bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–11–08
twelve papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
  2. Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
  3. Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.
  4. An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.
  5. MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate.
  6. Human adenine nucleotide translocator isoforms mediate functionally redundant mitochondrial ADP/ATP exchange.
  7. Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.
  8. Myeloid leukemia cells utilize branched chain keto acids to acquire intrinsic resistance to methotrexate.
  9. Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation.
  10. An IHC-based apoptotic priming profile from whole-slide imaging stratifies survival in venetoclax-based AML therapy.
  11. A low-populated helical region of the mitochondrial inhibitor IF1 drives interaction with the ATP synthase OSCP subunit.
  12. Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
  1. Elife. 2026 Nov 04. pii: RP107123. [Epub ahead of print]14
    Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
    Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Huel Cox, Anna Shevzov-Zebrun, Keene L Abbott, Renee Chang, Matthew G Vander Heiden.
      The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine-limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine-depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.
    Keywords:  NAD+/NADH ratio; biochemistry; cancer biology; cancer metabolism; chemical biology; human; lipid depletion; mitochondria; serine
    DOI:  https://doi.org/10.7554/eLife.107123
  2. J Biol Chem. 2026 Nov 04. pii: S0021-9258(26)02591-3. [Epub ahead of print] 113719
    Distinct proteomic and acylproteomic adaptations to succinate dehydrogenase loss in two cell contexts.
    Sherry X Zhou, Benjamin Madden, M Cristine Charlesworth, Taro Hitosugi, Judith Favier, Louis James Maher.
      The tricarboxylic acid (TCA) cycle and electron transport chain (ETC) are key metabolic pathways required for cellular ATP production. Though loss of these components impairs cell survival, such defects can paradoxically promote tumorigenesis. One example is loss of succinate dehydrogenase (SDH), which functions in both the TCA cycle and as Complex II of the ETC. Mutations in SDH subunits can cause pheochromocytoma and paraganglioma (PPGL), rare hereditary neuroendocrine tumors of chromaffin cells in the adrenal gland and the nerve ganglia. Why tumor formation upon SDH loss is limited to certain tissues remains unclear. We hypothesized that the metabolic and proteomic perturbations resulting from SDH loss are cell-type specific, favoring survival of chromaffin cells. We comprehensively examined the proteomic, acetylproteomic, and succinylproteomic effects of SDH loss in two cell models, immortalized mouse chromaffin cells (imCCs) and immortalized mouse embryonic fibroblasts (iMEFs). Perturbations in metabolite levels were determined by mass spectrometry. Effects of SDH loss on fatty acid β-oxidation (FAO) were assessed by stable isotope tracing and pharmacologic inhibition. SDH-loss imCCs show significant upregulation of mitochondrial proteins, including TCA cycle and FAO enzymes, with pronounced downregulation of nuclear proteins. Both imCCs and iMEFs demonstrate significant energy deficiency upon SDH loss, but FAO activity is uniquely increased in SDH-loss imCCs. While SDH loss increases both lysine-reactive acetyl-CoA and succinyl-CoA, SDH-loss imCCs and iMEFs show disproportionate hyperacetylation but mixed succinylation. Surprisingly, SDH-loss imCCs, but not iMEFs, display disproportionate hypoacetylation and hyposuccinylation of mitochondrial proteins.
    Keywords:  acetylation; energy deficiency; energy metabolism; fatty acid oxidation; paraganglioma; pheochromocytoma; protein acylation; proteomics; succinate dehydrogenase; succinylation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113719
  3. Cell Rep. 2026 Nov 06. pii: S2211-1247(26)01346-X. [Epub ahead of print]45(11): 118267
    Succinate promotes multiple myeloma cell proliferation through TCA cycle oxidation.
    Nancy Gudgeon, Taylor Fulton-Ward, Victoria Stavrou, Aidan Haslam, Graham McIlroy, Hannah Giles, Guy Pratt, Sarah Dimeloe.
