bims-celmim 2026-04-12 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–04–12
24 papers selected by
Marc Segarra Mondejar, AINA

Ferroptosis as an approach to leverage cancer metabolism.
Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.
Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.
Metabolomics across scales: from single cells to population studies.
Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.
STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers.
Astrocytic glucose metabolism regulates the survival of newborn hippocampal neurons in the adult brain.
The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
PHGDH is a targetable driver of PDAC progression.
Reconstruction of human metabolic models with large language models.
ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.
Lysosomal Membrane Proteins: Key Regulators of Glucose Metabolism and Its Associated Diseases.
In vivo visualization of lipophagy dynamics using the tfLiveDrop reporter mice.
Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina.
CRISPR-Cas-based live cell imaging of genome dynamics.
Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.
A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.
Endoplasmic reticulum architecture in liver metabolic regulation.
VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α.
iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.
MitoPerturb-Seq identifies links between nuclear and mitochondrial genomes in single cells.
NucleoNet and DropNet: Generalist deep learning models for instance segmentation of nuclei and lipid droplets from electron microscopy images.

Trends Cell Biol. 2026 Apr 09. pii: S0962-8924(26)00039-5. [Epub ahead of print]

Ferroptosis as an approach to leverage cancer metabolism.

Jenny Jin, Jiachen Hu, Mingyue Li, Wei Gu, Xuejun Jiang, Brent R Stockwell.

  Ferroptosis is a cell death process defined by the iron-mediated peroxidation of membrane phospholipids that overwhelms the cell's innate antioxidant capabilities. Sitting at the nexus of iron, lipid, reactive oxygen species stress responses, and cellular metabolism, ferroptosis is intricately tied to these pathways. The burgeoning field of cancer metabolism has revealed that cancer cells exhibit changes in ferroptosis-relevant metabolic pathways, thereby opening an important avenue of investigation into whether tumors can have characteristic metabolic alterations that render them exquisitely sensitive to ferroptotic cell death. In this review, we highlight recent findings in the metabolic pathways linking ferroptosis and oncogenesis, as well as implications for future cancer therapeutic strategies.

Keywords:  cancer metabolism; ferroptosis; lipid metabolism; lipidomics; metabolomics; oncogenic signaling

DOI:  https://doi.org/10.1016/j.tcb.2026.03.008
Nat Metab. 2026 Apr 07.

Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.

Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.

Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.

DOI: https://doi.org/10.1038/s42255-026-01499-8
Cell Death Dis. 2026 Apr 10.

Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling.

Dorottya Károlyi, Sólyom Bálint Bótor, Natali Neuhauser, András Rubics, Janka Szinyákovics, Tibor Kovács, Mária Péter, Gábor Balogh, Fergal O'Farrell, Szabolcs Takáts.

Biosynthesis of lipids and fatty acids (FAs) is essential for the normal functioning of cellular processes, and lipid availability determines the progression of multiple malignant tumor types. To date, the roles of individual steps in lipid biosynthesis during tumor growth and their interaction with intracellular signaling pathways are not well understood. Our study demonstrates that upregulation of de novo FA and lipid synthesis is a conserved characteristic of malignant tumors. In vivo tumor cell-specific silencing of components of the neutral lipid biosynthetic apparatus revealed that loss of several enzymes involved in FA and diacylglycerol synthesis inhibited tumor growth. Specifically, acetyl-CoA carboxylase (ACC), which catalyzes the first step of FA synthesis, drives late-stage tumor growth. FA synthesis perturbation led to inactivation of TORC1 (mechanistic Target of Rapamycin Complex 1)-accompanied by activation of the catabolic process autophagy. Moreover, TORC1 activity cannot be fully restored by hyperactivation of upstream Insulin/PI3K signaling or inhibition of AMP-activated kinase (AMPK) in ACC-deficient tumor cells, but supplementation with ectopic oleic acid can partially increase TORC1 activity and tumor progression. In addition to their metabolic value, the role of FAs in promoting TORC1 gives us new insight into cancer cell dependence on de novo FA synthesis.

