bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2026–03–08
nine papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
  2. Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
  3. Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
  4. Splice-switching of the oncogenic BCS1L isoform suppresses ovarian cancer progression by disrupting mitochondrial function.
  5. Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
  6. Rafoxanide disrupts mitochondrial homeostasis through VDAC1 modulation in colorectal cancer cells.
  7. Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.
  8. Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
  9. Regulatory T cells thrive in ammonia-rich tumors.
  1. Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]
    Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
    Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.
      The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.
    Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response
    DOI:  https://doi.org/10.1016/j.cell.2026.01.028
  2. Nat Commun. 2026 Mar 05.
    Post-catalysis structures of mitochondrial complex I with ubiquinol-10 bound in the active site.
    Injae Chung, Caroline S Pereira, John J Wright, Guilherme M Arantes, Judy Hirst.
      Respiratory complex I is a multi-subunit energy-transducing membrane enzyme essential for mitochondrial and cellular energy metabolism. It couples NADH oxidation and ubiquinone-10 (Q10) reduction to the concomitant pumping of four protons to generate the proton-motive force that powers oxidative phosphorylation. Despite recent advances in structural knowledge of complex I, many mechanistic aspects including the reactive binding poses of Q10, how Q10 reduction initiates the proton transfer cascade, and how protons move through the membrane domain, remain unclear. Here, we use electron cryomicroscopy to determine structures of mammalian complex I, reconstituted into phospholipid nanodiscs containing exogenous Q10 and reduced by NADH, to global resolutions of 2.0 to 2.6 Å. Two conformations of a reduced Q10H2 molecule are observed, fully inserted into the Q-binding channel in the turnover-relevant closed state. By comparing the quinone species bound in oxidised and reduced complex I structures, paired with molecular dynamics simulations to investigate the charge states of key surrounding residues, we propose a series of substrate binding poses that Q10 transits through for reduction. Our highly hydrated structures exhibit near-continuous proton-transfer connections along the length of the membrane domain, enabling comparisons between them to assist in identifying the proton-transfer control points that are essential to catalysis.
    DOI:  https://doi.org/10.1038/s41467-026-70030-0
  3. Autophagy Rep. 2026 ;5(1): 2635914
    Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.
      Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.
    Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2635914
  4. Cell Death Dis. 2026 Mar 03.
    Splice-switching of the oncogenic BCS1L isoform suppresses ovarian cancer progression by disrupting mitochondrial function.
    Meining Xu, Zixiang Wang, Siyuan Yang, Gaoyuan Li, Xiyu Zhang, Ling Zhao, Lei Yang, Chunhong Qiu, Xianguang Feng, Kai Zhang, Bin Liu, Jian-Jun Wei, Yuliang Li, Gang Liu, Baoxia Cui, Junchao Qin, Zhaojian Liu.
      Increasing evidences demonstrate that mitochondrial function is essential for cancer cell survival and metastasis. However, the role of mitochondrial metabolic reprogramming in ovarian cancer progression remains largely unknown. Here, we report that mitochondrial chaperone BCS1L generates two major alternative-spliced isoforms, a full-length isoform (BCS1L-L) and a short isoform lacking exon 2 (BCS1L-S). Interestingly, BCS1L-L is elevated in several human cancers, and it significantly increased oxidative phosphorylation and ATP production in the present work, which is required for the survival of cancer cells. In contrast, BCS1L-S was unable to localize to the mitochondria as BCS1L-L did, and this led to impaired metabolic function. Mechanistically, splicing factor USP39 promoted exon 2 inclusion, thus facilitating the generation of oncogenic BCS1L-L and, thereby, maintaining mitochondrial homeostasis and survival of ovarian cancer cells. Importantly, we developed splice-switch antisense oligonucleotides (ASOs) that successfully induced exon 2 skipping and decreased BCS1L-L abundance, resulting in impaired tumor growth. These findings suggest that targeting oncogenic BCS1L-L by ASOs is a novel approach for ovarian cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-026-08495-6
  5. Nat Commun. 2026 Mar 06. pii: 2244. [Epub ahead of print]17(1):
    Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma.
    Hongli Zhang, Zixuan Wang, Yiqi Zhao, Xiya Deng, Jian Zhang, Fei Shang, Hongjie Zhang, Yan Liu, Hongbo Wang, Yating Yang, Huiyu Lin, Bo Zhang, Ce Liu, Fan Guo, Ruolin Zhang, Qipeng Yuan, Yue Feng, Shi-Zhong Luo, Wei-Dong Chen, Yan-Dong Wang.
      Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.
    DOI:  https://doi.org/10.1038/s41467-026-70112-z
  6. Cell Death Discov. 2026 Mar 05.
    Rafoxanide disrupts mitochondrial homeostasis through VDAC1 modulation in colorectal cancer cells.
    Lorenzo Tomassini, Teresa Pacifico, Mattia Alberto Serra, Eduardo Maria Sommella, Manolo Sambucci, Giuseppe Sigismondo Sica, Luca Savino, Sara Vitale, Angela Ortenzi, Livia Biancone, Luca Battistini, Giovanna Borsellino, Ivan Monteleone, Vincenzo Barnaba, Micol Eleonora Fiori, Giovanni Monteleone, Carmine Stolfi, Federica Laudisi.
