bims-celmim 2026-10-25 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–10–25
twenty papers selected by
Marc Segarra Mondejar, AINA

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.
HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.
A cell death ballet in two acts.
In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.
Paraptosis, a new type of cell death that can be applied to cancer treatment.
Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal diet.
Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.
Construction of a Golgi apparatus-localization polarity-responsive fluorescent probe with large Stokes shift to screen the small-molecule drugs for the inhibition of ferroptosis.
Simultaneous and Real-Time Imaging of Mitochondrial and Lysosomal ATP with Inducible Excessive Mitophagy for Antitumor Therapy via a Multifunctional Fluorescent Probe.
Phosphorylation of the mitochondrial calcium uniporter beta subunit matrix domain locks a conformation that suppresses mitochondrial calcium flux.
The tumor macroenvironment as cancer metabolism's next frontier.
Stepwise Design of a High Signal-to-Background Ratio Dual-Emission Probe for Imaging Mitochondrial HClO and Microenvironmental Changes in Diabetic Liver and Kidney Injury.
TargetMITO: a rule-based model for generating functional synthetic mitochondrial targeting sequences in yeast.
Drosophila Appl loss disrupts proteins in mitochondrial oxidative and glycosylation pathways conserved in Alzheimer's disease.
BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.
Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.
Photostable rhodamine 6G-based fluorescent probe for selective and sensitive visualization of dynamic lysosomal pH.
Confocal microscopy-based radial profile analysis for submitochondrial protein localization.
Lipid requirements for brain development and function: what we can learn from Drosophila melanogaster.
Self-Amplifying Cascade Enzymatic Nanoplatform Orchestrating Metabolic Reprogramming and Oxidative Stress for Antitumor Therapy.

Proc Natl Acad Sci U S A. 2026 Oct 27. 123(43): e2613074123

Mitochondrial subpopulations promote cellular responses to changes in metabolic demand and signal transduction.

Tak Shun Fung, Elias Tzoc-Pacheco, Ruobing Cui, Shelby Brown, Simon Schwörer, Tullia Lindsten, Craig B Thompson, Keunwoo Ryu.

  When mammalian cells are under increased ATP demand, mitochondria segregate into two distinct subpopulations, one capable of oxidative phosphorylation (oxidative subpopulation) and another specialized in reductive synthesis of metabolic precursors (reductive subpopulation). Here we report that mitochondrial DNA (mtDNA) along with protein components of the mitochondrial nucleoid segregate to the oxidative subpopulation in response to increased ATP demand. This suggests that formation of the reductive mitochondrial subpopulation might serve to eliminate alternative uses of mitochondrial NAD(P)H when cells are under bioenergetic or nutrient stress. To examine this further, we studied mitochondria in cells exposed to low levels of glutamine. Mitochondria use glutaminase (GLS1) to maintain net glutamine uptake when cytosolic glutamine decreases, by converting glutamine to glutamate. The resulting glutamate can either be oxidized into α-ketoglutarate to enter the TCA cycle or utilized in the reductive synthesis of proline/ornithine. GLS1 can polymerize into hyperactive filaments in response to elevations in inorganic phosphate as might occur when ATP consumption exceeds production. However, when extracellular glutamine is reduced, GLS1 filaments segregated away from mtDNA, becoming colocalized with pyrroline-5-carboxylate synthase (P5CS) filaments in reductive mitochondria lacking ATP synthase markers. This cosegregation supported the ability of TGF-β signaling to enhance reductive proline/ornithine biosynthesis under low glutamine conditions despite compromising oxidative TCA cycle support from glutamine. The cosegregation of GLS1-P5CS filaments depended on continuing mitochondrial fission/fusion and occurred even in cells lacking mtDNA. Together, these data demonstrate that the reductive mitochondrial subpopulation is functional and under regulation by both metabolic demand and intercellular signal transduction.

Keywords:  GLS; P5CS; metabolism; mitochondria; mtDNA

DOI:  https://doi.org/10.1073/pnas.2613074123
FASEB J. 2026 Oct 31. pii: e72407. [Epub ahead of print]40(20):

HMOX1 Is Involved in the Upregulation of Mitochondrial Fatty Acid β-Oxidation Through Heme Catalysis.

Ko Suzuki, Jun-Ichiro Takahashi, Kiriko Kaneko, Kazumichi Furuyama.

