bims-mibica 2026-03-22 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2026–03–22
nine papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.
Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.
Catabolism of extracellular glutathione supplies cysteine to support tumours.
Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.
MFF budding from mitochondria regulates melanosome size and maturation.
Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.
MitoTracker transfers from astrocytes to neurons independently of mitochondria.
Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition-Associated Toxicity.
Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.

bioRxiv. 2026 Mar 03. pii: 2026.03.02.708949. [Epub ahead of print]

Protein S-acylation dynamics provide metabolic plasticity to acute myeloid leukemia cells.

Nithya Balasundaram, Ayşegül Erdem, Azeem Sharda, Veerle W Daniels, Phillip L Chea, Fleur Leguay, Youzhong Liu, Mark A Keibler, Charles Vidoudez, Andrew A Lane, Didier Vertommen, Hans Casteur, Michaël R Laurent, Sunia A Trauger, Gregory Stephanopoulos, David T Scadden, Nick van Gastel.

Though cancer cells' altered metabolism has been recognized for a century, the clinical success of metabolic targeting remains limited due to metabolic plasticity. Here, we use acute myeloid leukemia (AML) as a model to investigate this adaptability through combinatorial metabolic compound screening. Synthetic lethality emerged when AML cells were simultaneously treated with a glutaminase inhibitor and TOFA, a hypolipidemic agent. Sensitivity to this combination was also seen in primary patient samples and in other cancer types, while healthy hematopoietic progenitors were not affected. Unexpectedly, we discovered that TOFA acts through a non-canonical inhibition of protein S-acyltransferases. Protein S-acylation in AML cells specifically requires 16-to-18 carbon long fatty acids and is essential to maintain mitochondrial respiration upon glutaminolysis inhibition. Healthy cells in contrast have high intrinsic metabolic flexibility independent of S-acylation. Our results expose a unique mechanism of metabolic plasticity in cancer that could be targeted to enhance metabolic anti-cancer therapies.

DOI: https://doi.org/10.64898/2026.03.02.708949
Cell Rep. 2026 Mar 17. pii: S2211-1247(26)00185-3. [Epub ahead of print]45(4): 117107

Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer.

Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.

  Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

Keywords:  CP: cancer; CP: metabolism; GPT2; MYC; alanine metabolism; liver cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117107
Nature. 2026 Mar 18.

Catabolism of extracellular glutathione supplies cysteine to support tumours.

Fabio Hecht, Marco Zocchi, Emily T Tuttle, Nathan P Ward, Fatemeh Alimohammadi, Amal Afzal Khan, Veronica C Gomes, Bradley Smith, Jennifer J Twardowski, Bradley N Mills, Kevin A Welle, Sina Ghaemmaghami, Zhuoran Zhou, Yuhan Gan, Yun Pyo Kang, Juliana Cazarin, Zamira G Soares, Mete Emir Ozgurses, Huiping Zhao, Colin Sheehan, Guillaume Cognet, Lila D Munger, Dhvani Trivedi, Gloria Asantewaa, Sara K Blick-Nitko, Jason J Zoeller, Ying Chen, Vasilis Vasiliou, Bradley M Turner, Stephano S Mello, Brian J Altman, Alexander Muir, Jonathan L Coloff, Joshua Munger, Gina M DeNicola, Isaac S Harris.

Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.

DOI: https://doi.org/10.1038/s41586-026-10268-2
Genome Biol Evol. 2026 Mar 16. pii: evag067. [Epub ahead of print]

Lifespan Predicts Mitochondrial Substitution Rates Across Vertebrates, but Methodology Matters.

Jess E Sterling, Kendra D Zwonitzer, Justin C Havird.

