bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–09–27
eighteen papers selected by
Marc Segarra Mondejar, AINA
  1. Mitophagy's impact on obesity-related tissues.
  2. How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
  3. TPC2-mediated lysosomal Ca2+ release puts the brakes on store-operated Ca2+ entry.
  4. The emerging roles of disulfidptosis in cancer.
  5. DISC1 Orchestrates Mitochondrial Calcium Overload in Diabetic Encephalopathy Through a Dual Nucleocytoplasmic Mechanism.
  6. In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.
  7. Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
  8. Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
  9. Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
  10. Enhanced axonal mitochondrial motility and neural activity-induced energy deficits destabilize synaptic transmission in models of bipolar disorder.
  11. Metabolic reprogramming underlying EGFR-TKI resistance in lung cancer.
  12. Novel NaV1.6-Mitochondrial Complexes in Retinal Astrocyte Pockets Sequester GABA.
  13. FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
  14. Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
  15. Spiny mouse fibroblasts exhibit a baseline preference for glycolysis and are resilient to oxidative stress across lifespan.
  16. Chronic Methamphetamine Administration Increases Mitochondrial Density and Impairs Mitochondrial Function in the Substantia Nigra Pars Compacta.
  17. The SLC7A11 Thermostat: A Molecular Signaling Switch Between Ferroptosis and Disulfidptosis in Neurodegenerative Disease.
  18. Protocol for measuring fatty acid absorption and intracellular lipid accumulation in intestinal cells and organoids.
  1. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00166-2. [Epub ahead of print]406 87-130
    Mitophagy's impact on obesity-related tissues.
    Rana El Nahas, Sandra Cutanda-Tesouro, Meritxell Espino-Guarch, Pablo M Garcia-Roves.
      Obesity, a global health crisis, results from an energy imbalance, leading to metabolic dysfunction and associated conditions such as type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. A strong link exists between obesity and mitochondrial dysfunction, characterized by reduced mitochondrial mass, impaired oxidative capacity, and decreased ATP production. Mitophagy, a specific type of autophagy targeting mitochondria for degradation, plays a complex, tissue-specific role in regulating metabolism and mitigating the harmful effects of obesity. Both insufficient and excessive mitophagy can negatively influence disease progression. In white adipose tissue, mitophagy functions as a quality control mechanism that reduces oxidative stress and helps maintain insulin sensitivity. However, chronic obesity impairs mitophagy due to overactivation of mTORC1 and inhibition of AMPK, leading to inflammation and insulin resistance. In brown adipose tissue, mitophagy is essential for thermogenesis and energy expenditure, but excessive activation in obesity may impair thermogenesis. In the liver, mitophagy is crucial for preserving mitochondrial function and preventing metabolic dysfunction-associated steatotic liver disease. In the heart, mitophagy supports cardiac function, particularly in obesity-related cardiomyopathy. In skeletal muscle, obesity worsens impairments in mitochondrial quality control, disrupting the clearance of damaged mitochondria. Therefore, there is a pressing need for therapies that restore mitophagic balance in a context- and depot-specific manner, as the dysregulation of mitophagy contributes not only to local dysfunction but also to broader metabolic phenotypes.
    Keywords:  autophagy; mitochondria and metabolic dysfunction; mitophagy; obesity
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.12.003
  2. Commun Biol. 2026 Sep 24. pii: 1248. [Epub ahead of print]9(1):
    How mitochondrial heterogeneity fuels a dynamic organelle ecosystem.
    Pierre-Jean Desmaison, Giulia Bertolin.
      Mitochondria are traditionally viewed as a homogeneous network supporting cellular energy production. However, increasing evidence reveals substantial heterogeneity across biological scales, from intramitochondrial microdomains to specialised mitochondrial populations within cells and tissues. These subpopulations differ in morphology, metabolism, bioenergetics, and spatial organisation, reflecting adaptation to local functional demands. In this Review, we discuss the mechanisms underlying mitochondrial heterogeneity, the emerging concept of mitochondrial subclasses, their functional integration within cellular metabolism, and the challenge of distinguishing stable subclasses from transient states. We propose a shift from a network-based view toward a dynamic mitochondrial ecosystem with important implications for physiology and disease.
