bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–07–19
sixteen papers selected by
Marc Segarra Mondejar, AINA
  1. KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.
  2. Deep learning reveals FLAD1-mediated mitochondrial metabolic reprogramming in hypoxic tumors.
  3. Induction of paraptotic cell death in breast cancer cells by an iron chelator involved activation of UPR/MAPK pathway and inactivation of PI3K/AKT/mTOR.
  4. Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
  5. Genetic Deletion of Adenosine A2A Receptors Attenuates Aged-Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice.
  6. Endosomal TPC1-mediated Ca2+ nanodomains regulate transferrin receptor trafficking and iron homeostasis.
  7. Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.
  8. More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
  9. Kinome-wide CRISPR/Cas9-knockout screening reveals critical protein kinases in vasopressin V2-receptor signaling.
  10. ROS-mitochondrial nexus in stem cell growth and differentiation and implications in cancer and degenerative diseases.
  11. Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
  12. Targeting enolase isoenzyme 2 enables precision glycolysis inhibition in VHL-mutant renal cell carcinoma.
  13. ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
  14. Calcium imbalance drives organelle network collapse and immune remodeling: novel pathogenic mechanisms in MASLD progression.
  15. Peroxisomal import is circadian in glia and regulates sleep and lipid metabolism.
  16. Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
  1. Cancer Res. 2026 Jul 15. 86(14): 3374-3376
    KRAS on Empty: Lipid Oxidation Blockade Reveals a Metabolic Achilles' Heel in Pancreatic Cancer.
    Deborah de la Caridad Delgado Herrera, Christina M Ferrer.
      Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, driven by its aggressive biology and high metastatic incidence at diagnosis. With a 5-year survival rate of just 8%, PDAC remains one of the most lethal cancers. Mutant KRAS, present in more than 90% of cases, serves as a key driver of tumorigenesis and metabolic reprogramming. In this issue of Cancer Research, Thakur and colleagues uncover a novel metabolic adaptation that PDAC cells use to survive therapeutic stress. Their integrated metabolomic and lipidomic analyses show that ERK inhibition-targeting a key KRAS pathway effector-not only disrupts glycolysis and glutamine metabolism but also triggers a compensatory increase in fatty acid oxidation (FAO). This shift occurs through lipophagy, a lysosome-mediated lipid degradation process, rather than cytosolic lipolysis. Mechanistically, ERK inhibition promotes the nuclear translocation of TFEB, which drives the upregulation of FAO and lipophagy genes. This metabolic reprogramming enables PDAC cells to survive KRAS pathway blockade. Importantly, cotargeting FAO alongside ERK or KRAS inhibitors elicits a potent synergistic antitumor effect in vivo. This dual-target strategy holds promise for overcoming PDAC resistance to KRAS-targeted therapies, laying the groundwork for novel combination treatments. See related article by Thakur et al., p. 3519.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1877
  2. Cell Rep. 2026 Jul 17. pii: S2211-1247(26)00789-8. [Epub ahead of print]45(7): 117711
    Deep learning reveals FLAD1-mediated mitochondrial metabolic reprogramming in hypoxic tumors.
    Xiangyu Zhao, Tao Wu, Sanan Wu, Yujin Chen, Yu Zhang, Jing Chen, Kaixuan Diao, Zaoke He, Jiawei Yan, Tianzhu Lu, Chao Xu, Lu Liu, Gaofeng Fan, Dongliang Xu, Xinxiang Li, Xiaopeng Xiong, Jianjun Cheng, Fang Bai, Xue-Song Liu.
      Hypoxia, a hallmark of solid tumors, drives malignant progression and represents a major therapeutic challenge. Metabolic reprogramming induced by hypoxia creates unique metabolic vulnerabilities that can be exploited therapeutically. Here, we systematically compared the metabolic network differences between hypoxic and normoxic cells, and developed DepFormer, a transformer-based deep learning model, to nominate hypoxia-dependent metabolic genes in tumor cells. Oxidative phosphorylation was identified as the most significantly hypoxia-dependent metabolic pathway, and FLAD1 was predicted to be one of the key hypoxia-dependent metabolic genes. FLAD1 locus is amplified, and FLAD1 expression is upregulated across various tumor types, especially in hypoxic tumors. FLAD1 depletion disrupts activity of mitochondrial complex II, causing succinate/fumarate imbalance, which in turn prevents cancer cells from adapting to hypoxia. We further identified a drug-like inhibitor of FLAD1, which selectively inhibits growth of hypoxic tumor cells. Our study establishes DepFormer as an effective framework for predicting state-specific metabolic dependencies and reveals FLAD1 as a metabolic vulnerability and an innovative therapeutic target for hypoxic tumors.
