bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–06–07
thirteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.
  2. Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
  3. Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.
  4. Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
  5. Cancer as a window into mitochondrial biology.
  6. Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
  7. Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
  8. Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy.
  9. Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
  10. Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
  11. A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
  12. Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
  13. Mitochondria-targeted OXPHOS inhibition enhances radiotherapy efficacy by disrupting mitochondrial function.
  1. bioRxiv. 2026 May 21. pii: 2026.05.18.726122. [Epub ahead of print]
    Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.
    David Sokolov, Eric Zheng, Serwah Danquah, Madeleine L Hart, Lucas B Sullivan.
      Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.
    DOI:  https://doi.org/10.64898/2026.05.18.726122
  2. bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]
    Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
    Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.
      Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.
    DOI:  https://doi.org/10.64898/2026.05.20.726656
  3. Oncogenesis. 2026 Jun 03.
    Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.
    Zhe Wang, Mutian Tang, Marina Konopleva.
      The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
    DOI:  https://doi.org/10.1038/s41389-026-00632-2
  4. bioRxiv. 2026 May 21. pii: 2026.05.19.726308. [Epub ahead of print]
    Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
    Samantha A McLaughlin, Kendall W Knechtel, Zelia M Correa, J William Harbour, Daniel Pelaez.
      Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.
    DOI:  https://doi.org/10.64898/2026.05.19.726308
  5. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00188-9. [Epub ahead of print]38(6): 1085-1088
    Cancer as a window into mitochondrial biology.
    Thomas MacVicar, Laura C Greaves, Payam A Gammage, Stephen W G Tait, Kelsey H Fisher-Wellman, Gordon Freedman.
      Cancer has revealed that the mitochondrion is not a static organelle but a system of extraordinary plasticity. Here, we introduce fundamental mitochondrial behaviors that have been illuminated by cancer research and propose that further investigation in mitochondrial biology holds promise for oncology and beyond.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.003
  6. Nat Rev Endocrinol. 2026 Jun 03.
    Intestinal mitochondrial complex I inhibition essential for clinical benefits of metformin.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-026-01269-2
  7. Free Radic Biol Med. 2026 May 30. pii: S0891-5849(26)00827-0. [Epub ahead of print]253 463-477
    Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer.
    Kai Li, Chenggong Luo, Heng Zhang, Ting Yue, Tengda Wang, Yong Ban, Zhaoxuan Li, Xuan Liu, Lingyue An, Guangheng Luo, Zehua Ma.
      Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial oxidative phosphorylation (OXPHOS) is critical for development of androgen receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates reactive oxygen species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.
    Keywords:  Androgen receptor signaling inhibitors; Castration-resistant prostate cancer; Metabolic remodeling; Mitochondria; Oxidative phosphorylation; PGC-1α
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.323
  8. Front Cell Dev Biol. 2026 ;14 1817489
    Unmasking the apoptotic potential of DHODH inhibition through targeting adaptive mitophagy.
    Xiaowen Huang, Zichang Guo, Bowen Liu, Hongyun Tang.
      Targeting dihydroorotate dehydrogenase (DHODH) to restrict de novo pyrimidine synthesis is a promising anticancer strategy. However, the efficacy of DHODH inhibitors, such as brequinar (BQR), is often constrained by modest single-agent cytotoxicity, necessitating the exploration of combination therapies. Here, using mt-Keima-based mitophagy reporters and CRISPR/Cas9-mediated gene knockout models, we reveal a critical adaptive mechanism whereby BQR-induced mitochondrial reactive oxygen species (mtROS) trigger protective mitophagy. Crucially, we demonstrate that inhibiting this autophagy process synergistically enhances BQR's anti-tumor activity both in vitro and in vivo. This combination leads to enhanced mtROS accumulation and severe lipid peroxidation, ultimately triggering caspase-dependent apoptosis, while ferroptosis does not appear to be the dominant mechanism under these conditions. Our findings identify mitophagy as a key mechanism of resistance to DHODH inhibition and provide a strong rationale for a combinatorial strategy to enhance the therapeutic efficacy of this class of drugs.
    Keywords:  ATG7; DHODH inhibition; apoptosis; chloroquine; mitophagy; mtROS
    DOI:  https://doi.org/10.3389/fcell.2026.1817489
  9. Nat Commun. 2026 May 30.
    Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
    Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.
      Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.
    DOI:  https://doi.org/10.1038/s41467-026-73558-3
  10. bioRxiv. 2026 May 23. pii: 2026.05.22.727209. [Epub ahead of print]
    Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
    Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Ryan D Sheldon, Sara M Nowinski.