DOI: https://doi.org/10.1038/s41419-026-08738-6
iScience. 2026 Apr 17. 29(4): 115256

Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.

Shenshen Yao, Hongbo Guan, Jun Chai, Xiaomei Liu.

  Iron-sulfur (Fe/S) clusters are essential cofactors required for mitochondrial metabolism, redox regulation, DNA synthesis, and cellular viability. Defects in their biogenesis or function compromise mitochondrial homeostasis, iron balance, and genome stability, alterations frequently observed in cancer. Growing evidence indicates that Fe/S proteins participate in tumor cell proliferation, metabolic adaptation, oxidative stress tolerance, and therapeutic resistance. This review summarizes current knowledge on the mechanisms of Fe/S cluster assembly in distinct cellular compartments, including the mitochondria, cytosol, and nucleus, and outlines their physiological roles in normal and malignant cells. It further discusses the molecular mechanisms by which dysregulation of Fe/S cluster homeostasis contributes to tumorigenesis. In addition, we highlight emerging therapeutic strategies that exploit Fe/S cluster dependencies, including small-molecule approaches, regulated cell death pathways, and nanomedicine-based interventions. Collectively, these insights underscore the relevance of Fe/S cluster biology to cancer pathogenesis and its potential for therapeutic exploitation.

Keywords:  cancer; cell biology; functional aspects of cell biology

DOI:  https://doi.org/10.1016/j.isci.2026.115256
Nature. 2026 04;652(8109): 313-320

Metabolomics across scales: from single cells to population studies.

Theodore Alexandrov, Nicola Zamboni.

Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.

DOI: https://doi.org/10.1038/s41586-026-10277-1
Nat Commun. 2026 Apr 10.

Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.

Haizhou Jiang, Shihong Ni, Zi Li, Shanghai Chen, Xiaoying Li, Huijie Zhang, Wei L Shen, Xiaoxue Jiang, Peixiang Luo, Yousheng Shu, Feixiang Yuan, Kexin Tong, Fei Xiao, Feifan Guo.

A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ.

DOI: https://doi.org/10.1038/s41467-026-71581-y
Autophagy. 2026 Apr 11.

STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.

Jin-Yi Lin, Ze-Bo Huang, Evandro F Fang, Guang Lu.

  PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in C. elegans. These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.Abbreviations: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.

Keywords:  Alzheimer disease; PINK1; PRKN; STUB1; VCP/p97; memory; mitochondrial homeostasis; mitophagy; ubiquitin-proteasome system

DOI:  https://doi.org/10.1080/15548627.2026.2658848
Nat Commun. 2026 Apr 07. pii: 2877. [Epub ahead of print]17(1):

PHIP suppresses NuRD to enable the growth of SWI/SNF-mutant cancers.

Hayden A Malone, Jacquelyn A Myers, Emma G Gruss, Marc A Morgan, Jake D Friske, Tabitha C McCarty, John J Navarro, Sarah Robinson, Rebecca L Halliburton, Sandra J Kietlinska, Francisca N De Luna Vitorino, Baranda S Hansen, Shondra M Pruett-Miller, Benjamin A Garcia, Martine F Roussel, Janet F Partridge, Charles W M Roberts.

SWI/SNF chromatin remodeling complexes are perturbed in 20% of all cancers and in several developmental disorders, yet the mechanisms by which these mutations dysregulate transcription and drive disease are poorly understood. To both elucidate these mechanisms and identify vulnerabilities caused by these mutations, we leverage genome-wide CRISPR-Cas9 screening in hundreds of cancer cell lines and identify the chromatin reader protein PHIP as a specific dependency in cancers with broadly disrupted SWI/SNF function. Mechanistically, we reveal that PHIP cooperates with SWI/SNF to facilitate transcriptional activation by ubiquitinating and suppressing subunits of the repressive Nucleosome Remodeling and Deacetylase (NuRD) complex. We demonstrate that loss of SWI/SNF results in NuRD complexes accumulating at promoters where they would otherwise cause widespread transcriptional silencing if not antagonized by PHIP. Collectively, we identify PHIP as a regulator of the interplay between distinct chromatin regulators that function in development and disease and as a targetable vulnerability in cancers with broad SWI/SNF inactivation.