    DOI:  https://doi.org/10.1038/s42003-026-11029-7
  3. Cell Calcium. 2026 Sep 22. pii: S0143-4160(26)00090-4. [Epub ahead of print]138 103197
    TPC2-mediated lysosomal Ca2+ release puts the brakes on store-operated Ca2+ entry.
    Qianru Mu, Sandip Patel, David Yule, Siddhi Shetty.
      Lysosomal Ca2+ release can trigger endoplasmic reticulum (ER) Ca2+ mobilisation, which would be expected to activate store-operated Ca2+ entry (SOCE). Recent work by Lee et al. reveals that activation of the lysosomal two-pore channel TPC2 instead suppresses SOCE despite ER Ca2+ depletion. TPC2-derived Ca2+ signals recruit calmodulin to promote STIM1 inactivation, imparing STIM oligomerisation and coupling to Orai1. These findings identify a lysosomal feedback pathway that restrains Ca2+ influx and expand the role of TPC2 from an initiator of intracellular Ca2+ release to a brake on SOCE.
    Keywords:  Calcium signalling; Lysosome; STIM1; Store-operated Ca(2+) entry; TPC2
    DOI:  https://doi.org/10.1016/j.ceca.2026.103197
  4. Apoptosis. 2026 Sep 23. pii: 233. [Epub ahead of print]31(10):
    The emerging roles of disulfidptosis in cancer.
    Yong-Hao Zhu, Yi-Xuan Liu, Yu-Xiang Liu, Cun-Yuan Yu, Xin-Yu Li, Wen-Cang Zhao, Zi-Han Zhu, Hao-Xuan Liu, Bo Wang, Ke Zhang, Dong-Dong Wu.
      Cancer persists as a significant global health burden, with conventional therapeutic approaches frequently constrained by drug resistance and disease relapse, underscoring the urgent requirement for innovative treatment modalities. Recent advances in regulated cell death have uncovered promising therapeutic avenues for cancer. Amidst these newly identified processes, disulfidptosis-a distinct type of programmed cell death triggered by disulfide stress-has garnered significant attention because of its specific metabolic reliance. The underlying mechanism centers on pathological intracellular cystine accumulation coupled with depletion of NADPH reducing equivalents, stemming from elevated levels of the cystine transporter SLC7A11 during metabolic stress states such as glucose deprivation. This cascade induces aberrant disulfide bonding followed by actin cytoskeleton disruption, ultimately resulting in cellular demise. Evidence suggests that disulfidptosis-related genes exhibit altered expression across various malignancies, including lung, liver, and colorectal cancers, and are strongly correlated with disease progression and patient outcomes. Prognostic models constructed based on bioinformatics not only demonstrate good predictive efficacy but also reflect characteristics of the tumor immune microenvironment. This process reveals a fundamental weakness in cancer cells after metabolic reprogramming, establishing the induction of disulfidptosis via SLC7A11 inhibition or modulation of associated metabolic pathways as a promising new anticancer approach. It also provides a rationale for combination strategies with chemotherapy, targeted therapy, and immunotherapy. Nonetheless, its interaction with different cell death mechanisms (including ferroptosis), the variability observed across various cancer types, and the translation to clinical applications remain significant challenges and key avenues for future investigation.
    Keywords:  Cancer; Disulfidptosis; NADPH; SLC7A11; Targeted therapy
    DOI:  https://doi.org/10.1007/s10495-026-02444-6
  5. Biomolecules. 2026 Sep 20. pii: 1366. [Epub ahead of print]16(9):
    DISC1 Orchestrates Mitochondrial Calcium Overload in Diabetic Encephalopathy Through a Dual Nucleocytoplasmic Mechanism.
