bims-celmim 2026-10-18 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–10–18
27 papers selected by
Marc Segarra Mondejar, AINA

The role of metabolic crosstalk between Intestinal epithelial cells and immune cells in inflammatory bowel disease and targeting strategies.
Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.
Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.
NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.
Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.
Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.
Lipid Transporter TMEM24/C2CD2L Plays Essential Roles in Retinal Photoreceptor Survival by Regulating Calcium Signaling and Synaptic Transmission.
MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.
Neuronal fatty acid bioenergetics: An emerging pathway and potential point in convergence in hereditary spastic paraplegias.
Autophagy dependent HIF1α proteostasis is compromised in models of PEX1 deficiencies.
Macrophage-induced ferritin expression protects pancreatic cancer cells from ferroptosis.
Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer.
SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.
PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2.
Lipid Chemistry beyond the Bilayer: Roles for Nonbilayer Lipids in Biology, Disease, and Delivery.
Mitofusin 2 orchestrates mitochondrial metabolic homeostasis and suppresses cutaneous squamous cell carcinoma by stabilizing ER-mitochondria contacts.
Mitofusin-2 (MFN2) is a critical regulator of metabolic homeostasis in neuronal cells: A metabolomic and proteomic study.
Macrophage- or neutrophil-expressed UPP1 drives tumor growth and immune suppression in the tumor microenvironment.
Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.
Imaging and recording of synaptic zinc in the brain by covalent chemistry-based semisynthetic biosensors.
Innate immune signaling relays environmental cues to mitophagy for metabolic adaptation to obesity.
Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.
Illuminating NAD+ Metabolism in Live Cells and In Vivo Using a Genetically Encoded Fluorescent Sensor.
Fueling the sentinels: organelle remodeling and metabolic adaptation in tissue-resident memory T cell persistence.
Quinolinic acid contributes to maladaptive kidney injury and acute kidney injury-to-chronic kidney disease transition.
Regulation of PDH via cysteine oxidation on DLAT.

Front Immunol. 2026 ;17 1854880

The role of metabolic crosstalk between Intestinal epithelial cells and immune cells in inflammatory bowel disease and targeting strategies.

Heng Li, Beibei Wang, Xianhong Shi, Lulu Tian, Bin Li, Tianqi Zhou, Mingcan Qiu, Jiwei Yuan, Kai Yin.

  Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disorder characterized by disruption of the intestinal epithelial barrier and dysregulated immune responses. IBD pathogenesis is intricately linked to the metabolic reprogramming of the intestinal epithelial cells (IECs), which are central to both barrier maintenance and immune crosstalk. Mitochondrial dysfunction in the IECs leads to energy deficit, oxidative stress, and barrier failure, which activates the adjacent immune cells and establishes a vicious cycle of inflammation. This review focuses on the key role of the mitochondrial metabolism in IBD with a specific focus on the remodeling of the glucose, lipid, and amino acid metabolic pathways in epithelial and immune cells. We elaborate on the specific regulatory mechanisms underlying these metabolic processes and the functions of metabolic products as signaling molecules in cell-cell communication. In addition to causing energy crises and barrier defects in epithelial cells, metabolic remodeling directly controls the activation of immune cells and their polarization toward a pro-inflammatory phenotype. Thus, a deeper understanding of mitochondrial metabolism underlying IBD would provide a crucial theoretical foundation for developing novel precision therapies targeting metabolism. Additionally, elucidating these metabolic networks would provide new therapeutic opportunities for restoring homeostasis in IBD.

Keywords:  immune cells; immunometabolism; intestinal epithelial cells; metabolic reprogramming; mitochondrial dysfunction; therapeutic targets

DOI:  https://doi.org/10.3389/fimmu.2026.1854880
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2627551123

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.

Guozhong Huang, Roberto Docampo.

  Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.

Keywords:  Piezo channel; calcium; lysosomes; membrane contact sites; mitochondria

DOI:  https://doi.org/10.1073/pnas.2627551123
Methods Mol Biol. 2026 ;3057 189-200

Simultaneous Measurement of Mitophagic Flux and Mitochondrial Morphology During Myogenesis.

Fasih A Rahman, Joe Quadrilatero.

  Mitophagy is the selective degradation of mitochondria via autophagy and is essential for maintaining mitochondrial quality and cellular homeostasis as well as being required for skeletal muscle differentiation and myogenesis. While traditional techniques such as immunoblotting, electron microscopy, and live-cell imaging provide valuable insights, they often offer only static or indirect measurements of mitophagy. Mitophagy flux assays capture dynamic turnover events and are, therefore, more informative. In this chapter, we present a streamlined method for monitoring and measuring mitophagic flux in C2C12 myoblasts during differentiation. Further, this approach allows for simultaneous quantification of mitochondrial morphology, providing a powerful platform for studying mitochondrial quality control in vitro.

Keywords:  Adenovirus; Fluorescence mitophagy reporter; Mitochondrial network analysis; Mitochondrial quality control; Mitochondrial remodeling; Mitophagic flux; Mitophagy; Myogenesis

DOI:  https://doi.org/10.1007/978-1-0716-5396-8_15
Front Neurol. 2026 ;17 1943801

NAD+ signaling in Parkinson's disease: molecular mechanisms and therapeutic perspectives.

Tianbao Wang, Xue Zhou, Xinhua Chen.

  Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accumulation of α-synuclein (α-syn), mitochondrial dysfunction, and neuroinflammation. Nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in cellular energy metabolism, DNA repair, and epigenetic regulation, declines with aging and is markedly reduced in the brains of patients with PD. Emerging evidence suggests that supplementation with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), exerts neuroprotective effects through multiple mechanisms, such as activation of the mitochondrial unfolded protein response (UPR∧mt), enhancement of autophagy, and suppression of excessive poly(ADP-ribose) polymerase 1 (PARP1) activation. This review summarizes the central role of NAD+ dysregulation in the pathogenesis of PD, with particular emphasis on the interplay between NAD+ depletion, mitochondrial quality control, proteostasis, and neuroinflammation. Furthermore, we discuss recent advances in NAD+-boosting strategies in PD models and clinical studies, highlighting their potential therapeutic implications for PD intervention.

Keywords:  NAD+; Parkinson's disease; mitochondrial quality control; neuroprotection; nicotinamide riboside

DOI:  https://doi.org/10.3389/fneur.2026.1943801
bioRxiv. 2026 Oct 01. pii: 2026.09.26.754222. [Epub ahead of print]

Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.

Larissa Traxler, Oliver Borgogno, Kylie Champion, Joseph R Herdy, Monika Dzieciatkowska, Julie A Reisz, Ayk Petrosyan, Cat Siler, Colin C Anderson, Elisa Gorostieta-Salas, Raffaella Lucciola, Douglas Galasko, Fred H Gage, Angelo D'Alessandro, Jerome Mertens.

Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyperacetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.
Highlights: Sporadic Alzheimer's disease (AD) patient-derived directly induced neurons (iNs) shift metabolism toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY).Elevated nuclear acetyl-CoA causes hyperacetylation of RNA-binding proteins (RBPs).Patient iNs show pathogenic RNA splicing patterns similar to post-mortem AD brains.Inhibition of ACLY normalizes neuronal acetyl-CoA metabolism and restores RNA splicing homeostasis.

DOI: https://doi.org/10.64898/2026.09.26.754222
Front Cell Dev Biol. 2026 ;14 1935788

Mitochondrial protein import stress in Parkinson's disease: the TOM/TIM-PINK1/Parkin-DELE1/HRI axis linking mitochondrial proteostasis to neuronal death.

Bo Pang, Xin Li, Yunlong Sun, Lin Ding.

  Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but how impaired mitochondrial homeostasis drives the selective death of dopaminergic neurons is still poorly understood. At the center of this problem lies the mitochondrial protein import machinery-the TOM and TIM23 translocases-which doubles as a stress-sensing hub that coordinates two distinct quality control pathways. When import is compromised, the kinase PINK1 accumulates on the mitochondrial surface, recruits Parkin to ubiquitinate outer membrane proteins, and triggers mitophagy. Meanwhile, the stress sensor DELE1 is cleaved and released to the cytosol, where it activates the HRI kinase to phosphorylate eIF2α and engage the integrated stress response (ISR). These two pathways are not independent. Recent work shows they engage in antagonistic crosstalk: the DELE1-HRI-ISR axis suppresses PINK1/Parkin-dependent mitophagy by preserving mitochondrial import efficiency, acting as a molecular brake on organelle clearance. The balance between these pathways is governed by the SIFI E3 ubiquitin ligase complex, which targets both DELE1 and HRI for degradation. Disruption of SIFI causes progressive neurodegeneration in humans. Here we synthesize the structural, biochemical, and genetic evidence that defines the TOM/TIM-PINK1/Parkin-DELE1/HRI signaling axis, examine how its dysregulation contributes to dopaminergic neuron vulnerability, and evaluate therapeutic strategies targeting mitochondrial import stress in PD.

Keywords:  DELE1; HRI; PINK1; Parkinson’s disease; integrated stress response; mitochondrial protein import; mitophagy; parkin

DOI:  https://doi.org/10.3389/fcell.2026.1935788
FASEB J. 2026 Oct 31. 40(20): e72382

Lipid Transporter TMEM24/C2CD2L Plays Essential Roles in Retinal Photoreceptor Survival by Regulating Calcium Signaling and Synaptic Transmission.

Guangyi Chen, Jiajie He, Wenhan Wei, Zhenghao Wang, Xianjun Zhu, Yeming Yang.

Retinal neurotransmission is fundamental to vision, relying on the precise calcium-dependent release of glutamate at photoreceptor ribbon synapses. Disruptions in this pathway underlie multiple visual disorders in humans. TMEM24/C2CD2L, an SMP domain-containing phospholipid transporter enriched at endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, regulates phosphoinositide homeostasis and calcium signaling. However, its role in the retina remains unknown. Here, we show that C2CD2L is predominantly expressed in retinal photoreceptors. Using a rod-specific conditional knockout mouse, we demonstrate that loss of C2CD2L impairs rod-mediated visual function, causes progressive outer retinal degeneration, induces reactive Müller glia activation, and triggers apoptotic photoreceptor death. Transcriptomic profiling of pre-degenerative retinas revealed significant downregulation of genes associated with voltage-gated calcium channel complexes, postsynaptic density membranes, and visual perception. These changes were accompanied by severe synaptic defects, including fewer RIBEYE- and Bassoon-positive puncta, reduced ribbon-bearing terminals, shortened synaptic ribbons, and decreased ribbon-tethered synaptic vesicles. Our findings establish C2CD2L as a critical regulator of rod photoreceptor synaptic integrity, calcium-channel-associated signaling, and retinal homeostasis.

DOI: https://doi.org/10.1096/fj.202602920RR
Sci Adv. 2026 Oct 16. 12(42): eaed8795

MFN2-associated astrocyte dysfunction contributes to neuronal hyperexcitability and depressive-like behaviors.

Feng-Xia Ma, Min Wang, Shuo-Yan Fang, Xiao-Xin Wang, Shen-Han Xu, Xin-Xin Zhao, Yu-Xiao Liu, Cong Wang, Chen Qiao, Qiu-Ling Wang, Lei Cao.