DOI: https://doi.org/10.1038/s41467-026-70699-3
Neuron. 2026 Apr 06. pii: S0896-6273(26)00212-6. [Epub ahead of print]

Astrocytic glucose metabolism regulates the survival of newborn hippocampal neurons in the adult brain.

Xinxing Wang, Lu Chen, Thomas A Kim, Zhiyi Wang, Xike Peng, Michelle D Syty, Faye Wang, Yuhan Zhang, Patrick Wehrle, Yusuke Nasu, Qiaojie Xiong, Shaoyu Ge.

  In the adult brain, hippocampal activity precisely regulates the survival of newborn hippocampal neurons. However, the mechanisms by which these neurons acquire metabolites required for survival remain unclear. Using a genetically encoded glucose biosensor and in vivo imaging in freely moving animals, we tracked cellular glucose dynamics during contextual exploration. Newborn neurons recovered intracellular glucose slowly and expressed low levels of glycolysis- and glucose transport-related genes. By contrast, astrocytes surrounding newborn neurons exhibited rapid decreases in intracellular glucose during exploration, followed by prompt recovery afterward. In vivo lactate imaging revealed concurrent increases in astrocytic and extracellular lactate during exploration. Importantly, disrupting astrocytic glucose uptake, lactate production, or lactate transport in astrocytes or newborn neurons impaired activity-dependent survival. These results identify an astrocyte-to-newborn neuron metabolic pathway in which astrocytic glucose metabolism supports newborn neuron survival through lactate, with implications for adult neurogenesis in aging and disease.

Keywords:  activity-dependent survival; adult hippocampal neurogenesis; astrocyte-newborn neuron metabolic coupling; glucose metabolism; in vivo biosensor imaging; lactate transport

DOI:  https://doi.org/10.1016/j.neuron.2026.03.021
Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]

PHGDH is a targetable driver of PDAC progression.

Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.

Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

DOI: https://doi.org/10.64898/2026.03.11.711147
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2516511123

Reconstruction of human metabolic models with large language models.

Jiahao Luo, Hao Wang, Devlin Moyer, Zhetao Guo, Jonathan L Robinson, Johan Gustafsson, Mihail Anton, Yu Chen, Eduard J Kerkhoven, Jens Nielsen, Feiran Li.

  Genome-scale metabolic models (GEMs) have become essential tools for understanding human metabolism. Here, we introduce Human2, a consensus human GEM with enhanced precision and biological relevance, which leverages large language models (LLMs) and GitHub Action checks to streamline automated, efficient, and collaborative curation. Human2 supports the reconstruction of tissue- and organ-specific models tailored to sex- and age-specific human groups. By integrating transcriptomic, proteomic, and kinetic data, we reveal distinct metabolic features across these groups, such as significant differences in arachidonic acid and leukotriene metabolism. The specific models were integrated into a dynamic whole-body framework, marking an enzyme-constrained dynamic model that simulates interorgan metabolite exchanges under varying nutritional states, from feeding to fasting. Our work highlights the transformative role of LLMs in GEM reconstruction and introduces a whole-body dynamic simulation that integrates kinetic data, offering a powerful resource for multiscale human metabolism modeling.

Keywords:  genome-scale metabolic model; large language model; organ-specific model; whole-body model

DOI:  https://doi.org/10.1073/pnas.2516511123
Cell Death Dis. 2026 Apr 08.

ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape.