  Intracellular energy metabolism is strictly regulated by hormones and intracellular metabolites for the appropriate use of energy resources such as carbohydrates and fatty acids. Mitochondria are essential organelles in eukaryotic cells since they contain several metabolic machineries required for oxidative phosphorylation, such as the tricarboxylic cycle, electron transport chain, and fatty acid β-oxidation (FAO). Previously, we reported that FAO activity is increased in CLPX-knockout HepG2 cells (CLPX-KO cells). CLPX is the substrate recognition subunit of the mitochondrial protease ClpXP that regulates intracellular heme levels through the degradation of ALAS1 in the mitochondrial matrix. ALAS1 is the rate-limiting enzyme for heme biosynthesis; thus, we examined whether heme regulates FAO activity. We found that the inhibition of heme synthesis in CLPX-KO cells decreased FAO activity; in contrast, hemin treatment increased FAO activity in wild-type HepG2 cells (CLPX-WT cells). Furthermore, pretreatment of CLPX-WT cells with a chemical inhibitor or specific siRNA targeting the heme degradation enzyme HMOX1 blocked FAO activation induced by hemin, indicating that heme catabolites rather than heme itself are responsible for FAO activation by heme. Among the heme catabolites, we identified carbon monoxide (CO) as an essential metabolite for FAO activation through the activation of the LKB1/AMPK signaling pathway. In this manuscript, we revealed the previously unknown role of CO as an intrinsic inducer of mitochondrial FAO activity and revealed that an excess amount of heme increases FAO activity via CO production by HMOX1.

Keywords:  AMP‐activated kinase; carbon monoxide; fatty acid oxidation; heme; heme oxygenase; mitochondria

DOI:  https://doi.org/10.1096/fj.202603280R
Science. 2026 Oct 22. 394(6822): 383-384

A cell death ballet in two acts.

Cristina Muñoz-Pinedo, Seamus J Martin.

Two proteins that permeabilize mitochondria promote cell death through distinct mechanisms.

DOI: https://doi.org/10.1126/science.aem1247
Anal Chem. 2026 Sep 29. 98(38): 28330-28336

In Cellulo Observation of De Novo-Synthesized Nucleotide by Spectral Tracing of Glutamine-Derived Nitrogen Metabolism (QN-STIM) in Cancer Cells.

Jiro Karlo, Surya Pratap Singh.

De novo nucleotide biosynthesis is directly linked to glutamine-derived nitrogen metabolism in mammalian cells. It is a fundamental process tightly tied to cellular growth, proliferation, and metabolic reprogramming, particularly in cancer cells. Direct detection and imaging of glutamine-derived nitrogen metabolism at single-cell resolution remains a challenge. The conventional liquid chromatography-mass spectrometry-based approach for detecting de novo-synthesized nucleotide studies is mostly performed on metabolites extracted from a group of cells, which makes it inherently destructive. Herein, we introduce a vibrational spectroscopy-based single-cell metabolic detection and imaging framework, "glutamine (Q)-derived nitrogen spectral tracing and imaging (QN-STIM)". Using this strategy, we detected and mapped nitrogen flow from glutamine to de novo-synthesized nascent nucleotides at the single-cell level. First, a proof-of-concept analysis was conducted in human embryonic kidney HEK293T cells and demonstrated the feasibility of this approach in cancer cells, namely human lung carcinoma A549, human glioblastoma U87 MG, and mouse hepatoma Hepa1-6. QN-STIM technique holds immense potential to be an adjunct tool to advance our understanding of nucleotide dynamics during differentiation, stress adaptation, and immune activation, and to evaluate responses to metabolic drugs in cellulo.

DOI: https://doi.org/10.1021/acs.analchem.6c03877
Front Oncol. 2026 ;16 1959542

Paraptosis, a new type of cell death that can be applied to cancer treatment.

Xudong Wang, Jiaxing Ma, Bowen Tan, Yang Wang, Zhengwan Wang, Chunlan Hou, Qingjuan Chen, Xiang Jin.