Astrocyte pathology is increasingly recognized as a key factor in the pathogenesis of major depressive disorder (MDD), where disrupted glutamate clearance and impaired neuron-glia interactions contribute to synaptic dysfunction. However, the molecular mechanisms leading to astrocyte loss remain largely undefined. Mitochondrial dysfunction is a hallmark of MDD, yet most studies have focused on neuronal mitochondria, leaving astrocytic mitochondrial dynamics insufficiently investigated. Here, we identify mitofusin-2 (MFN2)-associated astrocyte dysfunction in depression. SMART-seq profiling of hippocampal astrocytes from chronic social defeat stress (CSDS) mice revealed Mfn2 up-regulation, accompanied by excessive mitochondrial fusion, impaired mitophagy, and astrocyte loss. Elevated MFN2 expression was detected in plasma, postmortem brain tissue, and iPSC-derived astrocytes from patients with MDD. Astrocyte-specific knockdown of Mfn2 restored mitochondrial morphology and mitophagy, thereby preserving astrocyte viability and alleviating depressive-like behaviors. Using mass spectrometry-based label-free proteomics, in vivo calcium imaging, and functional assays, we demonstrated that β-arrestin2 deficiency reduced STAT1 stability, releasing its transcriptional repression on Mfn2. Normalization of MFN2 expression through astrocytic Mfn2 knockdown or Stat1 overexpression reduced extracellular glutamate accumulation and prevented neuronal hyperexcitability in CSDS mice. Collectively, our findings define astrocytic MFN2-associated astrocyte dysfunction as a central pathological event in depressive behaviors, with the β-arrestin2-STAT1 pathway acting as an upstream regulatory mechanism. This work reveals an astrocytic pathway in depression and highlights a potential therapeutic target that directly addresses astrocyte pathology, beyond the neuron-centered focus of current antidepressant treatments.

DOI: https://doi.org/10.1126/sciadv.aed8795
Biochim Biophys Acta Mol Cell Biol Lipids. 2026 Oct 10. pii: S1388-1981(26)00061-2. [Epub ahead of print]1872(1): 159775

Neuronal fatty acid bioenergetics: An emerging pathway and potential point in convergence in hereditary spastic paraplegias.

Nyakuoy Yak, Merja Joensuu.

  The human brain is an energetically demanding organ. Neurons have traditionally been considered to rely predominantly on glucose to sustain neuronal activity under normal physiological conditions. However, recent advances challenge this long-standing view, demonstrating that neurons can oxidise endogenous and exogenous long-chain fatty acids through mitochondrial β-oxidation to create energy. In this mini-review, we discuss the emerging role of neuronal fatty acid β-oxidation and how fatty acid metabolism is integrated with glycolysis, lipid storages, and mitochondrial energy production. We further explore the ER-lipid droplet-mitochondria nexus as a metabolic hub coordinating fatty acid mobilisation, storage, and oxidation, and investigate how abnormalities in these organelles and their inter-organelle coupling converge across hereditary spastic paraplegia subtypes to disrupt neuronal lipid metabolism and mitochondrial bioenergetics. Finally, we discuss how these emerging mechanisms may reveal new therapeutic opportunities for hereditary spastic paraplegias.

Keywords:  Bioenergetics; Fatty acid; HSP; Hereditary spastic paraplegia; Lipid metabolism; Neuronal bioenergetics; SPG; β-Oxidation

DOI:  https://doi.org/10.1016/j.bbalip.2026.159775
bioRxiv. 2026 Sep 30. pii: 2026.09.29.755113. [Epub ahead of print]

Autophagy dependent HIF1α proteostasis is compromised in models of PEX1 deficiencies.

Soham P Chowdhury, Sambhav Jain, Milagros Esmerode, Henry Dong, Jonathan T Vu, Connor J Sheedy, Chris D Richardson, Brooke M Gardner.

  Peroxisomes, along with mitochondria, coordinate and compartmentalize oxidative metabolism in eukaryotic cells. Rare genetic disorders caused by mutations in PEX genes impair peroxisome function and cause Peroxisome Biogenesis Disorders, which are characterized by liver and neurological dysfunction, hearing and vision loss, and metabolic abnormalities. The majority of Peroxisome Biogenesis Disorders (PBDs) are caused by mutations in the gene encoding PEX1, which together with PEX6 forms a hetero-hexameric AAA-ATPase complex that drives the import of enzymes into the peroxisome lumen. One particular destabilizing mutation - PEX1G843D - results in almost 30% of all cases. Here we show that deficiencies in PEX1 lead to increased levels of the oxygen-responsive transcription factor HIF1α in normoxia, as well as a HIF1α transcriptional signature. The increase in HIF1α protein was rescued by overexpression of PEX1WT, suggesting PEX1 deficiencies modulate HIF1α signaling. The increased levels of HIF1α were not explained by defects in the oxygen responsive degradation pathway of HIF1α that relies on proline hydroxylase domain enzyme-dependent hydroxylation and von Hippel Lindau tumor suppressor protein-dependent ubiquitination. Instead, we found that PEX1 deficiency alters HIF1α proteostasis by reducing degradation through a hydroxylation- and autophagy- dependent mechanism. Notably, enhancing autophagic capacity by ULK1 agonism was sufficient to reduce HIF1α levels in PEX1 deficient cells. Lastly, we demonstrate that upon hypoxia-reoxygenation, PEX1 deficient cells are slower to reset HIF1α levels. Our results suggest that PBD patients with PEX1 deficiency may be susceptible to dysregulation of the HIF1α pathway, particularly in tissues where oxygen gradients are physiological or developmentally required.