Han Tao, Xiaojun Wang, Zhiyi Hu, Yiran Li, Mengwen Kong, Yeli Sun, Kun Gao, Xiaoping Wan.

Metabolic reprogramming is crucial in developing endometrial cancer (EC); however, the mechanisms through which tumor suppressors control metabolites that drive cell proliferation and tumor growth remain unclear. ARID1A, an SWI/SNF chromatin remodeling complex subunit, is frequently mutated in endometrium-related malignancies. Here, EC tumors with ARID1A deleted exhibit increased polyamine production, which enhances malignant proliferative capacity while inhibiting the efficacy of functional CD8+ T cells. Mechanistically, ARID1A depletion in tumor cells interrupts the competitive binding of ARID1A to YAP, causing excessive YAP activation and transcriptionally increasing the expression of polyamine metabolic enzymes, thereby enhancing polyamine synthesis. Increased spermidine production from polyamines can directly hypusinate eukaryotic translation initiation factor 5A (eIF5A) at lysine residues, resulting in efficient histone demethylase LSD1 protein translation. Moreover, polyamine accumulation suppresses the recruitment of CD8+ T cells and hampers antitumor immune responses in vivo. Notably, polyamine depletion induced by eflornithine (DFMO) significantly reduces EC cell proliferative capacity and enhances CD8+ T-cell efficacy. Together, these findings highlight the role of ARID1A in regulating polyamine metabolism and suggest that elevated polyamine levels in tumors enhance malignant cellular behaviors and contribute to immune evasion by inhibiting CD8+ T cell-mediated cytotoxic responses. Therefore, targeting polyamine biosynthesis could be an important therapeutic strategy for ARID1A-inactivated EC.

DOI: https://doi.org/10.1038/s41419-026-08722-0
FASEB J. 2026 Apr 30. 40(8): e71717

Lysosomal Membrane Proteins: Key Regulators of Glucose Metabolism and Its Associated Diseases.

Jiahao Xu, Yujie Jin, Shiqiang Liu, Song Dong, Chaoqun Xiong, Ruixi Zhang, Wenjun Pei, Xu Wu, Lizhuo Wang, Jialin Gao.

  Glucose homeostasis, which is critical for maintaining energy supply and health, involves glycogen metabolism, glycolysis, and gluconeogenesis. Lysosomal membrane proteins (LMPs) play core roles in regulating these processes. However, no focused systematic review of the topic has been reported. This review provides an in-depth analysis of the central roles of LMPs in glucose metabolism, focusing on the regulation of glucose homeostasis and their potential effects on metabolic diseases through the regulation of autophagy, signaling networks, specialized transporter functions, and other relevant mechanisms. In general, LMPs play core roles in lysosomal biosynthesis, and an in-depth study of their relationship with glucose metabolism could significantly highlight the important contribution of lysosomes in the development of related diseases.

Keywords:  gene regulation; glucose metabolism; lysosomal membrane protein; metabolism; molecular mechanisms

DOI:  https://doi.org/10.1096/fj.202501587R
J Lipid Res. 2026 Apr 02. pii: S0022-2275(26)00059-3. [Epub ahead of print] 101033

In vivo visualization of lipophagy dynamics using the tfLiveDrop reporter mice.

Siqiao Gong, Qiaofei Zhang, Hongluan Wu, Xiaocui Chen, Lijing Liu, Yongming Chen, ZeSen Feng, Shangmei Li, Hongyong Su, Jiansong Qi, Jixin Tang, Zhennan Ye, Chen Yang, Huafeng Liu.