    Keywords:  CP: cancer; FLAD1; deep learning; hypoxia; metabolic dependency; metabolism; therapeutic target
    DOI:  https://doi.org/10.1016/j.celrep.2026.117711
  3. Sci Rep. 2026 Jul 14.
    Induction of paraptotic cell death in breast cancer cells by an iron chelator involved activation of UPR/MAPK pathway and inactivation of PI3K/AKT/mTOR.
    Lei Yuan, Siwen Dong, Yong Shao, Changzheng Li.
      Breast cancer is the most frequently diagnosed cancer in the world, but its treatment effect is limited, so new treatment strategies are needed. An iron chelator, 2,2'-di-pyridineketone hydrazone dithiocarbamate butyric acid ester (DpdtbA), exerts significant growth inhibition in breast cancer cell lines. Our data showed that DpdtbA treatment significantly promoted extensive cytoplasmic vacuolization derived from the endoplasmic reticulum, mitochondrial swelling, and Alix downregulation in MDA-MB-231 and SK-BR-3 cell lines. Furthermore, cytoplasmic vacuolation could be abolished by cycloheximide (CHX) and antioxidant N-acetylcysteine (NAC), indicating that vacuole formation required new protein synthesis and was ROS-dependent. These results support that DpdtbA is able to induce paraptosis, a programmed cell death pattern. The enhanced cytoplasmic Ca2+after DpdtbA treatment or deceased Ca2+ upon co-treatment with the Ca2+ chelator (BAPTA-AM) prompted that ROS production may partially correlate with the Ca2+-mediated decrease in mitochondrial membrane potential. In addition, DpdtbA triggered ER stress and accumulation of unfolded proteins, leading to the activation of p-PERK/p-EIF2α and p-IRE1/ATF4/chop pathway, inactivation of ATF6 (activating transcription factor 6) that may contribute to the anti-proliferative effect. Furthermore, our data showed that DpdtbA treatment not only led to excessive activation of MAPKs (mitogen activated protein kinases) signaling, but also resulted in inactivation of the PI3K/AKT/mTOR pathway, both of which were involved in the regulation of paraptosis. The results demonstrated that paraptotic cell death induced by an iron chelator in breast cancer cells was partially involved in Ca2+-mediated ROS production, UPR(unfolded protein response)/MAPKs activation, and PI3K/AKT/mTOR inactivation.
    DOI:  https://doi.org/10.1038/s41598-026-62456-9
  4. Cell Metab. 2026 Jul 14. pii: S1550-4131(26)00246-9. [Epub ahead of print]
    Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
    Dandan Wang, Mark Li, Tian Lu, Mami Matsushita, Juro Sakai, Masayuki Saito, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.
    Keywords:  bioenergetics; brown adipose tissue; inter-organ communication; metabolic health; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.020
  5. Glia. 2026 09;74(9): e70197
    Genetic Deletion of Adenosine A2A Receptors Attenuates Aged-Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice.
    Cátia R Lopes, Samira G Ferreira, Rodrigo A Cunha, Paula Agostinho.
      Although brain disorders are the major burden of disease in Western countries and their incidence increases sharply with aging, the biological basis of brain aging is still poorly explored. Glial cells, namely microglia and astrocytes, maintain brain homeostasis and mount neuroinflammation that can contribute to age-related deterioration of brain functions. The purinergic system, particularly adenosine A2A (A2AR) and P2X7 (P2X7R) receptors, modulates glial function and neuroinflammation. The present study aims to investigate how aging affects microglia and astrocytes morphology and the NRLP3 inflammasome complex, a key driver of the inflammatory process, and if the genetic deletion of A2AR has a protective role in inflammaging. We resorted to wild-type and A2AR knockout mice with 3- and 24- month-old to investigate alterations in microglia and astrocytes morphology, in P2X7R, and in related NRLP3 inflammasome components in the hippocampus and prefrontal cortex. Data show that brain aging alters the tridimensional structure of microglia and astrocytes in the hippocampus and prefrontal cortex. Aging decreased the levels of P2X7R and of inflammasome components, NLRP3 and caspase 1, in the hippocampus. Remarkably, A2AR knockout abrogated age-related morphological changes of glial cells in both brain structures. Also, the decreased hippocampal P2X7R levels and the alterations in NLRP3 levels in both hippocampus and cortex, were no longer present in aged A2AR knockout mice. These findings indicate that A2AR might bolster NRLP3 inflammasome activation associated with an age-related neuroinflammation, and A2AR blockade might promote healthy brain aging.