  Paraptosis is a form of non-apoptotic cell death characterized by cytoplasmic vacuolization and swelling of the mitochondria and endoplasmic reticulum (ER). Recent studies have demonstrated that inducing paraptosis in cancer cells can circumvent apoptosis resistance and synergize with other forms of cell death and tumor immunity, providing a novel strategy for anti-tumor therapy. The underlying mechanism of paraptosis involves ER stress triggered by inducers, leading to the swelling of the ER and mitochondria. This subsequently alters the cytoskeleton and disrupts molecular processes, such as calcium (Ca2+) homeostasis, ultimately causing cytoplasmic vacuolization and cell death. Unlike other forms of programmed cell death, paraptosis is caspase-independent and is marked by mitochondrial and ER swelling, along with extensive cytoplasmic vacuolization, without nuclear pyknosis or cell membrane rupture. Various natural compounds, chemical agents, and nanomedicines have been shown to induce paraptosis, which also holds potential in immunotherapy by promoting immunogenic cell death (ICD) and systemic anti-tumor responses. Thus, in cases where cancer cells evade and develop resistance to conventional pro-apoptotic therapies, paraptosis induction offers an alternative therapeutic approach. A comprehensive understanding of the molecular mechanisms underlying paraptosis and its targeted induction may facilitate the development of novel cancer treatments. This paper explores the impact of paraptosis on cancer cells, the mechanisms by which different drugs induce paraptosis, and the potential applications of paraptosis in cancer therapy.

Keywords:  cancer therapy; cell death; endoplasmic reticulum; molecular mechanisms; paraptosis

DOI:  https://doi.org/10.3389/fonc.2026.1959542
J Biol Chem. 2026 Oct 21. pii: S0021-9258(26)02539-1. [Epub ahead of print] 113667

Demand for de novo serine biosynthesis in C. elegans embryos is buffered by the glycine cleavage system and maternal diet.

Joanna Zaino, Amanda Anderson, Omar Rachidi Alaoui, Olga Ponomarova.

  Metabolic network plasticity helps organisms survive change, including dietary fluctuations, transitions between developmental stages and genetic perturbations. To maintain a robust supply of resources under these conditions, metabolic networks must rebalance flux across individual pathways. However, how pathways coordinate their activity to support homeostasis remains poorly understood. Here, we use metabolomics, dietary supplementation, and genetic screening to investigate how the network compensates for the loss of phosphoglycerate dehydrogenase PHDH-1, the rate-limiting enzyme in serine biosynthesis. We find that PHDH-1 dysfunction causes developmental delay and substantially alters the metabolome of C. elegans embryos, but not that of adult animals. Despite these perturbations, Δphdh-1 mutant embryos remain viable through the compensatory activity of enzymes that we identified through a genetic interaction screen. The identified PHDH-1 interactions span the metabolic network and are alleviated by maternal serine supplementation, revealing wide-ranging functional links between serine metabolism and distant pathways. We further demonstrate how the joint action of PHDH-1, the glycine cleavage system and the maternal diet sustains embryonic one-carbon metabolism. Overall, our results reveal how metabolic networks buffer the supply of one-carbon units to compensate for enzyme dysfunction and support robust development.

Keywords:  C. elegans; Metabolism; embryo; glycine cleavage system; one-carbon metabolism; phosphoglycerate dehydrogenase; serine

DOI:  https://doi.org/10.1016/j.jbc.2026.113667
Nat Commun. 2026 09 18. pii: 10949. [Epub ahead of print]17(1):

Spatiotemporal metabolic networks in a preclinical model of pancreatic cancer and associated cachexia.

Blanca Majem, Min-Sik Lee, Kyung Cheul Shin, Insia Naqvi, Courtney Dennis, Lucas Dailey, Sarah Jeanfavre, Mari Mino-Kenudson, Joao B Xavier, Clary B Clish, Deepti Mathur, Nada Y Kalaany.

Cachexia or body wasting is a significant contributing factor to the morbidity and mortality of pancreatic cancer. Despite an unmet need, its metabolic underpinnings remain poorly understood. Here, we characterize a mouse model that recaptures the longitudinal progression of human cachexia during pancreatic cancer development. We profile the metabolomes of pre-, early- and late-stage cancer-associated cachexia in male and female pancreas, its interstitial fluid (IF), plasma, liver, adipose tissue and skeletal muscle. We find that each tissue has a unique metabolome and trajectory across stages and reveal a marked lipid enrichment in the tumor IF. Using mathematical modeling, we identify metabolites participating in cross-tissue networks and in vivo validate a lactate-glucose conversion. We find systemic metabolic changes prior to weight loss and use feature selection algorithms to identify early detection markers. Our study provides a resource for system-wide metabolic evolution of pancreatic cancer and associated cachexia, highlighting the potential for timely diagnostics and interventions.