  Lipophagy, a selective form of autophagy, is critical for maintaining cellular lipid homeostasis. However, understanding its dynamic regulation and pathophysiological significance in vivo has been hindered by a lack of sensitive and versatile monitoring tools. To address this gap, we generated the tfLiveDrop (mCherry-eGFP-LiveDrop) reporter mouse by integrating a tandem mCherry-eGFP fluorescent probe with the lipid droplet-targeting domain of glycerol-3-phosphate acyltransferase 4 (GPAT4, the rate-limiting enzyme in triacylglycerol synthesis), termed the LiveDrop domain. This model enables real-time, spatiotemporal visualization of lipophagic flux at single-cell resolution in living animals. We initially validated the sensitivity and specificity of the tfLiveDrop reporter in primary renal tubular epithelial cells (TECs). Systemic mapping of lipophagic activity across organs revealed pronounced heterogeneity in basal lipophagic activity under physiological conditions. Furthermore, in a model of Type 2 diabetes, we demonstrated that lipophagic flux is dysregulated in a tissue-specific manner in male mice, underscoring its pivotal role in disease-associated lipid metabolism. Notably, longitudinal tracking during kidney development uncovered a programmed wave of lipophagic activity that is essential for lipid homeostasis during renal maturation. Our findings provide a powerful and versatile platform for in vivo lipophagy research, establishing a foundation for elucidating its functional contributions to metabolic disorders and organ development.

Keywords:  Kidney development; Lipid droplets; Lipophagy; LiveDrop; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.jlr.2026.101033
PLoS Genet. 2026 Apr 08. 22(4): e1012100

Lactate and histone H3K18 lactylation are associated with metabolic control of gene expression in the retina.

Mohita Gaur, Matthew J Brooks, Xulong Liang, Ke Jiang, Anjani Kumari, Milton A English, Paolo Cifani, Maria C Panepinto, Jacob Nellissery, Robert N Fariss, Laura Campello, Claire Marchal, Anand Swaroop.

High aerobic glycolysis in retinal photoreceptors, as in cancer cells, is implicated in mitigating energy and metabolic demands. Lactate, a product of glycolysis, can exert epigenetic regulation through histone lactylation in cancer. Here, we show that enhanced ATP production during mouse retinal development is achieved primarily through increase in glycolysis. Histone lactylation, especially H3K18La, parallels increased glycolysis and lactate levels in the developing retina. Multi-omics analyses, combined with confocal imaging, reveal the localization of H3K18La near H3K27Ac in the euchromatin at promoters of active retinal genes. In mouse retinal explants, glucose metabolism is associated with lactate levels as well as H3K18La and consequently gene expression. However, inhibition of glycolysis with 2-deoxyglucose (2-DG) reduces global H3K18La and H3K27Ac marks with somewhat distinct transcriptional changes. Evaluation of accessible chromatin at H3K18La-marked promoters uncovers an enrichment of GC-rich motifs for transcription factors of SP, KMT and KLF families, among others, indicating the specificity of H3K18La-mediated gene regulation. Our results indicate glycolysis/lactate/H3K18La as a potential axis for transcriptional response to changing metabolic conditions in the retina, especially photoreceptors.

DOI: https://doi.org/10.1371/journal.pgen.1012100
Nat Rev Genet. 2026 Apr 08.

CRISPR-Cas-based live cell imaging of genome dynamics.

Yanyu Zhu, W E Moerner, Lei S Qi.

The 3D architecture and dynamics of the genome are crucial for regulation of genome stability, transcription and cellular function. CRISPR-based live imaging technologies have enabled real-time visualization of specific genomic loci and transcripts in living cells. These tools harness customized guide RNAs and nuclease-deactivated Cas effectors to achieve precise genomic targeting, and recent methodological advances provide the 3D spatiotemporal resolution required to decipher real-time chromatin communication. These methods are elucidating the biophysical properties of chromatin, linking dynamic enhancer-promoter interactions directly to transcription, and revealing the role of 3D genome dynamics in basic cellular processes and disease. Here, we summarize the development of CRISPR-based live-cell imaging techniques, highlight the complementary 3D microscopy and analysis methods compatible with these methods, and offer perspectives on their applications to uncover fundamental principles that govern genome dynamics and function.