    Keywords:  A2A receptors; NRLP3 inflammasome; P2X7 receptors; aging; astrocytes; brain; microglia
    DOI:  https://doi.org/10.1002/glia.70197
  6. Proc Natl Acad Sci U S A. 2026 Jul 21. 123(29): e2530835123
    Endosomal TPC1-mediated Ca2+ nanodomains regulate transferrin receptor trafficking and iron homeostasis.
    William J Burton, Alice Lin, Anthony J Morgan, Lianne C Davis, Cheng-Chang Chen, Antony Galione.
      Two-pore channel 1 (TPC1) is an endosomal Na+/Ca2+-selective channel implicated in membrane trafficking, endosome tubulation, and excitability, but how TPC1 regulates membrane trafficking is unknown. Using TPC1-null human cells, we demonstrate that TPC1 drives transferrin receptor (TfR) trafficking and recycling via Ca2+, and not Na+ fluxes or endosomal pH changes, since channel-targeted Ca2+-buffers inhibited trafficking, whereas a Na+-deficient Ca2+-permeable TPC1 mutant fully supported trafficking. TPC1 was unique since other Ca2+ sources did not support TfR trafficking. TPC1 activity depended on the lipid PI(3,5)P2, since trafficking was impaired by a lipid-insensitive TPC1 or inhibitors of lipid synthesis. Finally, a corollary of this reduced TfR trafficking is an iron-deficiency and storage phenotype in TPC1-deficient HeLa cells and mice. Our findings highlight endosomes as unique Ca2+ stores mobilized by a phosphoinositide-induced TPC1 channel that generates local Ca2+ nanodomains crucial for maintaining TfR trafficking and consequent iron homeostasis.
    Keywords:  calcium signaling; iron homeostasis; membrane trafficking; transferrin; two-pore channel
    DOI:  https://doi.org/10.1073/pnas.2530835123
  7. Front Cell Dev Biol. 2026 ;14 1826809
    Ammonia metabolic reprogramming in the tumor microenvironment: emergence of an immunosuppressive niche.
    Zihao Ye, Hao Wu, Zhanhao Li, Ruizhe Ye, Yingliang Rao, Bin Liu, Baoshan Gao.
      Metabolic reprogramming within the tumor microenvironment plays a pivotal role in tumor proliferation, progression, and immune evasion. Cancer cells exhibit altered lipid, glucose, and amino acid metabolism to adapt to hostile conditions such as hypoxia and nutrient deprivation. Particularly, ammonia metabolism has emerged as a critical aspect of tumor metabolic reprogramming. Oncogene mutations, such as those in c-MYC, KRAS, and p53, regulate key enzymes involved in amino acid metabolism, which in turn affects tumor cell survival and proliferation. Elevated ammonia levels in the TME (Tumor Microenvironment) not only provide essential nitrogen for cell growth but also impair immune cell function, including T cells and natural killer cells, contributing to immune evasion. High ammonia concentrations suppress T cell activation and promote exhaustion, while interfering with natural killer cell cytotoxicity by hindering perforin maturation. Moreover, ammonia accumulation fosters an immunosuppressive microenvironment, influencing cytokine secretion and facilitating tumor metastasis. Targeting ammonia metabolism, in combination with immune checkpoint inhibitors, presents a promising therapeutic strategy to enhance immune responses and inhibit tumor progression. This review consolidates recent findings on the role of ammonia metabolism in the TME, highlighting its potential as a therapeutic target to improve cancer treatment outcomes.
    Keywords:  SLC (solute carrier family); TME (tumor microenvironment); ammonia metabolism; cancer; metabolic reprogram
    DOI:  https://doi.org/10.3389/fcell.2026.1826809
  8. J Cell Biol. 2026 Aug 03. pii: e202606160. [Epub ahead of print]225(8):
    More gas, fewer brakes: Mitochondria withhold CoQ at the cost of ferroptosis defense.