DOI: https://doi.org/10.1038/s41467-026-77745-0
Spectrochim Acta A Mol Biomol Spectrosc. 2026 Oct 16. pii: S1386-1425(26)01561-1. [Epub ahead of print]367(Pt 2): 128990

Construction of a Golgi apparatus-localization polarity-responsive fluorescent probe with large Stokes shift to screen the small-molecule drugs for the inhibition of ferroptosis.

Xu Yang, Wenqing Han, Qi-Yun Feng, Baoli Dong, Tao Yue.

  Ferroptosis is a distinctive cell death form and has close connections with many diseases, and screening of ferroptosis-associated drug has great importance to delve into creative approaches against the currently intractable diseases. Herein, we developed a method for the ferroptosis-related small-molecule drugs screening by a GA-targeting polarity-responsive fluorescent probe (GP-1). The probe GP-1 showed large Stokes shifts in solvents (up to 194 nm), and displayed desirable sensitivity and selectivity to polarity. GP-1 was primarily distributed in Golgi apparatus (GA) rather than the other common organelles such as lysosome, mitochondria and endoplasmic reticulum (ER). Fluorescence imaging experiments revealed that erastin-induced ferroptosis could raise GA polarity noticeably. By using GA polarity as an indicator to assess the bioactivity of various small-molecule drugs, the imaging data showed that the natural active molecules (e.g. baicalein, rutin, curcumin, DHLA, lipoic acid, retinol, VE, 7-DHC) and edaravone can inhibit the significant changes of GA polarity, while the common Fe(II)-complexing agents (citric acid, tartaric acid) displayed nearly no inhibition effects to ferroptosis.

Keywords:  Drug screening; Ferroptosis; Fluorescence imaging; Golgi apparatus; Polarity

DOI:  https://doi.org/10.1016/j.saa.2026.128990
Anal Chem. 2026 Sep 29. 98(38): 28495-28510

Simultaneous and Real-Time Imaging of Mitochondrial and Lysosomal ATP with Inducible Excessive Mitophagy for Antitumor Therapy via a Multifunctional Fluorescent Probe.

Zhou Wu, Bin Yang, Jun Wang, Ruihong Yao, Zhihao Lu, Yong Li, Yanli Li, Yuemao Dou, Jiajia Zeng, Zhirong Geng, Zhilin Wang.

Mitophagy is essential for mitochondrial quality control and cellular homeostasis, while its aberrant hyperactivation has emerged as a promising strategy to selectively eliminate cancer cells. This process depends on the adenosine triphosphate (ATP) interplay between mitochondria and lysosomes, yet probes that simultaneously enable dual-organelle ATP imaging and mitophagy regulation are still lacking. Herein, we report MLA, a powerful fluorescent probe that integrates spectrally resolved ATP imaging in both organelles with inducible excessive mitophagy. Bearing pH-adapted fluorophores and a glutathione (GSH)-cleavable disulfide, MLA operates in two modes: at low doses, it serves as a biocompatible reporter to map ATP fluctuations under various perturbations; at high doses, it depletes mitochondrial GSH, thereby triggering a reactive oxygen species (ROS) burst that induces excessive mitophagy and cancer cell death. Mechanistically, it was discovered that this process consumes the transmembrane glycoprotein Mucin 1 (MUC1) whose degradation blocks autophagic flux, and thus leads to lethal accumulation of undegraded autophagosomes, markedly suppressing proliferation. In vivo, MLA enables specific imaging of intratumoral ATP and exhibits tumor-inhibitory capacity. Co-administration with the ATP synthase inhibitor oligomycin A (Omy A) further amplifies the tumor-suppressive effect, validating a simultaneous and drastic ATP/GSH dual-depletion strategy as a feasible combination therapy. MLA represents the first fluorescent probe to synergize dual-organelle ATP imaging with mitophagy regulation, offering a powerful tool for fundamental research and a new paradigm for the design of versatile fluorescent probes.

DOI: https://doi.org/10.1021/acs.analchem.6c04402
J Biol Chem. 2026 Oct 21. pii: S0021-9258(26)02533-0. [Epub ahead of print] 113661

Phosphorylation of the mitochondrial calcium uniporter beta subunit matrix domain locks a conformation that suppresses mitochondrial calcium flux.

Danielle M Colussi, Zoya Lehman, David Zhuang, Peter B Stathopulos.