      Multiple myeloma is a plasma cell malignancy that develops within the bone marrow. The bone marrow metabolome is altered in myeloma, with implications for malignant cell growth. Here, the impact of elevated bone marrow levels of the tricarboxylic acid (TCA) cycle metabolite, succinate, was interrogated. Succinate was found to promote proliferation of several myeloma cell lines. This was linked to its uptake and oxidation in the TCA cycle, as indicated by increased ATP-coupled mitochondrial respiration and incorporation of succinate-derived carbons into downstream TCA cycle intermediates, which also occurs in primary myeloma cells. Succinate-driven proliferation was dependent upon mitochondrial oxidative phosphorylation and abrogated by ATP synthase inhibition. Furthermore, interrogation of large-scale transcriptomic data identified that elevated expression of a mitochondrial succinate transporter associates with accelerated disease progression in myeloma, indicating this mechanism may promote plasma cell growth in vivo and highlighting a target for therapeutic intervention.
    Keywords:  CP: cancer; CP: metabolism; anti-tumour immunity; cancer; cancer metabolism; immunometabolism; metabolism; metabolites; mitochondria; multiple myeloma; succinate
    DOI:  https://doi.org/10.1016/j.celrep.2026.118267
  4. Br J Pharmacol. 2026 Nov 06.
    An inhibitor of the mitochondrial respiratory chain exerts synergistic anti-tumour effects when combined with alkylating agents.
    Emiri Omori Takaki, Yuya Hidoh, Yutaka Obuchi, Yoko Nagai, Shingo Nishikori, Yuki Kuniyoshi, Yasuhiro Sawai, Naoto Ohi.
       BACKGROUND AND PURPOSE: Cancer cells exhibit the Warburg effect, but oxidative phosphorylation (OXPHOS) is also important for cancer cell proliferation. Metabolic reprogramming from glycolysis to OXPHOS is one mechanism of resistance to anti-tumour drugs. Here, we have synthesized and characterized OPB-111077, a novel, first-in-class orally available small-molecule compound, and investigated its anti-tumour activity and therapeutic potential in combination with alkylating agents.
    EXPERIMENTAL APPROACH: Inhibition of mitochondrial function by OPB-111077 were assessed by measuring the oxygen consumption rate, ATP production and Complex I enzymatic activity. anti-tumour effects were evaluated in human haematological and solid tumour cell lines and in cell line-derived xenograft and lymphoma patient-derived xenograft models. Mechanistic studies included CRISPR screening, metabolomic analyses, and measurements of the oxygen consumption and extracellular acidification rates. Effects of OPB-111077 combined with alkylating agents were also assessed in mice.
    KEY RESULTS: OPB-111077 inhibited mitochondrial respiratory chain Complex I, suppressed OXPHOS, and exerted anti-tumour effects in several models. OPB-111077 demonstrated synergism with the alkylating agent bendamustine, with simultaneous inhibition of both OXPHOS and glycolysis. Bendamustine reprogrammed cancer cells into an OXPHOS-dominant state, thereby enhancing the efficacy of OPB-111077.
    CONCLUSION AND IMPLICATIONS: Based on these findings, we propose a novel anticancer therapeutic strategy of combining OXPHOS inhibitors with alkylating agents. OPB-111077 has demonstrated potential in combination therapy and was recently evaluated with bendamustine and rituximab in a Phase 1 clinical trial for patients with relapsed/refractory diffuse large B-cell lymphoma (NCT04049825).
    Keywords:  DLBCL; OXPHOS inhibitor; metabolic reprogramming; synergistic anti‐tumour effect
    DOI:  https://doi.org/10.1111/bph.70719
  5. Sci Adv. 2026 Nov 06. 12(45): eaej2662
    MYC primes a paralog synthetic lethality involving the mitochondrial translocase subunits TIMM17A and TIMM17B and N-Acetylaspartate.
    Sydney M Moyer, Nina Ilic, Sydney Gang, Lucas Dailey, Sehyun Oh, Jasmine Stavridi, Gaia Taig, Kathia E Rodarte, Joseph D DeAngelo, Andrea Jiang, Brian H Shim, Jonathan P Rennhack, John R Jacob, Melis A Akinci, Jonathan So, Helen Wang, Federica Piccioni, Jessica A Talamas, Hans R Widlund, David E Root, Clary B Clish, Nika N Danial, William C Hahn.