DOI: https://doi.org/10.1038/s41576-026-00949-z
Sci Rep. 2026 Apr 10.

Metformin treatment impairs the adenine nucleotide translocator activity and energy metabolism in human clear cell renal carcinoma cells.

Lidia de Bari, Mariano Francesco Caratozzolo, Giuseppe Petrosillo, Miriana Calò, Cinzia Antognelli, Tatiana Armeni, Andrea Scirè, Miklós Péter Kalapos.

  Although metformin (MET), the well-known antidiabetic drug, exhibits clear antineoplastic effects and is reported to target mitochondria, several issues are still open in this regard, thus limiting its utilization as an anticancer drug alone or in combination with other molecules. Here a functional investigation was carried out to reveal how MET impacted on mitochondrial functions and cell energy metabolism in human cultured clear cell renal carcinoma cells (ccRCCs), in which the anticancer effect of MET is already known. The in vitro effect of increasing MET concentrations on cell viability, necrosis and apoptosis of ccRCCs was checked and compared to normal immortalized HK2 cells. At the same time, the effect of MET on mitochondrial functions, ATP synthesis via oxidative phosphorylation, cellular ATP level, L-lactate (L-LAC) production and export, glucose consumption and key mitochondrial and cytosolic enzyme activities was also investigated in cancer cells. MET affected ccRCC viability and impaired mitochondrial respiration, membrane potential generation and ATP production by targeting complex I (CI), III and IV of the respiratory chain at a concentration near to the IC50 value (25 mM). Importantly, we first identified a significant inhibition of the adenine nucleotide translocator (ANT) activity in response to MET treatment. Notably, the sensitivity of ANT and CI activity to increasing MET concentrations differed markedly, the former being considerably inhibited already at a low, near-clinically relevant concentrations, while the latter only at concentrations ≥ 1 mM. The drug also induced a glycolytic shift in ccRCCs and increased the activity of the mitochondrial flavoenzymes succinate dehydrogenase (SDH) and D-lactate dehydrogenase (D-LDH), and of the key enzymes of the pay-off phase of glycolysis, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK) and pyruvate kinase (PK). Nevertheless, cellular ATP level dropped markedly, and the intracellular L-LAC amount was almost doubled in the presence of MET. Interestingly, MET-induced glycolytic shift showed a drug concentration dependence similar to that seen for CI inhibition, suggesting not ANT but rather CI inhibition may be the trigger for metabolic rewiring. These findings give new insights into MET mechanisms of action which may potentially improve its application and outcome in cancer as well as in other pathologies.

Keywords:  Adenine nucleotide translocator; Clear cell renal cell carcinoma; Glycolysis; Metformin; Mitochondrial respiratory chain complexes; Oxidative phosphorylation

DOI:  https://doi.org/10.1038/s41598-026-48200-3
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2535453123

A scalable embryonic stem cell-based platform for efficient generation of mitochondrial DNA mutant mice.

Weiwei Fan, Tae Gyu Oh, Lillian Crossley, Hunter Robbins, Mingxiao He, Yang Dai, Morgan L Truitt, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondria are central to energy metabolism and cellular signaling, and mutations in mitochondrial DNA (mtDNA) can disrupt these processes and contribute to human disease. However, progress in defining how mtDNA variation influences adaptation, pathophysiology, and disease susceptibility has been limited by the lack of suitable animal models. Although recent base-editing approaches enable direct mtDNA modification, their low efficiency restricts the generation of diverse models reflecting human mtDNA variation. Here, we develop a scalable embryonic stem (ES) cell-based platform for efficient production of mtDNA mutant mice. Random mutagenesis using an error-prone mtDNA polymerase generates a broad spectrum of mtDNA mutations, which are transferred into ES cells via a multiplexed cybrid fusion strategy coupled with sensitive mutation detection. Optimized ES cell-embryo aggregation enables robust contribution of mtDNA mutant ES cells to host embryos, producing chimeric mice with germline transmission. Using this platform, we generate a library of 155 donor fibroblast lines carrying distinct homoplasmic single-nucleotide mtDNA mutations that produce diverse mitochondrial phenotypes, including impaired oxidative phosphorylation, increased reactive oxygen species, and altered mitochondrial membrane potential. We further generate 34 female C57BL/6 ES cell lines harboring 18 mtDNA mutations across a range of heteroplasmy levels, yielding multiple chimeric mice and achieving germline transmission for one mutation. These data reveal a strong correlation between mitochondrial function and early embryonic development, suggesting a minimal energetic threshold required for normal development. This scalable resource enables systematic investigation of mtDNA variation in physiology, adaptation, disease mechanisms, and therapeutic development.