Mitochondrial calcium (Ca2+) uptake is a central regulator of metabolism, signal transduction and cell death pathways. The mitochondrial calcium uniporter complex (mtCU) mediates this flux through a tetrameric pore comprised of MCU and MCU beta (MCUb) subunits. The large, matrix-oriented amino (N)-terminal domains (NTDs) of both paralogs are critical regulatory hubs, responsive to both ion binding and post-translational modifications. Despite high sequence identity between the MCU and MCUb NTDs, we previously identified significant disparities in regulatory ion-binding mechanisms. Further, while phosphorylation of MCU-NTD at Ser92 by protein kinase C (PKC) is known to induce a conformational change that regulates mtCU flux, whether the conserved post-translational modification site on MCUb serves a similar or divergent regulatory role remains unexplored. Here, using a colorimetric phosphate release and phosphoprotein staining assays, solution NMR spectroscopy and LC-MS/MS, we reveal that PKCδ phosphorylates MCUb-NTD at Ser77. Moreover, an S77D phosphomimetic induced structural and molecular dynamics behaviour consistent with the phosphorylated state. Remarkably, the S77D substitution alone was sufficient to drive the MCUb-NTD into a conformation analogous to the Ca2+-bound state, in silico and in vitro, bypassing the requirement for ion binding. This phosphorylation-induced transition exhibited increased thermal stability but weakened hetero-oligomerization with MCU-NTD compared to wild-type. Functionally, MCUb-S77D reduced mitochondrial Ca2+ uptake in HEK293T and HeLa cells without altering colocalization with MCU. Collectively, our results show that Ser77 phosphorylation locks the MCUb-NTD into a Ca2+-insensitive conformation that mimics the Ca2+-bound state, potentiating the suppression of mitochondrial Ca2+ flux.

DOI: https://doi.org/10.1016/j.jbc.2026.113661
Trends Cancer. 2026 Oct 20. pii: S2405-8033(26)00218-9. [Epub ahead of print]

The tumor macroenvironment as cancer metabolism's next frontier.

Allison B Grenell, Joe L Rowles, Ronnie Fowle-Grider, Yin Cao, Leah P Shriver, Gary J Patti.

  The deregulated utilization of nutrients by tumors, first observed over a century ago, is recognized as a hallmark of cancer and continues to be exploited clinically to image neoplastic disease. Despite this historic focus on cancer cells and, more recently, their neighbors, metabolic reprogramming is not limited to the tumor microenvironment. Tumors also have the capacity to rewire the metabolism of cells throughout the body, including those at distant sites, often referred to as the tumor macroenvironment. Alterations in the metabolism of noncancerous tissues outside the local tumor ecosystem are gaining attention, but their origins and consequences remain incompletely defined. A deeper understanding of these changes may reveal previously unrecognized signatures of disease and unexplored opportunities for therapeutic intervention.

Keywords:  cachexia; glucose; glutamine; lipids; tumor macroenvironment; whole-body metabolism

DOI:  https://doi.org/10.1016/j.trecan.2026.09.007
Anal Chem. 2026 Oct 06. 98(39): 28967-28978

Stepwise Design of a High Signal-to-Background Ratio Dual-Emission Probe for Imaging Mitochondrial HClO and Microenvironmental Changes in Diabetic Liver and Kidney Injury.

Hailin Zhang, Min Deng, Jia Huang, Zibo Zhai, Qiqi Wen, Siyu Liao, Xijian Wang, Dan Cheng, Longwei He, Songjiao Li.

Diabetic hepatorenal injury is linked to oxidative stress, mitochondrial dysfunction, and ferroptosis. Elevated hypochlorous acid (HClO) levels, together with alterations in mitochondrial polarity and viscosity, are key indicators of diabetic hepatorenal injury. Early, in situ, real-time monitoring of these signals is essential for disease assessment and therapeutic intervention. However, most existing fluorescent probes target only single analytes or organs, restricting multi-signal and dual-organ monitoring, while their imaging signal-to-background ratios (SBRs) remain suboptimal. To overcome these limitations, we developed a series of dual-emission fluorescent probes, PVPH1-PVPH3, through a stepwise molecular engineering strategy. Extension of the π-conjugation system induced a red-shift in PVPH2 relative to PVPH1, whereas further incorporation of a dicyanovinyl electron-withdrawing unit into PVPH3 enhanced intramolecular charge transfer and molecular rotor characteristics, improving the probe SBR. PVPH3 enables dual-emission monitoring of HClO and viscosity/polarity-related mitochondrial microenvironmental changes. Spectroscopic studies demonstrated fluorescence enhancement factors of 201.83-fold, 85.75-fold, and 20.67-fold for viscosity, polarity, and HClO, respectively, together with excellent selectivity, stability, and low cytotoxicity. Cellular imaging further revealed that PVPH3 predominantly localizes in mitochondria and effectively visualizes HClO elevation and microenvironmental disruption during apoptosis, ferroptosis, and hyperglycemia-induced injury. In the streptozotocin (STZ)-induced diabetic mouse model, PVPH3 achieved noninvasive dual-channel in vivo imaging of the liver and kidneys and enabled monitoring of Met- and Dhq-induced intervention responses. Overall, PVPH3, with a high SBR achieved through layered molecular optimization, provides a visualization tool for early assessment of diabetic liver and kidney injury, investigation of ferroptosis-related mechanisms, and monitoring of drug-intervention responses.