Keywords:  Peroxisome; autophagy; cell signaling; hypoxia; hypoxia-inducible factor (HIF); proteostasis

DOI:  https://doi.org/10.64898/2026.09.29.755113
Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01158-7. [Epub ahead of print]45(10): 118079

Macrophage-induced ferritin expression protects pancreatic cancer cells from ferroptosis.

Eric C Cheung, Meng-Han Wu, Wen-Chi Cheng, Jack Coomes, Karen Blyth, Karen H Vousden.

  Reactive oxygen species (ROS) drive pro-tumorigenic signaling but also promote lipid peroxidation and ferroptosis, making ROS regulation critical during high oxidative stress stages of tumor progression, such as metastasis. Loss of the antioxidant TIGAR in pancreatic ductal adenocarcinoma (PDAC) cells raises ROS and enhances metastatic behavior but also sensitizes cells to ferroptosis. To understand how TIGAR-null cells survive to metastasize, we examine the role of macrophage infiltration, which is increased in TIGAR-null tumors. Co-culturing TIGAR-null PDAC cells with macrophages protects them from ferroptosis. The tumor cells induce macrophage IL-6 secretion, which leads to the activation of STAT3 and upregulation of the iron-sequestering protein ferritin (FTH1) in cancer cells. FTH1 depletion in TIGAR-null cells restores ferroptosis sensitivity and reduces lung metastasis. These results suggest that the outcome of increased ROS in tumors may depend on the activation of mechanisms that selectively prevent ferroptosis while preserving ROS-induced oncogenic signaling and metastasis-promoting pathways.

Keywords:  CP: cancer; CP: immunology; PDAC; ferritin; ferroptosis; macrophages; metastasis; oxidative stress; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.celrep.2026.118079
Cells. 2026 Oct 04. pii: 1811. [Epub ahead of print]15(19):

Novel Insights into the Biochemistry of Citrate and Its Transporters: Relevance to Metabolic Rewiring, Tumor Microenvironment, and Bone Metastasis in Cancer.

Vadivel Ganapathy, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju.

  Citrate intersects multiple biochemical pathways, yet its role in cancer has received limited attention. Similarly, the Na+-coupled citrate transporter (SLC13A5) has been investigated extensively in connection with epileptic encephalopathy, but its relevance to cancer remains understudied. This review focuses on novel insights into citrate biology and SLC13A5 that suggest a tumor-promoting role for SLC13A5/citrate. Cytosolic citrate is the building block for fatty acid and cholesterol synthesis necessary for membrane biogenesis and serves as a signaling molecule in regulating mitophagy and proteostasis in the endoplasmic reticulum. Cytosolic citrate pools derived from SLC13A5-mediated uptake across the plasma membrane and SLC25A1-mediated export from mitochondria have distinct functions. Citrate inhibits asparaginyl hydroxylase and thus potentiates transcription via hypoxia-inducible factors, consequently enhancing lactatogenic aerobic glycolysis and glutaminolysis in cancer cells. Citrate chelates iron and zinc; hence, cancer cells may be protected from ferroptosis and subjected to metabolic alterations by citrate. Human SLC13A5 is coupled to Na+ and H+, a feature that accelerates the delivery of extracellular citrate into cancer cells in the acidic tumor microenvironment (TME). SLC13A5 is also expressed in intracellular vesicles where it sequesters cytoplasmic citrate, thereby relieving citrate-mediated inhibition of glycolysis. Because the bone matrix is rich in citrate, osteolytic bone metastasis may increase citrate levels in the TME, providing a citrate-rich niche that facilitates cancer cell growth, metabolic reprogramming, and resistance to ferroptosis. Collectively, this review highlights novel biological aspects of citrate and SLC13A5 as they relate to tumor growth and bone metastasis and identifies SLC13A5 as a potential therapeutic target in cancer.

Keywords:  SLC13A3; SLC13A5; SLC25A1; bone metastasis; cancer; citrate; hypoxia-inducible factors; iron homeostasis; itaconate; lipid synthesis; osteolysis

DOI:  https://doi.org/10.3390/cells15191811
Sci Adv. 2026 Oct 16. 12(42): eaef3522

SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.

Raman Shulinski, Roman Loban, Danny Farhat, Benjamín Cartes-Saavedra, Matthew J Magda, Pavel Kotchetkov, Victoria Caminiti, Linda David, Yuri I Wolf, Conor O'Dwyer, Morgan Fullerton, Yan Burelle, Jyh-Yeuan Eric Lee, Andrea Raimondi, Eugene V Koonin, György Hajnóczky, Mary-Ellen Harper, Luca Pellegrini.

The double-membrane nature of mitochondria generates an intermembrane volume through which ions, reactive oxygen species, and metabolites must flux to reach the matrix or cytosol, but whether this volume is a genetically specified structure remains unknown. We identify SPRIZ (spatial regulator of the intermembrane zone), the product of Ccdc127, a gene conserved across deuterostome animals. SPRIZ assembles into an ∼18-nanometer homodimeric tether anchored in the outer mitochondrial membrane (OMM) and inserted into the inner mitochondrial membrane (IMM) through vertebrate-specific hydrophobic loops, physically spacing the two membranes and setting local intermembrane volume. Cryo-electron tomography of native mitochondria revealed rod-like densities spanning the intermembrane space (IMS), consistent with SPRIZ's predicted rigid coiled-coil architecture and membrane-spanning topology. In mouse liver, two-dimensional morphometry measured ∼3-fold expansion of IMS area with SPRIZ and ∼5.5-fold with lengthened mitochondrial artificial increaser of the IMS (MARTINI); 3D electron tomography confirmed MARTINI's greater OMM-IMM separation and normalized IMS volume. This expansion was functionally validated by increased 14C-mannitol accessibility to the IMS and by impaired mitochondrial Ca2+ uptake. Constitutive Ccdc127/SPRIZ knockout produced viable mice and, in liver mitochondria, preserved overall ultrastructure but caused modest IMS expansion, consistent with loss of local OMM-IMM constraints that stabilize membrane geometry at discrete sites. We therefore identify IMS volume as a genetically encoded and tunable architectural parameter of vertebrate mitochondria. In this model, SPRIZ is a molecular spacing system that locally sets OMM-IMM separation, shaping the environment through which metabolites, ions, and signals diffuse and establishing local gradients within the IMS.