    Mami Sato, Florencio Porto Freitas, José Pedro Friedmann Angeli.
      Coenzyme Q (CoQ or ubiquinone) is an essential cofactor for mitochondrial energy production and a vital radical-trapping antioxidant that maintains membrane integrity. Additionally, CoQ shares an early biosynthetic pathway with cholesterol biosynthesis. In this issue, Ndoci et al. (https://doi.org/10.1083/jcb.202507174) reveal a regulatory system that preserves mitochondrial CoQ levels when the mevalonate pathway is impaired, though this prioritization leaves cells vulnerable to oxidative stress.
    DOI:  https://doi.org/10.1083/jcb.202606160
  9. bioRxiv. 2026 Jul 06. pii: 2026.07.03.736393. [Epub ahead of print]
    Kinome-wide CRISPR/Cas9-knockout screening reveals critical protein kinases in vasopressin V2-receptor signaling.
    Euijung Park, Lihe Chen, Viswanathan Raghuram, Shaza Khan, Adrian R Murillo-de-Ozores, Chung-Lin Chou, Chin-Rang Yang, Mark A Knepper.
      Identification of signaling networks is an essential goal in systems biology. Here, we use CRISPR/Cas9 knockout screening (employing a whole kinome sgRNA library) to identify functionally critical protein kinases in a well-studied G α s-dependent G-protein coupled receptor (GPCR)-signaling model, namely the vasopressin V2 receptor (V2R) pathway. Screening was done using a specially-designed fluorescence-based reporter cell line with green-fluorescent protein (GFP) co-transcribed with Aqp2 , a gene whose transcription is dependent on vasopressin-mediated activation of protein kinase A (PKA). Positive regulators (n=14) included PKA-catalytic subunit α (Prkaca) and Dyrk1a ( minibrain homolog). Negative regulators (n=12) included PKA-regulatory subunit type Iα, Stk11 (catalytic subunit of liver kinase B1 [LKB1] complex), and three TGF-β receptor subunits (Tgfbr1, Tgfbr2, Tgfbr3) (see https://esbl.nhlbi.nih.gov/Databases/Kinome-CRISPR-screen/ for full list). Dyrk1a knockout cell lines failed to express AQP2 protein and exhibited a profound decrease in AQP2 mRNA. RNA-sequencing demonstrated widespread increases in cell-cycle transcripts, with a general defect in cell differentiation, accounting for AQP2 loss. TGF-β exposure to un-transformed cells results in a profound decrease in V2R and AQP2 mRNA abundance along with multiple additional transcriptional targets of V2R-PKA signaling, consistent with prior findings in TGF-β-mediated vasopressin 'escape'. Stk11/LKB1 knockout lines displayed marked increases in AQP2 protein and mRNA, even in the absence of vasopressin. RNA-sequencing showed a marked similarity between the responses to Stk11/LKB1 deletion and vasopressin exposure in untransformed cells. Phospho-proteomic data point to opposing roles of Stk11/LKB1 and PKA in the regulation of cAMP-responsive transcriptional coactivator (CRTC) proteins in the transcriptional response to V2R-PKA signaling.
    Significance Statement: Cells throughout the body are regulated by extracellular signals like the hormone, vasopressin. Hormonal effects on cellular function are mediated by membrane receptors that trigger biochemical changes, often by inducing chemical modification of the amino acids making up individual proteins, such as addition of function-altering phosphate groups (phosphorylation). Protein phosphorylation is mediated by enzymes known as "protein kinases". Here, we have screened all known protein kinases using modern CRISPR/Cas9 technology to identify those involved in vasopressin action in the kidney. As expected from prior knowledge, the screen identified protein kinase A and one of its regulatory subunits, but also identified several protein kinases not previously implicated in vasopressin action in the kidney.
    DOI:  https://doi.org/10.64898/2026.07.03.736393
  10. Biochim Biophys Acta Rev Cancer. 2026 Jul 16. pii: S0304-419X(26)00135-6. [Epub ahead of print] 189663
    ROS-mitochondrial nexus in stem cell growth and differentiation and implications in cancer and degenerative diseases.
    Mohd Javed Akhtar, Sudhir Panwar.