    Lu He, Hao Li, Rui Yin, Liangli Dai, Weijian Hang, Yong Liu, Man Li, Tao Liang, Yumei Wang, Juan Chen.
      Hyperglycemia-driven mitochondrial dysfunction is a primary driver of diabetic encephalopathy (DE). Here, we identify a novel nucleocytoplasmic "dual effect" of DISC1 that coordinates mitochondrial Ca2+ overload under high-glucose conditions. Using nucleocytoplasmic fractionation and mass spectrometry, we demonstrate that high glucose triggers PAK2-mediated phosphorylation of DISC1, necessitating its nuclear translocation. In the nucleus, DISC1 acts as a coactivator for the transcription factor RFX1 to induce Grp75, a critical tethering protein of the GRP75/IP3R1/VDAC1 complex that facilitates Ca2+ transfer from the endoplasmic reticulum to mitochondria. Conversely, we find that cytoplasmic DISC1 physically sequesters GRP75, hindering the assembly of the Ca2+ conduction complex. Enhanced nuclear translocation of DISC1 results in reduced cytoplasmic DISC1 levels. This depletion removes the "molecular brake" on Ca2+ influx, synergizing with the nuclear signaling pathway to drive mitochondrial Ca2+ overload. Together, our findings suggest that high glucose hijacks DISC1 through a bipartite mechanism: the upregulation of Ca2+ conduction and the concurrent loss of cytoplasmic inhibition. Targeting DISC1 may represent a potential therapeutic strategy for mitigating neurodegeneration in DE.
    Keywords:  DISC1; GRP75; diabetic encephalopathy; mitochondrion; nuclear localization
    DOI:  https://doi.org/10.3390/biom16091366
  6. Cells. 2026 Sep 09. pii: 1630. [Epub ahead of print]15(18):
    In Vitro Glutamine Adaptability in Murine Liver- but Not Lung-Metastasizing Triple-Negative Breast Cancer Cells.
    Marjorie Anne Layosa, Keigo Tomoo, Madeline P Sheeley, Michael F Coleman, Chaylen Andolino, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.
      Background: Metabolic adaptability plays a critical role in supporting the growth and survival of metastatic breast cancer cells, and potentially supports site-specific metastasis. This study investigates the differential metabolism of glutamine and adaptability to varying glutamine levels of triple-negative breast cancer (TNBC) cells that metastasize to the lungs (metM-WntLung) or liver (metM-WntLiver). Methods: The metastatic cell lines were exposed to varying in vitro glutamine concentrations (0.5, 2, and 4 mM). Cell viability, migration, 14C-glutamine uptake, mRNA abundance of metabolic enzymes, and 13C5-glutamine cellular flux, were measured. Results: At an intermediate level of in vitro glutamine supplementation (2 mM), metM-WntLung cells exhibited greater glutamine uptake, catabolic enzyme expression, and flux of glutamine-derived carbon into the TCA cycle compared with metM-WntLiver cells. Despite this, metM-WntLiver cells were more viable and migratory than metM-WntLung cells under both higher (4 mM) and lower (0.5 mM) glutamine levels, suggesting metabolic adaptability. Exposure to ammonia upregulated ammonia-assimilating enzymes in metM-WntLiver, but not metM-WntLung cells, plausibly mitigating ammonia toxicity in higher glutamine conditions. In glutamine-deprived conditions, the metM-WntLung cells maintained higher glutamine oxidation, but the metM-WntLiver cells had higher total glutathione and GSH/GSSG ratios and enhanced resistance to oxidative stress, suggesting glutamate utilization toward glutathione synthesis. Additionally, metM-WntLiver cells utilized glucose-derived carbons through pyruvate carboxylase (PC) to maintain TCA cycle activity, with elevated PC expression and M+3-labeled oxaloacetate enrichment to a greater extent than metM-WntLung cells. PC silencing in metM-WntLiver cells enhanced cell viability under glutamine deprivation, which was reversed by inhibiting phosphoglycerate dehydrogenase (PHGDH, a key enzyme in de novo serine synthesis). We propose that PC activity compensates for low glutamine levels, including diverting glucose to adaptive pathways such as de novo serine synthesis. Conclusions: Overall, our findings demonstrate that metM-WntLiver cells, but not metM-WntLung cells, exhibit glutamine-specific metabolic plasticity, characterized by the modulation of glutamine catabolism, enhanced ammonia metabolism and antioxidant defense, and support of glucose metabolism, which are associated with better cell survival and migration under glutamine excess and deprivation.