DOI: https://doi.org/10.1126/sciadv.aef3522
Nat Commun. 2026 09 12. pii: 10759. [Epub ahead of print]17(1):

PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2.

Mengqiong Wang, Junjie Cheng, Lin Ma, Jingjuan Yang, Cui Gao, Xin Fang, Ling Ma, Xianghui Fu, Aifu Lin, Songmin Ying, Weiqiang Lin, Yi Yang.

Chronic kidney disease (CKD) is a major global public health challenge, and cardiovascular complications such as vascular calcification (VC) are crucial in CKD-related mortality. Emerging evidence shows that open reading frames (ORFs) within non-coding genomic regions can encode micropeptides, but their roles in VC progression remain largely unexplored. In this study, we identify a 40-amino acid micropeptide, termed PKM2 AP, encoded by an ORF2-containing intron-retaining transcript derived from the LINC01139 locus. PKM2 AP localizes to both mitochondrial and cytoplasmic compartments and interacts with pyruvate kinase M2 (PKM2), thereby promoting its ubiquitination-dependent degradation. Mechanistically, PKM2 AP functions as a molecular glue that facilitates the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, leading to stabilization of the PKM2-PKM2 AP-STUB1 ternary complex and enhanced PKM2 degradation. Functionally, PKM2 AP-mediated PKM2 degradation suppresses aerobic glycolysis and lactate production, thereby attenuating osteogenic transition and VC progression. In vivo administration of PKM2 AP and genetic knock-in of ORF2 both alleviate vascular calcification phenotypes in mouse models. Collectively, our findings identify a VC-associated micropeptide functioning through a molecular glue-like mechanism and provide a potential therapeutic strategy for vascular calcification.

DOI: https://doi.org/10.1038/s41467-026-77693-9
ACS Chem Biol. 2026 Oct 15.

Lipid Chemistry beyond the Bilayer: Roles for Nonbilayer Lipids in Biology, Disease, and Delivery.

Daniel Milshteyn, Itay Budin.

Cell membranes are composed of both bilayer and nonbilayer lipids, whose molecular shape and interactions support or oppose their packing into flat bilayer sheets. While the role of the former in maintaining membrane structural integrity is clear, a growing body of data highlights the importance of nonbilayer lipids in membrane function, including fission and fusion processes in trafficking, and the dynamics of membrane-associated proteins. In this review, we provide a comprehensive overview of nonbilayer lipids and their roles in membrane biology, disease, and drug delivery. First, we introduce the lipid chemistry that gives rise to intrinsic curvature and curvature elastic stress (CES), and we survey the chemical diversity of nonbilayer lipids across organelles and cell types. Second, we discuss relevant methodological advances for characterizing the physicochemical properties of nonbilayer lipids, including X-ray scattering, lipidomics, and molecular dynamics. We then examine how nonbilayer lipids contribute to membrane fusion and fission and how the CES they generate modulates membrane protein localization and function. Next, we consider how the biophysical principles governing nonbilayer lipid behavior can inform the rational design of lipid nanoparticle formulations for therapeutic delivery. Finally, we explore how cells regulate lipid intrinsic curvature as a distinct homeostatic parameter and discuss the implications of its dysregulation in liver disease, neurodegeneration, and mitochondrial dysfunction. We highlight developments in methods spanning the interface between chemistry and biology that can help investigate the function and regulation of nonbilayer lipid chemistry, with far-reaching potential to answer questions in human health, disease, and drug delivery.

DOI: https://doi.org/10.1021/acschembio.6c00629
J Bioenerg Biomembr. 2026 Oct 15. pii: 58. [Epub ahead of print]58(1):

Mitofusin 2 orchestrates mitochondrial metabolic homeostasis and suppresses cutaneous squamous cell carcinoma by stabilizing ER-mitochondria contacts.

Xianpeng Ma, Jing Liu, Xiao Shao, Yupeng Huang, Guangyao Hu.

  This study aimed to elucidate the biological role of Mitofusin 2 (Mfn2) in cutaneous squamous cell carcinoma (cSCC) and evaluate how its regulation of mitochondria-associated membranes (MAMs) may suppress tumor progression by reshaping mitochondrial metabolic homeostasis and apoptosis. We compared Mfn2 expression between normal keratinocytes (HaCaT) and cSCC cells (A431), establishing a stable Mfn2-overexpressing (Mfn2-OE) A431 model. Structural impacts on ER-mitochondrial contacts and MAMs were evaluated using immunofluorescence, STED super-resolution microscopy, TEM, and subcellular fractionation (VDAC1/IP3R/Grp75). Functional assays assessed ER-mitochondrial calcium transport (probes), lipid peroxidation/ROS (C11-BODIPY/DCFH-DA), mitochondrial membrane potential, and ATP levels (JC-1/ATP assays). Mitochondria-dependent apoptosis (Bcl-2/p53/Cytochrome c/Caspase-3) was analyzed via flow cytometry, TUNEL, and Western blot. Phenotypes were assessed using CCK-8, EdU, colony formation, and Transwell assays. In vivo xenografts in nude mice were monitored, with H&E/IHC analysis. Proteomics and untargeted metabolomics (LC-MS) were performed (n = 6/group). Mfn2 protein levels were lower in A431 cSCC cells than in HaCaT keratinocytes. Mfn2-OE enhanced ER-mitochondrial contacts, increased MAMs, and stabilized the VDAC1-Grp75-IP3R complex. This enhanced calcium transport, reduced ROS/lipid peroxidation, stabilized MMP, and decreased ATP. Mfn2-OE inhibited Bcl-2, promoted p53 mitochondrial translocation and Cytochrome c release, activating Caspase cascades. Both in vitro and in vivo, Mfn2-OE suppressed proliferation, invasion, and tumor growth. Proteomics/metabolomics revealed metabolic reprogramming involving energy metabolism, lipid metabolism, and redox balance. Mfn2 may act as a tumor-suppressive regulator in the A431 cSCC model by stabilizing MAMs, remodeling mitochondrial metabolic homeostasis, and activating mitochondria-dependent apoptosis.