      Regenerative cells, also known as stem cells, exhibit transitioning between a resting state, crucial for long-term preservation with low metabolic activity, and an activation state defined by active proliferation and differentiation to repair old or damaged cells. Concomitant with stem cell transition, mitochondria also undergo a similar transition to support cell growth by providing energy and growth precursors. High mitochondrial activity during cell growth, however, results in reactive oxygen species (ROS). ROS function as signaling molecules and activate several metabolic pathways by rewiring key enzymes and proteins. During the resting state, often called quiescence, ROS production should be limited to prevent resumption of inappropriate growth and oxidation of essential components like DNA in a cell type whose main function is to divide and pass its genetic material to daughter cells for repair. Most stem cells in a resting state (also known as G0 phase) display reduced mitochondrial activity by suppressing oxidative phosphorylation (OXPHOS) due to active mitophagy maintained by quiescence regulators in cells. Mitogens and injury markers activate resting or quiescent stem cells to reenter the cell cycle and grow, a process that requires mitochondrial activity for the supply of nucleotides, non-essential amino acids, lipids and many more. Mitochondria undergo cell cycle-specific changes during the G1, S, and G2/M phases. This article examines how mitochondria regulate stem cell growth and control cell fate. Stem cell dysfunction leads to regeneration issues, contributing to premature aging and cancer. Understanding mitochondrial function can further enhance therapeutic interventions in cancer and aging, as highlighted at the end of the review.
    Keywords:  Metabolic plasticity; Mitochondrial dynamics; Redox signaling; Stem cell quiescence; cancer stem cells
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189663
  11. J Biol Chem. 2026 Jul 14. pii: S0021-9258(26)02204-0. [Epub ahead of print] 113332
    Conditional dependency of oncogenic KRAS in driving ketone body catabolism and pancreatic cancer growth.
    Runze Wang, Xue Li, Tongxin Zhang, Yinuo Chen, Juanjuan Liu, Yuanjing Wang, Xuanzhe Wang, Lianjing Cao, Zhimin Lu, Leina Ma.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy driven predominantly by oncogenic KRAS mutations, which enforce extensive metabolic reprogramming to support tumor progression. Although ketone body catabolism has emerged as a critical metabolic adaptation in PDAC, the signaling mechanisms that link mutant KRAS to the ketolytic machinery remain largely unexplored. Here, we identify a previously unrecognized, context-dependent role of oncogenic KRAS in driving ketone body utilization. We show that KRAS mutation alone is insufficient to fully activate ketolysis; instead, it primes the ketolytic pathway in a manner that requires cooperative input from additional tumor microenvironment signals. Mechanistically, oncogenic KRAS engages a downstream signaling cascade that leads to specific post-translational modifications of key mitochondrial enzymes. These modifications enhance the flux of ketone body catabolism, thereby increasing acetyl-CoA and ATP production and promoting pancreatic cancer cell proliferation and xenograft tumor growth. In a clinical PDAC cohort, activation of this KRAS-dependent ketolytic axis was elevated in KRAS-mutant tumors compared with KRAS wild-type cases, albeit with a trend that requires further validation. Collectively, our findings define a conditional dependency of mutant KRAS on cooperative signals to drive ketone body catabolism, linking oncogenic signaling to mitochondrial ketone metabolism in PDAC. This study expands our understanding of KRAS-driven metabolic reprogramming and highlights the ketolytic pathway as a context-dependent vulnerability for therapeutic intervention in pancreatic cancer.
    Keywords:  Ketolysis; Metabolic reprogramming; Oncogenic KRAS; PDAC; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jbc.2026.113332
  12. Cell Death Dis. 2026 Jul 14.
    Targeting enolase isoenzyme 2 enables precision glycolysis inhibition in VHL-mutant renal cell carcinoma.
    Jiannan Yao, Xiaona Fan, Huixian Xin, Fuhui Wan, Xichen Dong, Qianqian Sun, Xuying Huang, Heshu Liu, Xiangyu Chen, Yanjun Jia, Haili Qian, Tao Wen, Jian Liu.