    Keywords:  TNBC; breast cancer; glutamine; glutathione; metabolic adaptation; metabolic plasticity; metastasis; organotropic metastasis; pyruvate carboxylase
    DOI:  https://doi.org/10.3390/cells15181630
  7. J Biol Chem. 2026 Sep 22. pii: S0021-9258(26)02464-6. [Epub ahead of print] 113592
    Vps1 and select autophagic machinery are required for coenzyme Q uptake and trafficking to mitochondria.
    Michael D Guile, Kyle A Anderson, Akash Jain, Alexandre Toulmay, William A Prinz, Catherine F Clarke.
      Coenzyme Q (CoQ) is an important lipid found in nearly all cellular membranes in eukaryotes. Biosynthesis of CoQ occurs within mitochondria, where it functions as an electron carrier in oxidative phosphorylation and participates in key metabolic pathways. In both mitochondrial and non-mitochondrial membranes, the hydroquinone form of CoQ (CoQH2) also functions as a radical-scavenging antioxidant and participates in other processes required for cell maintenance and survival. Individuals with CoQ deficiency may benefit from high-dose CoQ supplementation; however, its bioavailability is limited, and treatment responses can vary. Here, we sought to gain mechanistic insight into how exogenous CoQ is trafficked to mitochondria. We used the yeast model system Saccharomyces cerevisiae, that produce CoQ6 with a polyisoprenyl tail containing six isoprene units. A CoQ6-deficient (coq2Δ) yeast mutant is used to investigate genes and corresponding pathways required for the cellular uptake and trafficking of exogenous CoQ6 to mitochondrial respiratory complexes. Specifically, we identify essential residues in the dynamin-like protein Vps1 that are required for CoQ6 trafficking and show that yeast vps1 mutants with known defects in autophagy are incapable of trafficking exogenously supplemented CoQ6 to mitochondria. Importantly, we identify a non-canonical role for several autophagic proteins in CoQ6 trafficking. Taken together, our data suggest that uptake of exogenous CoQ6 and its delivery to the mitochondria relies on a novel, specialized lipid trafficking pathway comprised of select autophagic and endosomal membrane trafficking proteins, and the lytic compartment which serves as a transport hub.
    Keywords:  Saccharomyces cerevisiae; Vps1; autophagy; dynamin; lipid raft; lipid trafficking; mitochondria; ubiquinone; vacuole; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113592
  8. Nat Rev Nephrol. 2026 Sep 24.
    Cardiovascular-kidney-metabolic syndrome as a mitochondrial systems disorder.
    Shen Li, E Dale Abel, Zoltan Arany, Joseph A Baur, Liming Pei, Katalin Susztak.
      Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals - including FGF21, GDF15, succinate and circulating mitochondrial DNA - enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41581-026-01127-4
  9. Nat Commun. 2026 Aug 21. pii: 10037. [Epub ahead of print]17(1):
    Fatty acid oxidation fuels mitochondrial respiration to drive epidermal stem cell fate and differentiation.
    Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor A Neel, Amy S Colwell, Christine G Lian, George F Murphy, Peter Carmeliet, Anna Mandinova.