Keywords:  Cutaneous squamous cell carcinoma; Mitochondria-associated membranes; Mitochondrial metabolism; Mitofusin 2; Tumor suppression

DOI:  https://doi.org/10.1007/s10863-026-10132-y
Mitochondrion. 2026 Oct 15. pii: S1567-7249(26)00116-9. [Epub ahead of print] 102226

Mitofusin-2 (MFN2) is a critical regulator of metabolic homeostasis in neuronal cells: A metabolomic and proteomic study.

Prakash G Kulkarni, Soumya S Sahoo, Vaibhavi M Mohire, Shilpy Sharma, Jeetender Chugh, Tanushree Banerjee, Amul J Sakharkar.

  The role of mitofusin 2 (Mfn2) in mitochondrial metabolism and neurodegeneration is largely unknown. The current study probes the role of Mfn2 in mitochondrial biogenesis and metabolism in SH-SY5Y neuronal cells using multi-omics strategies. Mfn2 knockdown (KD) by siRNA treatment resulted into diverse proteomic and metabolomic changes. Furthermore, a battery of cellular and molecular analyses associated Mfn2-KD with increased oxidative stress, perturbed mitochondrial membrane potential and reduced mtDNA copy numbers in the neuronal cells. In addition, Mfn2-KD induced dramatic alterations in cell cycle profiles inclusive of proliferation and apoptosis. SWATH-MS-based analysis showed downregulation and upregulation of 11 and 22 differentially expressed proteins (DEPs), respectively, that serve in ribosomal biogenesis, translation, apoptosis, aging, TCA, and OXPHOS metabolic pathways. Among these proteins, TARBP emerged as a hub protein. 1H NMR-based metabolomic analysis showed alterations in 7 metabolites in the Mfn2-KD cells, which were associated with mitochondrial metabolism. Among these metabolites, taurine, a neuromodulator, was significantly downregulated after Mfn2-KD. Interestingly, supplementation of taurine restored the Mfn2-KD-induced deleterious alterations in mitochondrial physiology and cellular metabolomics in the neuronal cells. These results suggest the vital role of Mfn2 in mitochondrial functions in neuronal cells, and taurine emerges as a potential metabolite in Mfn2-linked mitochondrial dysfunction.

Keywords:  Metabolomics; Mitochondria; Mitochondrial dysfunction; Mitochondrial metabolism; Mitofusin; Neuronal cells; Proteomics

DOI:  https://doi.org/10.1016/j.mito.2026.102226
Sci Adv. 2026 Oct 16. 12(42): eaea8798

Macrophage- or neutrophil-expressed UPP1 drives tumor growth and immune suppression in the tumor microenvironment.

Yin Li, Qin Ran, Anying Xiong, Manling Jiang, Fengkai Xu, Yongqi Wei, Jie Gu, Guoping Li, Di Ge, Chunlai Lu.

Uridine phosphorylase 1 (UPP1) has recently emerged as a metabolic regulator with critical roles in tumor cell biology. However, its expression pattern and functional significance in nonmalignant components of the tumor microenvironment (TME) remain largely unexplored. Here, we performed a comprehensive pan-cancer single-cell transcriptomic analysis revealing that UPP1 is highly expressed not only in tumor cells but also in tumor-associated macrophages (TAMs) and neutrophils (TANs). Clinically, UPP1 expression in TAMs and TANs correlates with poor prognosis and diminished response to immunotherapy across multiple cancer types. Mechanistically, UPP1 up-regulation could be driven by NF-κB signaling. Functionally, UPP1 reprograms macrophages toward a tumor-promoting phenotype, characterized by enhanced glycolysis, ATP-adenosine signaling activation, and increased production of immunosuppressive cytokines such as granulocyte colony-stimulating factor. In neutrophils, UPP1 also supports TAN polarization, influences neutrophil extracellular trap release, and contributes to broad immunosuppressive remodeling. In vivo, targeting UPP1 in macrophages or neutrophils reprograms the immune landscape and restrains tumor progression. Together, our findings uncover a previously underappreciated role of UPP1 in nonmalignant immune populations and establish it as a key immune mediator within the TME, offering a potentially promising therapeutic target for enhancing antitumor immunity.

DOI: https://doi.org/10.1126/sciadv.aea8798
Nat Commun. 2026 09 12. pii: 10770. [Epub ahead of print]17(1):

Reprogramming the Rossmann fold signature motif creates orthogonal redox biocatalysts.

Yu Ping, Jin Young Kim, Minh-Anh L Dinh, Emma Luu, Suphanida Worakaensai, Shiding Zhang, William B Black, Emma Monge, Hans Jefferson C Ng, Sean Perea, Yulai Zhang, Youtian Cui, Edward King, Justin B Siegel, Han Li.