DOI: https://doi.org/10.1021/acs.analchem.6c03681
Nucleic Acids Res. 2026 Oct 13. pii: gkag986. [Epub ahead of print]54(19):

TargetMITO: a rule-based model for generating functional synthetic mitochondrial targeting sequences in yeast.

Kewin Gombeau, Raymond Wan, Joshua S James, Déborah Tribouillard-Tanvier, Yizhi Cai.

Mitochondria are essential organelles containing their own genomes, encoding a few proteins essential for energy production. Most of the mitochondrial proteins are nucleus-encoded, translated as precursors in the cytosol, with a large fraction of these precursors properly addressed by an N-terminal mitochondrial targeting sequence (MTS). These MTS share common features but no consensus sequence can explain their functionality nor the precursors-specific determinants of mitochondrial import. To help understand this mechanism, we created a simple computational model to generate functional synthetic MTS while maintaining a tight control on the design parameters. Using the budding yeast, we demonstrated the presence of precursors-specific import capabilities in addressing artificially nucleus-relocated OXPHOS proteins. Our research confirms the existence of cargo-dependent functional compatibilities and takes us one step closer towards improving gene therapy-based treatment of mitochondrial diseases.

DOI: https://doi.org/10.1093/nar/gkag986
iScience. 2026 Nov 20. 29(11): 117781

Drosophila Appl loss disrupts proteins in mitochondrial oxidative and glycosylation pathways conserved in Alzheimer's disease.

Zachary M Smith, Fernando J Vonhoff.

  The physiological functions of the amyloid precursor protein (APP) remain unclear due to genetic redundancy and complex phenotypes. For decades, Drosophila amyloid precursor protein-like (Appl) research has relied on Appl d, a presumed null allele generated by irradiation. Here, we show that Appl d contains complex chromosomal rearrangements and background mutations confounding the interpretation of gene function. To address this, we created a precise CRISPR toolkit, including a clean null and a reporter allele. Deep proteomic profiling reveals that true Appl loss affects proteins associated with N-linked glycosylation, mitochondrial, and metabolic functions in a distinct signature from the background of Appl d. This conserved metabolic signature mirrors alterations in human patients and mouse Alzheimer's models and is associated with disrupted sleep and locomotion in flies. Our findings correct the genetic understanding of Appl, establishing it as a conserved regulator of metabolic balance essential for neuronal function.

Keywords:  APP; Appld; CRISPR mutant; Drosophila melanogaster; amyloid precursor protein; genome assembly; glycosylation; lipid oxidation; mitochondrial metabolism; proteomics

DOI:  https://doi.org/10.1016/j.isci.2026.117781
Science. 2026 Oct 22. 394(6822): eaea2181

BAK and BAX form a multiprotein complex to drive mtDNA efflux and caspase-independent cell death.

Shaoyuan Yang, Hyungjin Kim, Guanghong Liao, Na Ta, Ho-Chou Tu, Shriram Ramani, Chih-Yu Chen, Zih-Yu Li, Nobuhiro Tanno, James J Hsieh, Emily H Cheng.