      Skin barrier function relies on the epidermis, whose integrity is maintained by basal stem cells that continuously renew and differentiate into a multilayered architecture. Disrupted epidermal differentiation underlies numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate late differentiation, the molecular events driving early commitment remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation, is a determinant of differentiation initiation. We identify fatty acid oxidation as the primary metabolic pathway fueling oxidative phosphorylation during this process. Pharmacological and genetic inhibition of fatty acid oxidation, in vitro and in vivo, disrupts differentiation and compromises stratification, causing defective responses to physical insults. Mechanistically, fatty acid oxidation enables ATP production in committed epidermal cells to support the differentiation process, linking lipid metabolism and epidermal homeostasis. These results uncover an unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight fatty acid oxidation as a promising therapeutic target for restoring differentiation defects in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77023-z
  10. Nat Commun. 2026 Aug 22. pii: 10159. [Epub ahead of print]17(1):
    Enhanced axonal mitochondrial motility and neural activity-induced energy deficits destabilize synaptic transmission in models of bipolar disorder.
    Sunan Li, Gui-Jing Xiong, Zezhi Li, Zu-Hang Sheng.
      Synaptic communication requires mitochondria to supply ATP and buffer calcium at presynaptic terminals. In bipolar disorder, manic episodes are associated with elevated mood and neural activity, but the underlying cellular mechanisms remain unclear. Here we show that hiPSC-derived cortical neurons from donors with bipolar disorder exhibit increased axonal mitochondrial motility and frequent mitochondrial entry-exit transitions, reducing stable mitochondrial retention at presynaptic terminals. This destabilizes local ATP maintenance and calcium buffering, increasing synaptic variability without altering mean synaptic strength. Knockdown of the bipolar disorder risk gene AKAP11 in mouse neurons reproduced these synaptoenergetic deficits. HiPSC-derived neurons from donors with bipolar disorder exhibited reduced expression of the mitochondrial anchor protein syntaphilin(SNPH), and  snph knockout mice displayed manic-like behavioral phenotypes. Lithium restored presynaptic mitochondrial retention, improved ATP maintenance, rescued synaptic variability, and reversed behavioral phenotypes. These findings support impaired presynaptic mitochondrial retention and activity-induced synaptoenergetic deficits as cellular mechanisms contributing to bipolar disorder.
    DOI:  https://doi.org/10.1038/s41467-026-76722-x
  11. Biochim Biophys Acta Mol Cell Res. 2026 Sep 21. pii: S0167-4889(26)00122-9. [Epub ahead of print]1873(8): 120223
    Metabolic reprogramming underlying EGFR-TKI resistance in lung cancer.
    Xiaolong Huang, Tao Cheng, Fengkai Xu, Di Ge, Cheng Zhan.
      Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the clinical efficacy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, acquired resistance to EGFR-TKIs remains an unavoidable therapeutic bottleneck. The metabolic reprogramming underlying this resistance is crucial for understanding the resistance mechanisms and identifying new therapeutic targets. Recently, an increasing number of studies have focused on the impact of metabolic reprogramming on acquired EGFR-TKI resistance. Collectively, this review reveals the core driving role of metabolic reprogramming in EGFR-TKI resistance, focuses on the systematic adjustments of resistant cells in terms of glucose metabolism, lipid metabolism, amino acid metabolism, and nucleotide metabolism, and also pays attention to the effects of ferroptosis and changes in the metabolic pattern of the tumor immune microenvironment on EGFR-TKI resistance. In addition, we summarize the application of potential therapeutic approaches targeting metabolic reprogramming in overcoming lung cancer resistance.
    Keywords:  EGFR-TKI resistance; Metabolic reprogramming; NSCLC
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120223
  12. Glia. 2026 Nov;74(11): e70238
    Novel NaV1.6-Mitochondrial Complexes in Retinal Astrocyte Pockets Sequester GABA.
    Joseph Matthew Holden, David John Calkins.