      To identify the genes and pathways required for the survival of MYC-amplified cancers, we engineered an isogenic cell system in which transformation is driven by oncogenic MYC. Using a genome-scale CRISPR-Cas9 library, we identified the mitochondrial membrane translocase TIMM17A as uniquely essential for the survival of MYC-transformed cells. This dependency arises from MYC-driven suppression of TIMM17B, the paralog of TIMM17A. TIMM17A/B is an essential component of the TIM23 mitochondrial protein import complex, and the MYC-induced suppression of TIMM17B creates a strong dependency on TIMM17A. N-acetylaspartate supplementation rescued TIMM17A dependency in MYC-amplified cell lines, highlighting the unique and crucial role of this metabolite in the cell fitness of MYC-amplified cancers. These observations identify a paralog dependency required for the survival of a subset of MYC-driven cancers.
    DOI:  https://doi.org/10.1126/sciadv.aej2662
  6. J Biol Chem. 2026 Nov 04. pii: S0021-9258(26)02600-1. [Epub ahead of print] 113728
    Human adenine nucleotide translocator isoforms mediate functionally redundant mitochondrial ADP/ATP exchange.
    Macie S Sheridan, John Z Chan, Steven M Claypool, Nanami Senoo.
      The adenine nucleotide translocator (ANT) is essential for cellular energy metabolism, mediating the exchange of ADP and ATP across the inner mitochondrial membrane. While mammals express multiple ANT isoforms, it remains unclear whether they possess distinct properties or whether their diverse expression patterns reflect functional specialization as widely posited. In this study, we employed a controlled human cell system to directly compare the transport kinetics and bioenergetic contributions of individual human ANT isoforms. By evaluating endogenous knockout cells and systematically re-expressing each isoform, we demonstrate that ANT1, ANT2, and ANT3 are functionally redundant. The three ANT isoforms exhibited near-identical transport rates in both forward (ADPin/ATPout) and reverse (ATPin/ADPout) exchanges. While transport kinetics were equivalent, cells solely expressing ANT2 or ANT3 exhibited slightly different resilience to respiratory inhibition, suggesting isoform-specific roles that may be related to non-transport functions. Our findings provide a refined view of ANT-mediated mitochondrial nucleotide flux and suggest that ANT isoform-specific differences, if they exist, are likely subtle and not innately tied to ADP/ATP exchange.
    Keywords:  ADP; ATP; bioenergetics; exchanger; mammal; membrane protein; mitochondria; mitochondrial transport
    DOI:  https://doi.org/10.1016/j.jbc.2026.113728
  7. Am J Physiol Cell Physiol. 2026 Nov 06.
    Beyond ATP Synthesis: The Proton Motive Force as a Shared Energetic Resource in Mammalian Mitochondria.
    Jarrod A Call, Junwon Heo, Edmund R S Kunji, Kelsey H Fisher-Wellman.
      The proton motive force (PMF) across the inner mitochondrial membrane drives ATP synthesis. Biochemistry textbooks give a maximum yield of 30-32 ATP per glucose, but this is a theoretical ceiling, reached only under complete coupling with ATP synthase as the sole consumer of the gradient. No living cell operates there. The PMF is a shared resource, and its allocation among consumers sets the mitochondrion's effective output: the gap between theoretical and effective yield is a reallocation to transport, redox maintenance, and biogenesis. This review re-examines the textbook yield, including the c-ring stoichiometry of ATP synthase, and catalogs the major PMF consumers and their proton costs. The widely quoted figure corresponds to no measured or structurally determined stoichiometry, a mismatch noted previously and consolidated here, and the c-ring subunit count is an upper bound on synthase efficiency under ideal coupling. We assemble these costs into a consolidated proton budget: a range whose upper limit is the ceiling at which the PMF drives ATP synthesis alone. Its lower limit cannot yet be calculated, because the resting flux through most PMF consumers has never been measured; we therefore list every term that this calculation would require and mark those still missing. The result is a framework for reasoning, not a closed set of numbers. Practical consequence: the PMF and membrane potential are composite quantities, so a change in membrane potential should not be read as a change in ATP synthesis, nor the non-phosphorylating residual as passive leak.