The apoptotic regulators BAX and BAK, once activated, form homo-oligomers to trigger mitochondrial outer membrane permeabilization (MOMP), activating the apoptosome and caspases. Activation of BAX-BAK without apoptosome activation triggers sustained efflux of mitochondrial DNA (mtDNA) and caspase-independent cell death. However, the molecular basis of mtDNA efflux remains unclear. We purified a macromolecular complex comprising BAK, BAX, activator BH3-only molecules, voltage-dependent anion channels 1 and 2 (VDAC1 and VDAC2), and prohibitins that released mtDNA from mitoplasts. BAX-BAK activation resulted in VDAC closure, mitochondrial calcium influx, and mtDNA efflux. Loss of VDAC1, VDAC2, or prohibitins prevented BAX-BAK activation-induced mtDNA efflux and caspase-independent cell death without affecting MOMP or mitochondrial inner membrane herniation. These findings support differential regulation of cytochrome c and mtDNA efflux by distinct BAX-BAK complexes.

DOI: https://doi.org/10.1126/science.aea2181
Nat Chem Biol. 2026 Oct 22.

Chemogenetic activation of mitochondria counteracts the Warburg effect in tumor cells.

Dina Y Bass, Ekaterina S Potekhina, Alexander V Ivanenko, Aleksandr A Moshchenko, Dmitry A Korzhenevskiy, Alexey M Nesterenko, Evgeny K Shevchenko, Anastasia E Karnaeva, Natalia F Zakirova, Alexander V Ivanov, Liubov E Shimolina, Marina V Shirmanova, Olga V Lyang, Olga I Patsap, Olga M Kudryashova, Guzel R Gazizova, Elena I Shagimardanova, Sofia S Mariasina, Vasiliy A Ivlev, Ivan Bogeski, Oleg A Gusev, Vsevolod V Belousov.

Upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation, termed as the Warburg effect, is characteristic of tumor cells. Restriction of pyruvate flux into the mitochondrial matrix is one of the major mechanisms underlying this phenomenon. Warburg metabolism is beneficial for rapidly proliferating cells; however, the metabolic consequences of activation of mitochondrial respiration in such cells remain unclear. Here we created a chemogenetic instrument, Grubraw, that generates pyruvate from ᴅ-alanine directly in the mitochondrial matrix, bypassing restricted pyruvate influx. In cancer cells, Grubraw-produced mitochondrial pyruvate increased oxidative metabolism. Chemogenetic activation of mitochondria slowed the growth rate of human melanoma xenografts. Moreover, activation of cancer cell mitochondria suppressed the transcription of genes that control cell-cycle progression, cell proliferation and DNA replication. Surprisingly, we found that cancer cells with Warburg metabolism control carbon flux by disposing of excess mitochondrial pyruvate produced by Grubraw and exporting it out of the cell.

DOI: https://doi.org/10.1038/s41589-026-02350-7
Spectrochim Acta A Mol Biomol Spectrosc. 2026 Oct 16. pii: S1386-1425(26)01565-9. [Epub ahead of print]367(Pt 2): 128994

Photostable rhodamine 6G-based fluorescent probe for selective and sensitive visualization of dynamic lysosomal pH.

Dongyan Hu, Jiao Guan, Jiaming Luo, Liushuang Zhang, Zhijuan Bao.

  Lysosomal pH is tightly linked to diverse cellular physiological and pathological processes, and real-time monitoring of its dynamic shifts is critical for uncovering underlying disease mechanisms. Herein, we developed a new lysosome-targeted pH fluorescent probe RGB with facile synthesis, low cytotoxicity, favorable biocompatibility and efficient cell membrane permeability. Its fluorescence emission intensity exhibits a well-defined linear correlation with environmental pH, enabling rapid, sensitive and quantitative detection of subtle pH changes at the single-lysosome level. RGB functions via a pH-triggered spirolactam ring-opening ICT fluorescence turn-on mechanism, with a measured pKa value of 4.12. Confocal fluorescence imaging results verify that RGB can evaluate oxidative stress-induced cellular damage and dynamically visualize autophagy in live tumor cells. As a robust molecular imaging reagent, RGB holds great promise for subcellular pH detection and basic mechanistic exploration of lysosome-associated disorders.

Keywords:  Autophagy; Cellular imaging; Lysosome-targeting; Rhodamine; pH fluorescent probe

DOI:  https://doi.org/10.1016/j.saa.2026.128994
Methods. 2026 Oct 22. pii: S1046-2023(26)00210-0. [Epub ahead of print]

Confocal microscopy-based radial profile analysis for submitochondrial protein localization.

Sunmin Kwon, Gun Kim, So Yeong Lee.