      α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that LA exists in two functionally distinct cellular pools: a low-abundance free pool and a protein-bound pool generated through mitochondrial fatty acid synthesis (mtFAS). Disruption of the mtFAS pathway abolishes protein lipoylation and impairs oxidative phosphorylation without altering free LA levels. Conversely, supplementation with exogenous LA markedly increases free intracellular LA without restoring protein lipoylation, mitochondrial respiration, or cell proliferation. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.05.22.727209
  11. J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):
    A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
    Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.
      Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.
    DOI:  https://doi.org/10.1083/jcb.202511088
  12. bioRxiv. 2026 May 22. pii: 2026.05.20.726663. [Epub ahead of print]
    Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
    Salma Sharmin, Jennifer A Kashatus, Sara J Adair, Emma Bakall Loewgren, Mohammad Fallahi-Sichani, Todd W Bauer, David F Kashatus.
       Background: In RAS-mutant tumors, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumor-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown.
    Methods: We developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance.
    Results: We find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signaling axis drives reactivation of mitochondrial fission in the absence of MAPK signaling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitization to trametinib in resistant lines.
    Conclusion: These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.
    DOI:  https://doi.org/10.64898/2026.05.20.726663
  13. Radiother Oncol. 2026 Jun 03. pii: S0167-8140(26)00456-1. [Epub ahead of print] 111617
    Mitochondria-targeted OXPHOS inhibition enhances radiotherapy efficacy by disrupting mitochondrial function.
    Anne P M Beerkens, Paolo S Taracatac, Wenny J M Peeters, Johannes P W Peters, Gosse J Adema, Sandra Heskamp, Johan Bussink, Paul N Span.
       INTRODUCTION: Reducing tumor cell oxygen consumption has emerged as a promising strategy to counter hypoxia-induced radioresistance in solid tumors. Previously, we found that OXPHOS inhibition using PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) and mitochondria-targeted tamoxifen (MitoTam) alleviated hypoxia in tumor spheroids. Here, we investigated the underlying metabolic and redox-related mechanisms-of-action and examined whether mitochondria-targeted OXPHOS inhibition enhances radiotherapy (RT)-induced DNA damage.
    METHODS: The metabolic and redox-related effects of Mito-PEG-ATO and MitoTam alone or combined with RT were examined in B16OVA, MOC1.3D5 and MC38 cells or clones containing an HRE-eGFP-ODD construct. Viability was assessed using a CCK-8 assay on 2D cells. ROS levels were measured after treatment with Mito-PEG-ATO and MitoTam for 24 h with CellRox green and fluorescence monitoring via IncuCyte Zoom. Antioxidant capacity was measured after OXPHOS inhibition relative to Trolox, an analogue of Vitamin E used as antioxidant standard, and mitochondrial membrane potential (MMP) was examined using MitoTracker Orange. Intracellular ATP and metabolic dehydrogenase activity was assessed in tumor spheroids via CellTiter-Glo and CCK-8 assays. Viability, MMP, ATP levels and metabolic activity were measured at 4 h and 24 h post-RT. DNA damage was quantified by γH2AX immunofluorescence in spheroids. Tumor hypoxia following treatment with Mito-PEG-ATO was determined with immunohistochemistry in MOC1.3D5 tumor-bearing mice.
    RESULTS: Mito-PEG-ATO and MitoTam reduced cell viability independent of hypoxia and increased ROS production, which was most pronounced for Mito-PEG-ATO, while no effect was observed on antioxidant capacity. Mitochondrial function was impaired by OXPHOS inhibition, shown by MMP disruption, ATP depletion and reduced metabolic activity, with no further impairment upon combination with RT. However, combining Mito-PEG-ATO or MitoTam with RT increased DNA damage compared to either treatment alone. Treatment with Mito-PEG-ATO in MOC1.3D5 tumor-bearing mice did not alleviate hypoxia or alter lactate levels.
    CONCLUSION: Mito-PEG-ATO and MitoTam increase ROS production and disrupt mitochondrial function, enhancing RT-induced DNA damage and potentially improving RT efficacy. However, mice treated with Mito-PEG-ATO did not show a reduction in tumor hypoxia.
    Keywords:  Antioxidant capacity; Hypoxia; Mito-targeted OXPHOS inhibitors; ROS; Radio sensitivity; Radiotherapy
    DOI:  https://doi.org/10.1016/j.radonc.2026.111617
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