  Why do some species live for mere months, while others persist for centuries? A leading explanation implicates mitochondria. The mitochondrial theory of aging predicts that mitochondrial efficiency diminishes with age due to the accumulation of mutations within mitochondrial DNA (mtDNA). While experimental evidence for this theory is mixed, evolutionary analyses offer an ideal opportunity to determine if mitochondrial substitution rates are linked to longevity. Here, we explored the relationship between mtDNA evolution and species' lifespans across four clades-Aves, Actinopterygii, Bivalvia, and Sebastidae-using five normalization strategies. Across most methods, long-lived vertebrates showed reduced synonymous and nonsynonymous substitution rates, suggesting lower mtDNA mutation. However, we found that the strength and direction of these relationships varied drastically depending on the normalization approach used (i.e., correcting for divergence, generation time, and phylogeny). We also analyzed mtDNA mutation spectra and found similar patterns in long- and short-lived species, suggesting decreased rates of mtDNA mutations in long-lived species are not due to suppression of specific mutation processes, as predicted from the free-radical theory of aging. We also find little evidence for a relationship between selection on mitochondrial protein-coding genes and lifespan. Our results align with the idea that decreased mutation rates may help preserve mitochondrial integrity in long-lived vertebrate species, but that these species have not been selected to have particularly efficient OXPHOS or protection against a specific mitochondrial mutation process. Together, these findings underscore the critical link between mitochondrial stability and lifespan, and highlight the power of natural systems in this field.

Keywords:  Mitochondrial DNA; comparative genomics; generation time; longevity; phylogenetic comparative methods; substitution rates

DOI:  https://doi.org/10.1093/gbe/evag067
Nat Commun. 2026 Mar 14.

MFF budding from mitochondria regulates melanosome size and maturation.

Ana Paula Magalhães Rebelo, Aurora Maracani, Samuele Greco, Federica Dal Bello, Lucia Santorelli, Marco Gerdol, Alberto Pallavicini, Tomas Knedlik, Sara Schiavon, Luca Scorrano, Philip S Goff, Christian Frezza, Elena V Sviderskaya, Paolo Grumati, Marta Giacomello.

Melanosomes are lysosome-related organelles that produce and accumulate melanin. Their maturation is regulated through interactions with mitochondria and involves the export and recycling of proteins via tubular transport and fission events whose mechanisms are unknown. Here, we demonstrate that the mitochondrial fission factor protein (MFF) is involved in melanosome fission. MFF is trafficked between mitochondria and melanosomes and locates at melanosome fission events. Upon downregulation of MFF, but not of dynamin-related protein 1 (DRP1), melanosomes enlarge, intracellular melanin accumulates, and melanosomal lumenal catabolism increases, indicating that MFF-dependent melanosome fission is required for their maturation. We show that MFF interacts with regulators of the ARP2/3 complex, which drives F-actin nucleation. Actin filaments accumulate between melanosomes at MFF-enriched membrane constriction sites, and silencing of ARP2/3 subunits mimics the increase in melanosome size. MFF regulates actin-dependent fission of melanosomes via the ARP2/3 complex, indicating an extramitochondrial function for MFF in the regulation of melanosome homeostasis.

DOI: https://doi.org/10.1038/s41467-026-70572-3
Nat Commun. 2026 Mar 17.

Structures of respiratory supercomplexes and ATP synthase oligomers in mammalian mitochondrial inner membrane.

Atsuki Nakano, Takahiro Masuya, Shinsuke Akisada, Moe Ishikawa-Fukuda, Kaoru Mitsuoka, Hideto Miyoshi, Masatoshi Murai, Ken Yokoyama.

Understanding the functional mechanisms of membrane protein complexes requires structural analysis within their native membrane environment. Here, we applied cryo-electron microscopy to determine the structures of FoF1 ATP synthase and respiratory supercomplexes (SCs) on sub-mitochondrial particles (SMPs) isolated from bovine heart mitochondria. Most FoF1 complexes were observed as dimers stabilized by the regulatory factor IF₁, and a tetrameric assembly comprising two FoF1-IF₁ dimers arranged linearly was also identified. This finding indicates that the tetrameric units of FoF1 are present in the mitochondrial inner membrane and contribute to shaping cristae tips in mammalian mitochondria. Fo domain maps resolve the e-subunit- c₈-ring interface and show no discrete density for a tightly bound lipid within the c₈-ring. In addition to the previously reported SCs compositions CI₁CIII₂CIV₁ and CI₁CIII₂CIV₂, our analysis identified an additional assembly with the composition CI₁CIII₂CIV₃, as well as a CI₂CIII₂CIV₆ mega-complex. This approach enables rapid structural determination of FoF1 ATP synthase and SCs from minimal membrane fractions, providing a foundation for elucidating the molecular basis of metabolic disorders and mitochondrial diseases at the level of higher-order architecture.