      Clear cell renal cell carcinoma (ccRCC) exhibits glycolytic addiction due to VHL mutation, making it vulnerable to metabolic intervention. While conventional inhibitors targeting core housekeeping glycolytic enzymes show robust antitumor efficacy, their clinical use is limited by on-target systemic toxicity. Here, we identify enolase 2 (ENO2) as an isoform-specific glycolytic vulnerability specific to VHL-deficient ccRCC. Although ENO2 is physiologically redundant (compensated by ENO1) in normal glycolysis, it becomes essential for sustaining ccRCC malignancy via VHL loss-HIF2α-driven glycolytic flux. Targeting ENO2 specifically suppressed glycolysis in VHL-deficient ccRCC cells, reducing their malignancy and enhancing their response to axitinib, doxorubicin, and gemcitabine. Importantly, pharmacological ENO2 blockade displayed superior tumor selectivity compared to traditional glycolysis inhibitors, effectively eliminating VHL-deficient ccRCC cells while sparing VHL-intact normal and malignant cells, despite causing slightly weaker glycolytic suppression. Mechanistic investigations revealed that ENO2 ablation inactivated up to ~78% of VHL loss-induced oncogenic effectors, including a pleiotropic oncoprotein MDK, through dual modulation of lactate metabolism and interferon signaling. Collectively, this work reveals ENO2 as a genotype-specific metabolic dependency in ccRCC, thereby enabling precision glycolytic therapy. Our work also suggests that targeting physiologically redundant metabolic isoenzymes may offer a precision medicine strategy for cancers with defined genetic alterations.
    DOI:  https://doi.org/10.1038/s41419-026-09102-4
  13. Sci Adv. 2026 Jul 17. 12(29): eaed2430
    ALR couples IMS redox and heme biosynthesis beyond the disulfide relay.
    Julia Racho, Dylan Stobbe, Jan Jirschitzka, Marijana Croon, Carmelina Petrungaro, Muna Ali, Dario Wernet, Markus Habich, Nele Sophie Gawellek, Julian Strippel, Finn Dicke, Jörn Dengjel, Stephanie Kath-Schorr, Bent Brachvogel, Thomas Langer, Aleksandra Trifunovic, Ines Neundorf, Jan Riemer.
      Proteins in the mitochondrial intermembrane space (IMS) play essential roles in respiratory chain assembly, metabolism, signaling, and organelle dynamics. Their stability and functionality often depend on structural disulfide bonds introduced by the mitochondrial disulfide relay, mediated by MIA40 and ALR. In this system, the sulfhydryl oxidase ALR reoxidizes MIA40, which in turn oxidizes incoming substrate proteins. Although evidence has suggested that ALR can also act independently of MIA40, its endogenous substrates have remained unknown. In this study, we captured proteins directly oxidized by ALR. Among these, we found coproporphyrinogen III oxidase (CPOX), a key enzyme in heme biosynthesis. We show that ALR-mediated disulfide bond formation is crucial for maintaining CPOX stability in the IMS, thereby ensuring effective heme biosynthesis and mitochondrial functionality. Notably, while disulfide-deficient CPOX failed to rescue CPOX loss when localized to the IMS, it retained functionality when redirected to the cytosol. However, this bypass compromised pathway efficiency, leading to the accumulation of protoporphyrinogen IX, a highly hydrophobic and redox-active intermediate that sensitized cells to cell death. Together, our findings reveal that ALR has functions beyond the MIA pathway and highlight that oxidative protein folding in the IMS relies not only on a relay mechanism but also on a broader disulfide-introducing network of enzymes.
    DOI:  https://doi.org/10.1126/sciadv.aed2430
  14. Front Immunol. 2026 ;17 1879836
    Calcium imbalance drives organelle network collapse and immune remodeling: novel pathogenic mechanisms in MASLD progression.
    Senping Xu, Ziyang Jiang, Qing Zhang, Jiawei Guo.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is initiated by ectopic lipid accumulation, but the precise mechanochemical transducers driving its progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis remain incompletely understood. This review comprehensively elucidates the central pathogenic role of intracellular calcium signaling dysregulation in MASLD. We detail how the metabolically toxic microenvironment induces pathological biophysical remodeling of lipid rafts and key calcium transporters across the plasma membrane (PM), endoplasmic reticulum (ER), and mitochondria. This pervasive transmembrane and inter-organellar calcium imbalance precipitates severe organelle network collapse, characterized by calcium depletion-driven ER stress, mitochondrial dysfunction, and the structural derangement of mitochondria-associated ER membranes (MAMs). Aberrant calcium fluxes function as critical secondary messengers that dictate hepatic immune microenvironment remodeling, at the cellular level driving Kupffer cell pro-inflammatory polarization, NLRP3 inflammasome assembly, and the amplification of damage-associated molecular patterns (DAMPs). These calcium-dependent immune-metabolic feedback loops synergistically trigger hepatic stellate cell (HSC) transdifferentiation and fibrogenesis. Finally, we highlight the latent calcium-regulatory mechanisms of current metabolic therapeutics and prospect the translational potential of targeted calcium modulators coupled with advanced nanodelivery systems, advocating for multi-targeted pharmacological strategies to arrest irreversible liver injury.