Biological reducing power is carried by nicotinamide adenine dinucleotide (phosphate) (NAD(P)/H), which supports cellular functions and cannot be specifically directed to engineered metabolic pathways. Nicotinamide mononucleotide (NMN(H)) has emerged as an orthogonal redox cofactor to address this. Herein, to create NMN(H)-specific enzymes that no longer interact with cellular NAD(P)/H pools, we perturb the ancient, conserved GxGxxG motif in Rossmann fold enzymes that enables persistent NAD(P)/H recognition. We build variants NRC-01 and NRC-02 on phosphite dehydrogenase (PTDH), which eliminate electron leaking to NAD(P)H-dependent side reactions while driving NMNH-dependent biotransformation with ~240-fold higher productivity than existing catalysts. Testing the design principle on 12 other vastly diverse enzymes yields additional NMN(H)-orthogonal enzymes catalyzing valuable biomanufacturing reactions, and reveals a potential rule predicting the translatability of this method. Rosetta modeling, structural alignment, and experimental results reveal that Rossmann fold reprogramming, paired with engineered structural reinforcement, may offer a general route to orthogonal redox biocatalysts.

DOI: https://doi.org/10.1038/s41467-026-77633-7
Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2606947123

Imaging and recording of synaptic zinc in the brain by covalent chemistry-based semisynthetic biosensors.

Hao Zhu, Seiji Sakamotob, Keisuke Nakamura, Chengli Qiu, Kohei Nakajima, Hiroshi Nonaka, Itaru Hamachi.

  Labile zinc ions (Zn2+) are stored in glutamatergic vesicles at specific excitatory synapses in the central nervous system and released into synaptic clefts in an activity-dependent manner. However, the precise roles of synaptic Zn2+ remain unclear due to a lack of tools capable of analyzing Zn2+ with synapse-level spatial resolution in vivo. Here, we developed neuroreceptor-based semisynthetic biosensors that function as integrating dosimeters, recording synaptic Zn2+ by covalent chemistry in the living mouse brain. Using a chemical knock-in strategy, we introduced activity-based Zn2+ probes with distinct affinities into endogenous α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid or γ-aminobutyric acid type A receptors. These in-brain-constructed Zn2+ sensors enabled region-specific mapping of Zn2+ in synaptic clefts in the living mouse brain. Imaging-based analyses revealed differences in apparent Zn2+ levels at excitatory and inhibitory synapses across hippocampal regions during kainate-induced seizures, providing insights into the physiological and pathological functions of synaptic Zn2+.

Keywords:  chemical knock-in; endogenous neuroreceptor; ligand-directed chemistry; semisynthetic biosensor; zinc

DOI:  https://doi.org/10.1073/pnas.2606947123
Autophagy. 2026 Oct 13. 1-3

Innate immune signaling relays environmental cues to mitophagy for metabolic adaptation to obesity.

Courtney J Campbell, Scott A Soleimanpour.

  The mechanisms by which pancreatic β cells sense and communicate environmental cues to mitochondria to maintain insulin secretion remain poorly understood. We identified that β cells transduce metabolic stress, such as during obesity or glucolipotoxicity, through the innate immune signaling adaptor TRAF6 to regulate mitochondrial quality control. TRAF6 was dispensable for β-cell function at baseline yet was essential for glucose-stimulated insulin secretion in mouse or human β cells following nutrient excess. TRAF6 was required for the recruitment of components of both ubiquitin- and receptor-mediated mitophagy pathways to clear dysfunctional mitochondria following metabolic stress. Interestingly, concomitant loss of the ubiquitin-mediated mitophagy effector Parkin restored glucose homeostasis and mitophagy flux in TRAF6-deficient β cells by relieving impediments in receptor-mediated mitophagy. Together, we found that TRAF6 forms a molecular relay linking environmental signals to multiple mitophagy pathways to equip β cells with the means to adapt to metabolic demand and prevent diabetes.Abbreviations: ADP: adenosine diphosphate; ATP: adenosine triphosphate; BNIP3: BCL2 interacting protein 3; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; MFN2: mitofusin 2; PRKN: parkin RBR E3 ubiquitin protein ligase; RNF41/NRDP1: ring finger protein 41; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TAX1BP1: Tax1 binding protein 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6.

Keywords:  Autophagy; beta cell; innate immunity; mitochondria; parkin; traf6

DOI:  https://doi.org/10.1080/15548627.2026.2747028
Nat Metab. 2026 Oct 14.

Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.

Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan.

An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.

DOI: https://doi.org/10.1038/s42255-026-01640-7
Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01195-2. [Epub ahead of print]45(10): 118116

TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.

Emad Heidary Arash, Marko Groeger, James P Grenert, Torsten Wittmann, Robert L Raffai, Jacquelyn J Maher, Holger Willenbring.

  Although a loss-of-function variant of TM6SF2 is a highly penetrant risk factor for steatotic liver disease, including progression to cirrhosis and cancer, its normal function is largely unknown. Here we show that endoplasmic reticulum (ER)-localized TM6SF2 forms membrane contact sites (MCSs) with late endosomes/lysosomes, where it activates the small GTPase RAB7 to enable an endolysosomal route for selective secretion of lipid-rich very low-density lipoprotein (VLDL) particles. In accord, TM6SF2 and RAB7 deficiency similarly cause endolysosomal VLDL retention and accumulation of enlarged late endosomes/lysosomes. TM6SF2 further binds to VAMP-associated protein (VAP) ER-anchor proteins to maintain MCSs between the ER, endosomes, and the trans-Golgi network, with TM6SF2 deficiency causing Golgi fragmentation and disruption of cGAS-STING signaling known to prevent cirrhosis and cancer by clearing senescent hepatocytes. Our findings establish TM6SF2 as an ER-MCS component that enables endolysosomal VLDL secretion and maintains Golgi structure, which suggests that TM6SF2 loss of function causes liver disease through steatosis-dependent and independent mechanisms.