Keywords:  ES cell; aggregation; mouse model; mtDNA; transgenesis

DOI:  https://doi.org/10.1073/pnas.2535453123
Trends Cell Biol. 2026 Apr 07. pii: S0962-8924(26)00035-8. [Epub ahead of print]

Endoplasmic reticulum architecture in liver metabolic regulation.

Leonardo Luis Artico, Sophia Hakam, Güneş Parlakgül, Ana Paula Arruda.

  The endoplasmic reticulum (ER) is a central hub for essential cellular processes, including lipid and glucose metabolism, protein folding, calcium homeostasis, and detoxification. The ER exhibits a complex architecture, comprising multiple subdomains such as the nuclear envelope and the peripheral ER, which is further organized into sheets, tubules, three-way junctions, and contact sites. Both ER form and function are highly adaptive, with a robust capacity to respond to changes in environmental cues such as nutritional states. Here, we discuss remodeling of ER shape - as a fundamental mechanism of metabolic regulation, which enables the diversification and fine-tuning of metabolic function in physiology, while also representing a potential point of vulnerability during metabolic stress. We focus on the liver, a central organ in systemic energy homeostasis, and examine how hepatic ER morphology and its dynamic interorganelle interactions are reorganized in response to nutritional fluctuations and how this remodeling reflects on metabolic function.

Keywords:  endoplasmic reticulum; hepatocytes; lipids; liver; metabolism; organelle contacts

DOI:  https://doi.org/10.1016/j.tcb.2026.03.004
Cell Death Dis. 2026 Apr 10.

VHL-recruiting PROTAC attenuates AKI-CKD transition via simultaneous degradation of Smad3 and stabilization of HIF-2α.

Yuyi Ruan, Dan Wang, Yuzhu Xu, Jiayi Yang, Yutong Chen, Jinjin Fan, Sydney C W Tang, Wei Chen, Xin Wang.

Acute kidney injury (AKI) impairs renal function in the short term and may eventually progress to chronic kidney disease (CKD) in the long term. The activation of Smad3 and an imbalance in hypoxia-inducible factors-α (HIF-α) expression constitute vital mechanisms leading to the AKI-CKD transition. We have designed a Smad3-targeted Proteolysis-Targeting Chimera (PROTAC) named P1705434, which recruited VHL to degrade Smad3 and meanwhile stable HIF-2α levels. We established a cisplatin nephrotoxicity model and folic acid nephropathy (FAN) model to explore its role and possible mechanisms in the early stage and development of AKI. The results demonstrated that P1705434 alleviated inflammation and fibrosis in progressing AKI by degrading Smad3 and increasing HIF-2α. This was confirmed in both the cisplatin nephrotoxicity and FAN mice models, as evidenced by the reduction percentage of maladaptive proximal tubular cells (PT) and down-regulation of the TNF pathway, which ameliorated injury in S3-PT. Furthermore, we identified a transitional collecting duct (tCD) cell type that had a trend to differentiate into fibroblast but P1705434 treatment reduces the propensity of tCD cells and mitochondrial injury in CD cells by up-regulating the oxidative phosphorylation (OXPHOS) pathway.