      Voltage-gated sodium channels are best known for their capacity to generate and propagate electrical currents in neurons and muscle. Their expression in glial cells may also be of great importance given these cells' involvement in various disease processes. Here we identify a previously unrecognized voltage-gated sodium channel NaV1.6-enriched microdomain in mouse retinal astrocytes. Using super-resolution confocal microscopy, electrophysiology, and transcriptomic analyses, we show that NaV1.6 forms high-density clusters within intracellular compartments devoid of the calcium-binding protein, S100β, typically understood to distribute throughout the entire astrocyte. These NaV1.6 pockets are polarized, clustering only on the bilayer facing retinal ganglion cell neurons, and are packed with unusually large, anaplerotic, and relatively depolarized mitochondria that closely appose NaV1.6 puncta. These metabolic compartments also accumulate high levels of GABA. Together, our findings reveal a specialized NaV1.6-mitochondrial complex in retinal astrocytes that expands the functional repertoire of voltage-gated sodium channels beyond direct neuronal electrical excitability.
    DOI:  https://doi.org/10.1002/glia.70238
  13. Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01107-1. [Epub ahead of print]45(10): 118029
    FluxAtlas is a pan-cancer metabolic flux atlas that identifies tumor-selective dependencies and prognostic biomarkers.
    Manas Kohli, Aurélien Tripp, Anastasiia Shcherbakova, George Poulogiannis.
      Metabolic reprogramming is a hallmark of cancer, yet dynamic metabolic flux has been difficult to study systematically. Here, we present FluxAtlas, a pan-cancer atlas of metabolic flux generated from genome-scale metabolic modeling of over 10,000 tumors across 28 The Cancer Genome Atlas (TCGA) cancer types. By integrating enzyme constraints and nutrient diffusion limits, we reveal conserved and tissue-specific metabolic rewiring, including alterations in bile acid recycling, urea metabolism, and amino acid biosynthesis. We identify a bile acid-associated program that remodels glutathione homeostasis and drives gastrointestinal-specific lipid metabolism. Comparisons with matched normal models uncover tumor-selective metabolic dependencies, such as increased reliance of renal cancers on de novo purine synthesis. Under nutrient limitation, modeling predicts convergence on glutamine-dependent aspartate synthesis while preserving tissue-specific metabolic states. Machine learning models based on fluxomics predict patient survival and highlight biotin uptake as a prognostic biomarker. FluxAtlas defines the functional metabolic landscape of human cancer and is accessible at https://software.icr.ac.uk/app/flux-atlas.
    Keywords:  CP: cancer; CP: metabolism; FluxAtlas; cancer; genome-scale metabolic modeling; metabolic flux; metabolic reprogramming; prognostic biomarkers; therapeutic targets
    DOI:  https://doi.org/10.1016/j.celrep.2026.118029
  14. Elife. 2026 Sep 24. pii: RP108681. [Epub ahead of print]14
    Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila.
    Farheen Akhtar, Dania M Malik, Arjun Sengupta, Paula Haynes, Andrew D Nguyen, C Jaco Klok, Amita Sehgal, Aalim Weljie.
      Sleep and circadian rhythms shape organismal energy patterns, but how this timing connects to oxygen use and carbon dioxide production remains incompletely understood. We combined high-resolution respirometry with liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster, resolving genotype-specific impacts of sleep disruption and circadian regulation. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. Short-sleep mutants (fmn, sss) exhibited elevated metabolic rates, with reactive shifts of fuel preferences toward lipid and amino acid catabolism, and altered mitochondrial respiration. The clock mutant (per01) and flies under constant darkness (WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems contribute to aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.
    Keywords:  D. melanogaster; biochemistry; chemical biology; circadian rhythms; metabolic flexibility; metabolism; metabolomics; respirometry; sleep
    DOI:  https://doi.org/10.7554/eLife.108681
  15. J Biol Chem. 2026 Sep 24. pii: S0021-9258(26)02477-4. [Epub ahead of print] 113605
    Spiny mouse fibroblasts exhibit a baseline preference for glycolysis and are resilient to oxidative stress across lifespan.