  Mitochondria are double-membrane organelles whose functions depend on membrane proteins. Identifying whether proteins localize to the outer mitochondrial membrane (OMM) or inner mitochondrial membrane (IMM) is important but often requires specialized techniques. Here, we developed a confocal laser scanning microscopy (CLSM)-based radial profile analysis for the localization of submitochondrial proteins. Based on this method, cytochrome c oxidase subunit 4 (COX4), adenine nucleotide translocase 2 (ANT2), mitochondrial calcium uniporter (MCU) and calcium-activated potassium channel subunit alpha-1(KCa1.1) signals were spatially distinct from translocase of outer mitochondrial membrane 20 (TOM20) signals in isolated mitochondria. Moreover, osmotic shock increased the apparent spatial separation between OMM- and IMM-associated signals, making it easier to distinguish translocase of inner mitochondrial membrane 23 (TIM23) or pore-forming subunit of the mitochondrial ATP-gated potassium channel (MITOK) signals from TOM20 signals in isolated mitochondria. Our approach provides a practical screening tool for assessing submitochondrial protein localization without specialized instrumentation or expertise.

Keywords:  Confocal microscopy; Immunofluorescence; Mitochondria; Radial profile analysis; Submitochondrial localization

DOI:  https://doi.org/10.1016/j.ymeth.2026.10.005
Genome. 2026 Oct 18.

Lipid requirements for brain development and function: what we can learn from Drosophila melanogaster.

Karen He, Madeleine Margaret Dee, Andrew J Simmonds.

Lipids are required for brain development and function. Impaired lipid metabolism is associated with various neurodevelopmental conditions. Recent work in Drosophila has begun to reveal the cellular and molecular basis of the role of lipids in this process. Here, we focus on the requirement of lipids in the neuroblasts, neurons, and glia of the Drosophila brain. Specifically, we discuss their role in neuroblast proliferation and fate determination, cellular morphology, neuronal fueling, and phagocytosis. We conclude by reviewing lipid profiling techniques and discuss the implications of these roles on neurodevelopment and disease.

DOI: https://doi.org/10.1139/gen-2026-0087
ACS Nano. 2026 Oct 20. 20(41): 27748-27761

Self-Amplifying Cascade Enzymatic Nanoplatform Orchestrating Metabolic Reprogramming and Oxidative Stress for Antitumor Therapy.

Yusheng Chen, Qiang Liu, Mengluan Gao, Lingjian Zhang, Hengke Liu, Shan Lei, Jing Lin, Rujia Zou, Peng Huang.

  Nanocatalytic tumor therapy utilizes nanomaterials to catalyze chemical reactions, producing cytotoxic species that kill tumor cells; however, the metabolic heterogeneity of tumor cells significantly compromises therapeutic efficacy. Herein, we developed a self-amplifying cascade enzymatic nanoplatform (ReS2@GOx) for nanocatalytic tumor therapy by orchestrating metabolic reprogramming and oxidative stress. This nanoplatform integrates rhenium disulfide (ReS2) nanozyme possessing trimodal enzyme-mimetic activities (catalase (CAT)-like, nicotinamide adenine dinucleotide (NADH) oxidase (NOX)-like, and glutathione oxidase (GSHOx)-like activities) with glucose oxidase (GOx), enabling three interlocked therapeutic actions: (1) external energy-independent singlet oxygen (1O2) generation through ReS2-mediated hydrogen peroxide (H2O2) conversion involving a superoxide anion (•O2-) intermediate; (2) attenuation of metabolic circuits through NADH oxidation and glutathione depletion; and (3) a cyclic cascade reaction driven by GOx-mediated glucose oxidation and H2O2 production, coupled with CAT-mediated H2O2-to-O2 conversion, sustaining glucose oxidation and NADH consumption. Mechanistic studies reveal a noncanonical 1O2 generation pathway involving electron shuttle-mediated •O2- conversion, establishing a redox loop fueled by endogenous substrates (e.g., glucose, NADH). The coordinated enzymatic triad achieves dual tumor suppression, including blocking adenosine triphosphate (ATP) production by inhibiting glycolysis/oxidative phosphorylation (OXPHOS) and inducing lipid peroxidation. This work demonstrates a nanocatalytic tumor therapy strategy that orchestrates tumor metabolism to potentiate oxidative lethality, highlighting the therapeutic potential of metabolic regulation for tumor treatment.

Keywords:  cascade enzymatic nanoplatform; glucose oxidase; nanocatalytic tumor therapy; rhenium disulfide (ReS2) nanozyme; tumor metabolic reprogramming

DOI:  https://doi.org/10.1021/acsnano.6c09137