DOI: https://doi.org/10.1038/s41419-026-08726-w
Nat Metab. 2026 Apr 10.

iNOS modulates inflammatory responses in an NO-independent manner through direct interaction with IRG1 in mitochondria.

Marina Diotallevi, Carlos Outeiral, Priyanka Patel, Gareth S D Purvis, Surawee Chuaiphichai, Thomas Nicol, Faseeha Ayaz, Daniel A Nissley, Ganna O Krasnoselska, Svenja Hester, John H McVey, Roman Fischer, Benedikt Kessler, Charlotte M Deane, Raymond J Owens, Keith M Channon, Mark J Crabtree.

Nitric oxide (NO) has fundamental roles in numerous physiological and pathophysiological processes. In macrophages, NO produced by inducible nitric oxide synthase (iNOS) modulates metabolic changes that are essential to macrophage activation and plasticity, driving the characteristic metabolic switch from oxidative phosphorylation to glycolysis1,2. Itaconate, derived from the TCA cycle by decarboxylation of cis-aconitate by IRG1 (also referred to as CAD, ACOD1), is one of the most upregulated metabolites during the inflammatory response3. Itaconate regulates macrophage polarization by electrophilically modifying cysteines of key enzymes that control inflammatory states (such as ATF3, Jak1, IFNβ), participate in glycolysis (for example, GAPDH, LDHA) and limit oxidative stress through structural competitive inhibition of succinate dehydrogenase4-9. We recently reported that macrophages that are deficient in iNOS, and subsequent NO generation, produce strikingly higher levels of intracellular itaconate (up to ~15-fold) compared to wild-type cells when stimulated with inflammatory cytokines1,2,10. Here we show that iNOS inhibits IRG1 activity and itaconate levels through a conformation-dependent protein-protein interaction rather than through the production of NO. Using a variety of biochemical and computational approaches, we show that a direct interaction between iNOS and IRG1 occurs within mitochondria, in mouse and human cells, and that it depends on binding of the cofactor BH4 to iNOS but does not require its capability to produce NO. Our findings reveal a non-canonical cellular function for iNOS that places it at the centre of a signalling hub, linking redox signalling and metabolism to modulation of the inflammatory response in macrophages.

DOI: https://doi.org/10.1038/s42255-026-01492-1
Nat Struct Mol Biol. 2026 Apr 09.

MitoPerturb-Seq identifies links between nuclear and mitochondrial genomes in single cells.

DOI: https://doi.org/10.1038/s41594-026-01780-0
bioRxiv. 2026 Apr 05. pii: 2026.04.02.713930. [Epub ahead of print]

NucleoNet and DropNet: Generalist deep learning models for instance segmentation of nuclei and lipid droplets from electron microscopy images.

Abhishek Bhardwaj, Chris W Dell, Melissa R Mikolaj, Helen Spiers, Adam Harned, Balamurugan Kuppusamy, Peng Liu, Donglai Wei, Esta Sterneck, Kedar Narayan.

Automating cellular organelle segmentation is key to increasing the throughput in electron microscopy (EM) and volume EM (vEM) workflows. Deep learning (DL) has accelerated this process, but model development has predominately centered on mitochondria, partly because of a scarcity of suitable training datasets for other features. Here, we crowdsourced the manual step of labeling nuclei and lipid droplets (LDs) from complex cellular EM images and trained Panoptic DeepLab (PDL) models on these large, heterogenous annotated datasets as well as on publicly available vEM datasets. NucleoNet and DropNet , the resulting instance segmentation models for nuclei and LDs, respectively, yield high-quality results on varied benchmarks. We applied these models to quantify differences between 2D and 3D in vitro cancer models versus in vivo tumors, highlighting a path toward robust quantitation in EM. NucleoNet and DropNet are publicly available on our napari plugin, empanada v1.2 , for easy point-and-click segmentation of 2D and 3D cellular EM images.

DOI: https://doi.org/10.64898/2026.04.02.713930