    Ebenezer Aryee, Ajoy Aloysius, Sandeep Saxena, Renee Donahue, Brennan Riddell, Hemendra Vekaria, Patrick G Sullivan, Huazhen Liu, Pradeep Kachroo, Ashley W Seifert.
      Although metabolism was originally studied across an array of mammals, contemporary metabolic studies moved towards human and mouse cells. A newfound interest in how metabolism regulates cell state during homeostasis, tissue repair and disease has uncovered key roles for energy flux inside and outside of mitochondria. Fibroblasts are key mediators of wound healing outcomes and prior work uncovered that cells from highly regenerative mammals (spiny mice and rabbits) exhibit enhanced resistance to oxidative stress compared to those from non-regenerating laboratory mice and rats. Using a battery of cellular tests in primary ear pinna fibroblasts from spiny mice, rabbits, laboratory mice and rats, we show that cells from spiny mice and rabbits exhibit a baseline preference for glycolysis supporting lower ROS-production. Mitochondria from spiny mouse fibroblasts were generally low respiring and depolarized while exhibiting a large, spherical morphology. We observed this large, spherical phenotype consistently across lifespan in ear pinna fibroblasts from fetal, young and old spiny mice and cells from all ages were highly resistant to oxidative stress. While rabbit, mouse and rat fibroblasts had polarized tubular mitochondrial networks typical of adult mammalian fibroblasts, isolated rabbit and spiny mice fibroblasts shared lower oxygen consumption efficiency even in the absence of a potential gradient. Taken together, our results support that a shared metabolic signature exists in stromal cells from highly regenerative mammals, although possibly driven by different mechanisms, to converge on a ROS-resistant phenotype that increases cellular resilience.
    Keywords:  aging; electron transport system; mitochondria; mitochondrial metabolism; reactive oxygen species; regeneration
    DOI:  https://doi.org/10.1016/j.jbc.2026.113605
  16. J Neurochem. 2026 Sep;170(9): e70554
    Chronic Methamphetamine Administration Increases Mitochondrial Density and Impairs Mitochondrial Function in the Substantia Nigra Pars Compacta.
    Aishwarya Bhowmik, Jennifer A Wilking, Duha Alshareef, Colin Campbell, Steven M Graves.
      Methamphetamine (meth) is an addictive psychostimulant that induces monoamine oxidase (MAO)-dependent mitochondrial oxidative stress and MAO-dependent degeneration of substantia nigra pars compacta (SNc) dopamine neurons in male mice, suggesting that meth-induced mitochondrial oxidative stress is necessary for degeneration. However, the impact of chronic in vivo meth administration on SNc mitochondria is unclear. We therefore examined the impact of chronic meth administration on the expression of mitochondrial fission 1 (FIS1) and Dynamin-related protein 1 (DRP1), proteins involved in mitophagy, as well as mitochondrial density and mitochondrial function in the SNc. Male C57BL/6J mice received saline or meth (5 mg/kg; i.p.) for 28 days; chronic meth administration decreased SNc expression of both DRP1 and FIS1 proteins, suggesting impaired mitophagy. Consistent with this, mitochondrial density in SNc dopamine neurons was also increased. Moreover, this increase in mitochondrial density was MAO-dependent, suggesting that chronic meth-induced SNc degeneration is associated with an increase in mitochondrial density. To determine whether mitochondria were functional, high-resolution respirometry assessments were conducted using SNc tissue from mice treated with either chronic meth or saline. Results indicate that chronic in vivo meth administration decreased mitochondrial complex I as well as complex I + II oxidative phosphorylation capacities and coupling efficiencies in the SNc. Presented data suggest that chronic in vivo meth administration results in an accumulation of functionally compromised mitochondria in the SNc, which is associated with and may potentially contribute to chronic meth-induced neurodegeneration.