      Functional mitochondria are essential for cancer cells, as they sustain oxidative phosphorylation, metabolic flexibility and survival. Targeting mitochondrial homeostasis has therefore emerged as a promising strategy to sensitize cancer cells to cell death. Rafoxanide is a halogenated salicylanilide originally developed as a veterinary anthelmintic and described to exert mitochondrial uncoupling activity in parasitic organisms. Although rafoxanide has been shown to exert potent antitumor activity against colorectal cancer (CRC), the mechanisms underlying this effect remain incompletely understood. Here, we investigated the impact of rafoxanide on mitochondrial function and stress responses in CRC cells. Rafoxanide rapidly impaired mitochondrial respiration, reducing basal and maximal oxygen consumption and ATP-related respiration, and induced a progressive but reversible dissipation of mitochondrial membrane potential. Integrated transcriptomic, proteomic, and metabolomic analyses revealed that prolonged rafoxanide exposure resulted in sustained mitochondrial dysfunction, failure of metabolic adaptation, and release of cytochrome c from the mitochondria into the cytosol. Mechanistically, rafoxanide inhibited mitochondrial respiratory chain complexes I and III, leading to a rapid increase in total cellular reactive oxygen species. This redox imbalance promoted voltage-dependent anion channel (VDAC1) oligomerization and mitochondrial outer membrane permeabilization. Notably, mitochondrial superoxide production was reduced at later time points, consistent with the loss of mitochondrial membrane potential rather than the absence of a cellular oxidative stress response. Finally, proteomic analysis of colonic lesions from a murine model of sporadic CRC, as well as human CRC explants and intestinal organoids, confirmed that rafoxanide consistently alters mitochondrial protein expression and function across in vitro, in vivo, and ex vivo systems. In conclusion, our results identify rafoxanide as a modulator of mitochondrial homeostasis that induces redox-dependent VDAC1 activation and progressive mitochondrial dysfunction in CRC cells, providing mechanistic insight into its antitumor activity and supporting further exploration of mitochondrial stress modulation as a therapeutic strategy in CRC.
    DOI:  https://doi.org/10.1038/s41420-026-02986-3
  7. Cell Biochem Funct. 2026 Mar;44(3): e70190
    Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.
    Bhanu Priya Awasthi, Bhanupriya Tanwar, Akshi Shree, Sumedha Saluja, Jayanth Kumar Palanichamy, Sameer Bakhshi, Archna Singh.
      The interaction of cellular organelles is crucial for maintaining intracellular homeostasis, particularly highlighting the impact of the cytoskeleton on mitochondrial dynamics. The aim of our study is to find direct molecular connections between cytoskeletal disturbance and mitochondrial failure which are inadequately characterized particularly in B-ALL. We investigated the effects of cytoskeleton inhibition on mitochondria in B-ALL using Pironetin (an alpha-tubulin inhibitor) and Latrunculin B (an actin inhibitor). Our findings indicate that these inhibitors caused mitochondrial fragmentation, characterized by smaller, rounder mitochondria with disordered cristae, increased Drp1 expression (fission protein), and decreased Mfn 1/2 and OPA 1 (fusion proteins) together with significantly modified the expression of essential mitochondrial transporters, such as VDAC and ANT2. These alterations were linked to increased mitochondrial membrane depolarization & mitochondrial reactive oxygen species and gradual mtDNA depletion, indicative of impaired oxidative phosphorylation (increased non-mitochondrial oxygen consumption, decreased mitochondrial reserve capacity) and diminished mitochondrial functionality. These mitochondrial alterations indicate that communication between the cytoskeleton and mitochondria is essential for preserving mitochondrial homeostasis. This study potentially enhances our understanding of how cancer cells modulate mitochondrial function during progression or therapeutic interventions.
    Keywords:  cytoskeleton; latrunculin B; leukemia; mitochondria; pironetin
    DOI:  https://doi.org/10.1002/cbf.70190
  8. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2516372123
    Stochasticity in mammalian cell growth rates drives cell-to-cell variability independently of cell size and divisions.
    Ethan Levien, Joon Ho Kang, Kuheli Biswas, Scott R Manalis, Ariel Amir, Teemu P Miettinen.
      Cell growth rates exhibit cell-intrinsic cell-to-cell variability, which influences cell fitness and size homeostasis from bacteria to cancer. It remains unclear whether this variability arises from stochasticity in cell growth or division processes, or from cell-size-dependent growth regulation. To separate these potential sources of growth variability, single-cell growth rates need to be examined across different timescales. Here, we study cell size and growth regulation by tracking lymphocytic leukemia cell mass accumulation with high precision and minute-scale temporal resolution along long ancestral lineages. We first show that correlations between growth rates and cell-size nor asymmetric divisions explain cell-to-cell growth variability. We then isolate growth fluctuations by smoothing and detrending the growth rate dynamics using a Gaussian process regression. We find that these growth fluctuations drive cell-to-cell growth variability within ancestral lineages despite being independent of cell divisions, cell cycle, and cell size. Overall, our results provide a quantitative framework for understanding single-cell growth rates, and indicate that cell-intrinsic long-term patterns in growth are a byproduct of short-term growth fluctuations.
    Keywords:  cell divisions; cell growth; cell size; cellular noise; heterogeneity
    DOI:  https://doi.org/10.1073/pnas.2516372123
  9. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00046-X. [Epub ahead of print]38(3): 447-448
    Regulatory T cells thrive in ammonia-rich tumors.
    Chenxian Ye, Greg M Delgoffe.
      In a recent issue of Cell, Gu et al. find that regulatory T (Treg) cells metabolize tumor-derived ammonia via the urea cycle and spermine synthesis, promoting immunosuppression through PPARγ-dependent oxidative phosphorylation. Inhibition of tumor glutamine metabolism reduces ammonia levels and overcomes Treg cell-mediated resistance to anti-PD-1 therapy.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.003
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