    Keywords:  P/O ratio; membrane potential; molecule and ion transport; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpcell.90010.2026
  8. J Biochem. 2026 Nov 04. pii: mvag082. [Epub ahead of print]
    Myeloid leukemia cells utilize branched chain keto acids to acquire intrinsic resistance to methotrexate.
    Naoki Tamura, Ayuna Hattori, Kenkyo Matsuura, Takashi Sakamoto, Hiroshi Arima, Akifumi Takaori-Kondo, Takahiro Ito.
      Cancer reprograms cellular metabolism to support and accelerate malignant properties, which is known as cancer metabolism. The cancer metabolism has specific roles in acquiring drug resistance mechanisms in multiple types of cancer tissues. Myeloid leukemia cells deregulate branched chain amino acid (BCAA) metabolism to maintain their proliferation and undifferentiated status, but the contribution of this rewired pathway to drug resistance remains poorly understood. Here, we demonstrate that supplementation with branched chain keto acids (BCKAs), the transamination products of BCAAs, specifically attenuates methotrexate (MTX) toxicity in myeloid leukemia cells, whereas direct BCAA supplementation fails to provide a similar protective effect. Conversely, BCKA supplementation inhibits lymphoid leukemia cells, an effect potentially mediated by the activation of hypoxia-inducible factor 1α (HIF-1α). Gene expression analysis further suggests the involvement of activating transcription factor 5 (ATF5) in the BCKA-mediated rescue from MTX toxicity. Clinically, MTX serves as a standard-of-care treatment for lymphoid malignancies, whereas it typically exhibits limited efficacy against myeloid leukemia. Our results highlight a divergent, lineage-specific response to BCKAs, which may underlie metabolic basis for the intrinsic resistance of myeloid leukemia to MTX.
    DOI:  https://doi.org/10.1093/jb/mvag082
  9. Nat Commun. 2026 10 05. pii: 11353. [Epub ahead of print]17(1):
    Fumarate hydratase deficiency triggers disulfidptosis under glucose deprivation.
    Peng Dou, Xin Lu, Pengyu Geng, Yasemin Cole, Miao Bao, Xin Ge, Siming Pu, Lina Zhou, Xinyu Liu, Hang Li, Jinhui Zhao, Hang Gao, Fating Chen, Zhikun Lin, Ting Wang, Qi Li, Jianwen Hu, Jie Dai, Xu Qian, Zhengping Zhuang, Guowang Xu.
      Disulfidptosis is cell death caused by abnormal disulfide bonds, previously observed in cells with high SLC7A11 expression under glucose starvation. Whether other conditions can induce disulfidptosis remains unclear. However, we demonstrate that fumarate hydratase (FH)-deficient cells undergo disulfidptosis under glucose starvation. FH deficiency drives abnormal disulfide accumulation, promotes actin contraction, and consequently leads to cytoskeleton-plasma membrane dissociation. Under glucose starvation conditions, impaired oxidative tricarboxylic acid (TCA) cycle function in FH-deficient cells compromises NAD(P)H (the reduced forms of nicotinamide adenine dinucleotide and its phosphate) homeostasis, leading to redox system collapse. We find that targeting mitochondrial complex I enhances the reductive TCA cycle activity driving NADPH consumption while simultaneously suppressing the oxidative TCA cycle, thereby inducing disulfidptosis in the presence of glucose. Our findings establish a mechanistic link between FH deficiency and disulfidptosis, and define a therapeutically actionable vulnerability in FH-deficient tumors.
    DOI:  https://doi.org/10.1038/s41467-026-78274-6
  10. Virchows Arch. 2026 Nov 05.
    An IHC-based apoptotic priming profile from whole-slide imaging stratifies survival in venetoclax-based AML therapy.
    Te-Lin Hsu, Yu-Hsun Lin, Chun-Kuang Tsai, Chiu-Mei Yeh, Chia-Jen Liu.