Keywords:  CP: cell biology; Golgi; RAB7; TM6SF2; VAP; cGAS-STING; endoplasmic reticulum; late endosomes/lysosomes; membrane contact sites; steatotic liver disease

DOI:  https://doi.org/10.1016/j.celrep.2026.118116
Dev Cell. 2026 Oct 10. pii: S1534-5807(26)00361-8. [Epub ahead of print]

Illuminating NAD+ Metabolism in Live Cells and In Vivo Using a Genetically Encoded Fluorescent Sensor.

Yejun Zou, Aoxue Wang, Li Huang, Xudong Zhu, Qingxun Hu, Yinan Zhang, Xianjun Chen, Fengwen Li, Qiaohui Wang, Hu Wang, Renmei Liu, Fangting Zuo, Ting Li, Jing Yao, Yajie Qian, Mei Shi, Xiao Yue, Weicai Chen, Zhuo Zhang, Congrong Wang, Yong Zhou, Linyong Zhu, Zhenyu Ju, Joseph Loscalzo, Yi Yang, Yuzheng Zhao.

DOI: https://doi.org/10.1016/j.devcel.2026.09.013
Front Immunol. 2026 ;17 1969351

Fueling the sentinels: organelle remodeling and metabolic adaptation in tissue-resident memory T cell persistence.

Ziheng Zheng, Xuechun Yang, Minqian Ou, Yuedong Chen, Deyong Gan.

  Tissue-resident memory T (TRM) cells persist at barrier and parenchymal sites where oxygen, nutrients, and inflammatory signals fluctuate. Their durability therefore cannot be explained by tissue retention alone. Evidence from skin, liver, intestine, lung, tumors, and inflamed tissues supports a coupled program in which local nutrient capture, mitochondrial fuel selection, organelle dynamics, autophagy, mitophagy, and proteostatic responses sustain survival while preserving rapid effector competence. We propose "organelle-niche matching" as a testable four-step working model: tissue inputs engage nutrient-, oxygen-, danger-, cytokine-, and antigen-sensing pathways; these regulate mitochondrial biogenesis, fusion-fission balance, respiratory-chain organization, and selective turnover; organelle state controls bioenergetic reserve, redox balance, apoptosis, and metabolite availability; and these outputs may reinforce or destabilize transcriptional residency and recall. The model integrates evidence across contexts, not one pathway established in a single TRM population. Direct TRM evidence is distinguished from tumor-infiltrating lymphocyte data and extrapolation from conventional memory CD8+ T cells. Lipid uptake and fatty-acid oxidation are prominent in selected TRM niches but are not universal, and mitophagy should not be equated with mitochondrial health. This framework identifies causal links already demonstrated in TRM cells, relationships that remain correlative, and therapeutic opportunities to strengthen protective residents without sustaining pathogenic populations.

Keywords:  autophagy; fatty-acid oxidation; immunometabolism; mitochondria; mitophagy; persistence; tissue niche; tissue-resident memory T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1969351
Sci Transl Med. 2026 Oct 14. 18(871): eaec9689

Quinolinic acid contributes to maladaptive kidney injury and acute kidney injury-to-chronic kidney disease transition.

Marie Christelle Saade, Afaf Saliba, Amanda J Clark, Subrata Debnath, Shiqi Zhang, Nagarjunachary Ragi, Valerie Etzrodt, Rahil Al-Humaidi, Kyle Vu, Yu Tao, Esmeralda Trevino, Alejandra L Lorenzen, Guanshi Zhang, Anders H Berg, Jason C O'Connor, Samir M Parikh, Kumar Sharma.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA, an intermediate in de novo nicotinamide adenine dinucleotide biosynthesis, is metabolized by quinolinate phosphoribosyltransferase (QPRT). We investigated whether QA contributes to kidney injury using models of folic acid-induced AKI-to-CKD transition and cisplatin-induced AKI, genetic and exogenous approaches to alter QA, and clinical observations. Untargeted kidney metabolomics identified QA as one of the most elevated metabolites after folic acid injury. After folic acid injury, Qprt haploinsufficiency exacerbated kidney injury and fibrosis-related gene expression; aged Qprt-haploinsufficient mice exhibited increased fibrosis-associated gene expression without overt renal dysfunction. Exogenous QA administration increased serum creatinine in uninjured mice and worsened renal dysfunction and fibrosis-related gene expression in the folic acid AKI-to-CKD model. Conversely, mice deficient in either 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) or kynurenine 3-monooxygenase (KMO), which reduce flux toward QA, showed improved renal outcomes after folic acid injury and cisplatin-induced AKI. Multimodal spatial metabolomics analysis of kidney biopsies from patients with AKI revealed QA accumulation in regions of inflammatory infiltration. Last, children with CKD exhibited higher urinary QA compared with healthy individuals. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD.

DOI: https://doi.org/10.1126/scitranslmed.aec9689
Nat Commun. 2026 Oct 14. pii: 10784. [Epub ahead of print]17(1):

Regulation of PDH via cysteine oxidation on DLAT.

Fabiola Garcia-Cortizo, Tobias Weber, Hana Nůsková, Daniel Pfaff, Michael Büttner, Angela Wirth, Elisabeth Kliemank, Gernot Poschet, Marc Freichel, Thomas Fleming, Alba Sulaj, Peter Paul Nawroth, Julia Szendroedi, Aurelio A Teleman.

Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H2O2 and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.

DOI: https://doi.org/10.1038/s41467-026-78266-6