    Keywords:  methamphetamine; mitochondria; monoamine oxidase; substantia nigra pars compacta
    DOI:  https://doi.org/10.1111/jnc.70554
  17. Mol Neurobiol. 2026 Sep 23. pii: 916. [Epub ahead of print]63(1):
    The SLC7A11 Thermostat: A Molecular Signaling Switch Between Ferroptosis and Disulfidptosis in Neurodegenerative Disease.
    Mohammed Zayed, Maha Mahmoud, Ahmed Massoud, Renad Darwish, Byung-Hoon Jeong.
      Neurodegenerative diseases are characterized by a metabolic paradox, a balance regulated at the molecular level by a narrow set of redox-sensitive signaling checkpoints. The cystine/glutamate antiporter SLC7A11 plays a central role in this challenge. Traditionally recognized as an antioxidant guardian that prevents ferroptosis through NRF2-KEAP1-driven glutathione synthesis, SLC7A11 can become a burden under metabolic stress. Under glucose restriction or mitochondrial dysfunction, impaired NADPH regeneration prevents cells from reducing imported cystine, leading to disulfide stress in cytoskeletal actin-binding proteins and a novel form of regulated cell death called disulfidptosis. We suggest that neural cell fate and intercellular redox support depend not only on the presence of SLC7A11 activity but also on its specific calibration in each cell type, taking into account cystine availability, glutamate management, and NADPH regeneration. Since baseline system Xc⁻ activity in the CNS is primarily observed in astrocytes and microglia, this regulatory mechanism may operate both within individual cells and across cell types via the astrocyte-neuron metabolic network. Within this proposed framework, insufficient SLC7A11 activity may increase ferroptotic susceptibility, whereas sustained cystine uptake under severe NADPH limitation may create conditions permissive for disulfidptosis. In Alzheimer's disease, chronic cerebral glucose hypometabolism might lead to disulfide stress in neural cells with high SLC7A11 levels, although the typical disulfidptosis process has not yet been confirmed in vivo. We argue that traditional antioxidant supplements or SLC7A11 modulation are unlikely to succeed without understanding this dual-risk profile at the level of molecular pathways. We propose shifting toward precise adjustment via biomarker-guided redox modulators and metabolic priming to enhance NADPH reserves. By examining SLC7A11 as a dynamic molecular regulator, this review offers a hypothesis-generating framework that may help resolve conflicting findings and inform the development of focused neuroprotective approaches relevant to the molecular neurobiology of neurodegenerative disease.
    Keywords:  Cell death; Disulfidptosis; Ferroptosis; Molecular neurobiology; Neurodegenerative diseases; SLC7A11 signaling
    DOI:  https://doi.org/10.1007/s12035-026-06219-7
  18. STAR Protoc. 2026 Sep 23. pii: S2666-1667(26)00506-X. [Epub ahead of print]7(4): 104853
    Protocol for measuring fatty acid absorption and intracellular lipid accumulation in intestinal cells and organoids.
    Jiaqi Wu, Yu Gu, Shuangshuang Liu, Shupei Wang, Li-Hao Huang.
      Quantitative assessment of intestinal epithelial cells is essential for studies of metabolism and disease. Here, we present a protocol to quantify fatty acid uptake and lipid accumulation in intestinal epithelial cell lines and primary intestinal organoids using a flow cytometry-based approach with BODIPY FL C16. We describe steps for assessing fatty acid uptake and accumulation in intestinal epithelial cell lines and intestinal organoids. This rapid and reproducible technique can also be adapted to investigate fatty acid metabolism in other cell types. For complete details on the use and execution of this protocol, please refer to Wu et al.1.
    Keywords:  Cell Biology; Cell culture; Cell isolation; Cell-based Assays; Flow Cytometry; Metabolism; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2026.104853
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