione biosynthesis and redox homeostasis. These findings reveal that BCAA transamination maintains critical glutamate and glutathione levels in glutamine-deprived ccRCC, explaining why CB-839 treatment has been ineffective in ccRCC clinical trials and demonstrate an approach to treat ccRCC by targeting BCAA transamination to create a vulnerability to glutaminase inhibition.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-0563
  13. Cell Death Discov. 2026 Jul 30. pii: 427. [Epub ahead of print]12(1):
    Mitophagy-dependent mitochondrial DNA release links ionizing radiation to immunogenic cell death in pancreatic cancer.
    Chenghao Li, Yanxian Ren, Yong Chen, Huaying Yu, Jintao Cui, Fei Wang, Jin Li, Ao Sun, Heng Zhou.
      Ionizing radiation (IR) elicits both cytotoxic and immunomodulatory effects, yet the precise link between mitochondrial remodeling and immunogenic cell death (ICD) remains elusive. Here, we report that IR triggers robust mitophagy in pancreatic cancer cells, marked by mitochondrial damage, Parkin/BNIP3 upregulation, and increased autophagic flux. In parallel, IR induces key hallmarks of ICD, including calreticulin exposure, HMGB1 translocation, and the release of ATP and IFN-β. Notably, genetic or pharmacological inhibition of mitophagy attenuated this immunogenic profile, whereas mitophagy induction amplified it. We further demonstrate that mitophagy triggers the cytosolic release of mitochondrial DNA (mtDNA) to activate immune signaling, which can be reversed by blocking mtDNA replication. In murine models, Parkin overexpression enhanced mitophagy and ICD marker expression, leading to reduced tumor burden and prolonged survival following irradiation. Collectively, our findings indicate that mtDNA leakage downstream of mitophagy links mitochondrial remodeling to radiation-induced ICD, suggesting that modulation of mitochondrial dynamics may represent a strategy to enhance both radiosensitivity and the immunogenic potential of radiotherapy in pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41420-026-03269-7
  14. Science. 2026 Oct 29. 394(6823): eaed2525
    Stimulated protein degradation to promote mitochondrial function and neuronal survival.
    Srividya Chandrasekhar, Rachael McMinimy, Andrew G Manford, Eddie Wehri, Christine L Gee, Caitlyn Miller, Baris Bingol, John Kuriyan, Julia Schaletzky, Michael Rapé.
      Targeted protein degradation is a promising modality to treat cancer or inflammation, but whether it can provide a similar benefit for disorders caused by pervasive protein dysregulation is unclear. We describe stimulated protein degradation (SPD) as a strategy that leverages agonists of stress-responsive E3 ubiquitin ligases to simultaneously eliminate multiple pathogenic factors. Specifically, we show that activators of the reductive stress response E3 CUL2FEM1B boost degradation of multiple physiological substrates to improve mitochondrial import and electron transport chain assembly. In this manner, CUL2FEM1B agonists preserve mitochondrial function and neuronal survival in models of neurodegenerative COX deficiency syndrome and Friedreich's ataxia. By activating E3 ligases that evolved to safeguard cellular integrity, SPD expands the use of compound-induced protein degradation to complex pathologies of high unmet need.
    DOI:  https://doi.org/10.1126/science.aed2525
  15. Med Oncol. 2026 Oct 26. pii: 356. [Epub ahead of print]43(11):
    SLC25A39: A key regulator of mitochondrial metabolism and a promising therapeutic target in cancer.
    Tian Tian, Yan Jin, Penghua Cui, Suwei Lan.
      The mitochondrial solute carrier (SLC25) family regulates solute transport across the mitochondrial inner membrane. Among them, SLC25A39 has emerged as a critical player in tumor biology, primarily through its dual role in mediating mitochondrial glutathione (mGSH) transport and maintaining iron-sulfur cluster homeostasis. Recent evidence implies that SLC25A39 dysfunction disrupts mGSH metabolism, thereby influencing iron-sulfur cluster synthesis and driving metabolic reprogramming in tumors. Notably, SLC25A39 is governed by a GSH-Fe-S-AFG3L2 feedback circuit, a feature not shared by its closest homolog SLC25A40. Additionally, upregulation of SLC25A39 is frequently observed in multiple malignancies, including colorectal, pancreatic, and liver cancers, where it correlates with enhanced proliferation, metastasis, and poor prognosis. Furthermore, SLC25A39 expression is intricately associated with remodeling of the tumor immune microenvironment and the development of therapeutic resistance, although these associations are primarily based on correlative evidence and require functional validation before causal conclusions can be drawn. This review synthesizes current knowledge on the molecular mechanisms by which SLC25A39 integrates mGSH transport with iron metabolism, and critically evaluates its emerging roles across different cancer types. We propose that beyond serving as a candidate prognostic biomarker, SLC25A39 represents a potential therapeutic target whose clinical utility remains to be established, and we discuss key unanswered questions regarding its tissue-specific functions and the translational challenges that lie ahead.
    Keywords:   SLC25A39 ; Glutathione; Metabolic reprogramming; Mitochondria; Tumor
    DOI:  https://doi.org/10.1007/s12032-026-03466-5
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