DOI: https://doi.org/10.1038/s41467-026-70578-x
Cell Rep Methods. 2026 Mar 13. pii: S2667-2375(26)00038-X. [Epub ahead of print] 101338

MitoTracker transfers from astrocytes to neurons independently of mitochondria.

Katriona L Hole, Rosalind Norkett, Emma Russell, Patrick Cottilli, Molly Strom, Jack H Howden, Nicola J Corbett, Janet Brownlees, Michael J Devine.

  The neuroprotective transfer of mitochondria from astrocytes to neurons has been primarily investigated by labeling astrocytic mitochondria with the dye MitoTracker. Here, we labeled astrocytic mitochondria with both a genetically encoded fluorophore (GFP) and MitoTracker dye and then imaged neurons immediately after co-culture with astrocytes or astrocyte-conditioned media (ACM). We report that MitoTracker transfers to neurons from both astrocytes and ACM, independently of mitochondrial transfer. Our observations provide an essential caveat to the use of this reagent and suggest that the investigation of astrocyte-neuron mitochondrial transfer, and other systems in which contact-independent transfer has been reported, requires the use of alternative labeling techniques.

Keywords:  CP: cell biology; CP: neuroscience; MitoTracker; astrocyte; intercellular mitochondrial transfer; mitochondria; neuron

DOI:  https://doi.org/10.1016/j.crmeth.2026.101338
ACS Med Chem Lett. 2026 Mar 12. 17(3): 642-648

Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition-Associated Toxicity.

Haowen Jiang, Alessio Macorano, Enming Xing, Mohamed Jedoui, Shabber Mohammed, Vanessa Lee, Jeffrey Cheng, Lain McDonough, Xiaolin Cheng, Jiangbin Ye, Pui Kai Li.

  Niclosamide, an FDA-approved anthelmintic, functions as a mitochondrial uncoupler with promising anticancer potential, yet its efficacy remains limited, often ascribed to poor bioavailability. We identify a more fundamental constraintits narrow therapeutic window arising from a biphasic mechanism that promotes uncoupling at low doses but inhibits respiration at higher doses. To overcome this limitation, we synthesized 30 niclosamide analogs, systematically profiled their mitochondrial responses using Seahorse MitoTox assay, and developed QSAR models to uncover structural determinants of efficacy and toxicity. Niclosamide exhibited a narrow uncoupling range (0.5-1 μM) beyond which respiration was suppressed. Several analogs, including Nic-2, Nic-8, Nic-40, and Nic-43, sustained uncoupling for up to 9 h at concentrations up to 10 μM, with some showing improved signal modulation and reduced cytotoxicity. QSAR analysis revealed that substitution electronic properties and ring-specific hydrophobicity are related to the therapeutic index. These findings expand niclosamide's therapeutic window through rational scaffold tuning, enabling safer mitochondrial reprogramming strategies for cancer therapy.

Keywords:  Mitochondrial uncoupler; Niclosamide; Structure−activity relationships; Warburg effect

DOI:  https://doi.org/10.1021/acsmedchemlett.5c00439
Blood. 2026 Mar 18. pii: blood.2025031201. [Epub ahead of print]

Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.

Hongzhi Miao, Tao Wu, Trupta Purohit, Dong Chen, Szymon Klossowski, Dmitry Borkin, Bradley Clegg, Joshua Martin Ray, SeRa Park, Rhiannon Stevens, EunGi Kim, Katarzyna Kempinska, Yi Wang, Miao He, Bo Wen, Joshua W Goldman, Jennifer E Agrusa, Chao Ding, Maria Luisa Sulis, Duxin Sun, Rajen Mody, Annette S Kim, Pingda Ren, Lian-Sheng Li, Yi Liu, Francis Burrows, Linda Kessler, Tomasz Cierpicki, Jolanta Grembecka.

The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

DOI: https://doi.org/10.1182/blood.2025031201