      Venetoclax-based regimens are used for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy, but prognostic biomarkers for this regimen remain limited. This study investigated the association between immunohistochemistry (IHC)-based profiling of BCL-2 family proteins and clinical outcomes in elderly AML patients treated with venetoclax-based therapy. We retrospectively analyzed 52 newly diagnosed elderly AML patients treated with venetoclax-based therapy at Taipei Veterans General Hospital (2019-2023). Diagnostic bone marrow biopsies were assessed for 11 BCL-2 family proteins via immunohistochemistry with whole-slide imaging and digital quantification (QuPath), providing an IHC-based apoptotic priming profile reflecting the balance of pro- and anti-apoptotic protein expression; expression levels were dichotomized using Youden's index-derived H-score cutoffs. The median age was 74 years, with 26.9% aged ≥ 80 years; 76.9% had adverse-risk cytogenetics per ELN 2022. In multivariable analysis, age ≥ 80 years (HR 2.46, p = 0.046) and adverse ELN risk (HR 6.02, p = 0.004) independently predicted mortality. In multivariable models, higher expression of the BH3-only proteins BAD, HRK, and NOXA was associated with longer overall survival, whereas elevated anti-apoptotic BCL-XL and MCL-1 were associated with poorer outcomes. These findings suggest that WSI-enabled, IHC-based apoptotic pathway profiling may provide additional prognostic information beyond established clinical and cytogenetic factors in elderly AML patients receiving venetoclax-based therapy.
    Keywords:  Acute myeloid leukemia; BCL-2 family proteins; ELN risk classification; QuPath; apoptotic priming; immunohistochemistry; venetoclax; whole-slide imaging
    DOI:  https://doi.org/10.1007/s00428-026-04700-1
  11. Protein Sci. 2026 Dec;pii: e70844. [Epub ahead of print]35(12):
    A low-populated helical region of the mitochondrial inhibitor IF1 drives interaction with the ATP synthase OSCP subunit.
    Simone Fabbian, Galo Ezequiel Balatti, Marco Carrello, Celeste Quaggia, Lorenzo Cracco, Maria Ludovica Macchia, Stefano Mammi, Valentina Giorgio, Marta De Zotti, Alice Sosic, Sebastian Fernandez Alberti, Massimo Bellanda.
      The upregulation of mitochondrial IF1 is associated with the progression of several cancer types. In HeLa cells, naturally overexpressing this protein, IF1 binds to the ATP synthase OSCP subunit, resulting in inhibition of permeability transition-dependent apoptosis. This newly identified protein-protein interaction represents a promising therapeutic target in tumors characterized by IF1 overexpression. However, the rational design of targeted molecules is currently limited by a lack of structural data on the binding mechanism. Here we employed native mass spectrometry and NMR spectroscopy to identify the minimal IF1 segment required to target the OSCP subunit. NMR revealed that the interaction is weak in solution, with an affinity KD in the low millimolar range, consistent with a binding event occurring exclusively when IF1 is overexpressed in cancer cells. These findings guided the design of a model peptide containing the IF1 binding epitope, which was used in molecular dynamics simulations (MD) aimed at investigating its binding mechanism to the OSCP subunit. NMR and MD converged to show that the IF1 binding epitope requires a helical folding for OSCP engagement, consistent with a helical Molecular Recognition Feature (αMoRF) mechanism. Helicity of the epitope is strictly necessary for productive binding, with key contacts involving IF1 residues E30, E31, Y33, F34, and Q37 packing against OSCP helix H3. Structural analysis of the binding complex provided a first molecular framework to inspire the design of molecules capable of displacing IF1 from the OSCP subunit and potentially exerting anticancer activity.
    Keywords:  IF1; NMR; OSCP; binding mechanism; cancer; molecular dynamics; native MS; peptides; protein–protein interaction (PPI); therapeutic target
    DOI:  https://doi.org/10.1002/pro.70844
  12. bioRxiv. 2026 Oct 27. pii: 2026.10.25.761647. [Epub ahead of print]
    Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
    Feroza K Choudhury, Basma A Yasseen, Paloma González-Sánchez, Meredith Long, Samantha Caldwell, Pritin N Soni, Suehelay Acevedo-Acevedo, Yun Huang, Elsa R Flores, Chang Jiang, Nathan P Ward, Gina M DeNicola.
      The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.
    DOI:  https://doi.org/10.64898/2026.10.25.761647
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