    Keywords:  NLRP3 inflammasome; calcium signaling dysregulation; immune microenvironment remodeling; lipotoxicity; liver fibrosis; metabolic dysfunction-associated steatotic liver disease; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2026.1879836
  15. PLoS Biol. 2026 Jul 15. 24(7): e3003901
    Peroxisomal import is circadian in glia and regulates sleep and lipid metabolism.
    Anurag Das, Irma Magaly Rivas-Serna, Ankur Kumar, Lakpa Sherpa, Kerui Huang, Hia Kalita, Marlene Dorneich-Hayes, Ruiqi Liu, Vera C Mazurak, John P Vaughen, Hua Bai.
      Peroxisomes are critical organelles that detoxify cellular waste while also catabolizing and anabolizing lipids. How peroxisomes coordinate protein import and support metabolic functions across complex tissues and timescales remains poorly understood in vivo. Using the Drosophila brain, we discover a striking enrichment of peroxisomes in the neuronal soma and the cortex glia that enwrap them. Unexpectedly, import of peroxisomal proteins into cortex glia, but not neurons, oscillated across time and peaked in the early morning. Rhythmic peroxisomal import in cortex glia autonomously required the circadian clock and Peroxin 5 (Pex5; peroxisomal biogenesis factor 5 homolog), with import persistently elevated in clock mutants. Notably, reducing Pex5 in cortex glia, but not neurons, caused hyperactivity and reduced total sleep. Moreover, brain lipid metabolism was dramatically altered upon Pex5 knockdown, with glia impacting sphingolipids and triacylglycerols, and neurons impacting phospholipids. The cell-type specificity of these Pex5 phenotypes highlights unique roles for peroxisomal import in both sleep and lipid metabolism in the brain.
    DOI:  https://doi.org/10.1371/journal.pbio.3003901
  16. Mol Biol Rep. 2026 Jul 17. pii: 1192. [Epub ahead of print]53(1):
    Differential NAD + availability may drive asymmetric SIRT7 activity in tumor and immune cells.
    Francisco Alejandro Lagunas-Rangel.
      Metabolic competition within the tumor microenvironment shapes the availability of nutrients and metabolites that regulate both tumor progression and antitumor immunity. Among the molecules linking metabolism to gene regulation, the NAD + -dependent enzyme SIRT7 has emerged as an important regulator of ribosome biogenesis, genome stability, chromatin organization, and metabolic adaptation. Although SIRT7 is frequently associated with tumor progression, emerging evidence indicates that it also supports the metabolic fitness and effector functions of immune cells, suggesting that its biological consequences are highly cell type-dependent. However, the mechanisms underlying these apparently opposing functions remain poorly understood. A conceptual framework is presented in which differences in intracellular NAD + availability contribute to asymmetric SIRT7 activity in tumor and immune cells within the tumor microenvironment. Many tumor types preserve intracellular NAD + through metabolic rewiring, whereas infiltrating immune cells frequently experience sustained metabolic stress and progressive NAD + depletion owing to nutrient competition. Although direct evidence demonstrating that physiological fluctuations in intracellular NAD + regulate SIRT7 activity in vivo remains limited, biochemical studies indicate that SIRT7 displays a relatively high apparent Michaelis constant (Km) for NAD + compared with other mammalian sirtuins, providing a biochemical rationale for increased sensitivity to changes in intracellular NAD + availability. Current evidence from SIRT7 biology, cancer metabolism, and immunometabolism is integrated to evaluate this conceptual framework, identify key limitations in the available data, and highlight experimental questions that should be addressed to determine whether differential NAD + availability represents a fundamental mechanism underlying the context-dependent functions of SIRT7.
    Keywords:  Immune dysfunction; PD-L1; Sirtuin; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12400-x
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