bims-celmim 2026-06-14 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–06–14
twenty-one papers selected by
Marc Segarra Mondejar, AINA

Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.
Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.
A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
Mitochondrial permeability transition in redox homeostasis and ferroptosis.
Cell size modulates ferroptosis susceptibility.
Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.
Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.
Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.
Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.
STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
Mitochondria directly interact with the nuclear pore complex.
A pericyte chloride clamp mechanism governs capillary control of cerebral blood flow.
Mitophagy: an emerging therapeutic target in mitochondrial diseases.
WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts.
Responsive NIR fluorescent probes targeting PKM2 with enzyme-activating properties for precision cancer diagnosis.
Lipid droplet associated protein HILPDA promotes hypoxia-induced ferroptosis by driving LPCAT3-mediated polyunsaturated phospholipids enrichment.
Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities.

Nat Commun. 2026 Jun 12.

Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.

Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.

To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.

DOI: https://doi.org/10.1038/s41467-026-74127-4
Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):

CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.

Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.

Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41467-026-74080-2
Sci Adv. 2026 Jun 12. 12(24): eaee9856

Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.

Shuliang Chen, Subhrajit Banerjee, Dongmei Liu, Kamal Kumar, Christopher J Obara, Peter Novick, William A Prinz, Susan Ferro-Novick.

During cell stress, endoplasmic reticulum autophagy (ER-phagy) receptors remodel the ER by sequestering membrane proteins (cargo) into autophagosomes for degradation. The conserved ER-phagy receptor, Atg40, contains a motif that binds to Atg8 and a reticulon homology domain that is needed for vacuolar/lysosomal delivery. Cargo capture, however, requires the Atg40 binding partner Lst1/SEC24C. To address whether lipids regulate cargo capture during ER-phagy, we analyzed autophagy in neutral lipid-deficient cells. Unexpectedly, we found that Atg40 was delivered to the vacuole in autophagosomes without Lst1/SEC24C or cargo in mutant cells. Lipidomic analysis revealed changes in the ratio of phosphatidylethanolamine to phosphatidylcholine in the neutral lipid-deficient cells that are predicted to alter ER membrane bendability. Our findings imply that phospholipids control cargo sequestration by regulating receptor-cargo coupling at autophagic sites.

DOI: https://doi.org/10.1126/sciadv.aee9856
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2604082123

Alpha-synuclein fibrils induce budding of mitochondrial-derived vesicles.

Thomas Braun, Viviane Reber, Cinzia Tiberi, Andri Fränkl, Dhiman Ghosh, Roland Riek, Tetiana Serdiuk.

α-synuclein (α-syn) aggregation is a hallmark of synucleinopathies, a class of neurodegenerative disorders such as Parkinson's disease (PD). Several lines of evidence indicate the involvement of mitochondria in the disease pathology. Despite extensive study, the link between α-syn aggregation and mechanisms of mitochondrial toxicity remains not fully understood. Using high-resolution imaging with electron microscopy, we examined SH-SY5Y cells exposed to α-syn fibrils vs control cells with a focus on mitochondria. We found that upon exposure to α-syn fibrils, mitochondria cristae structure gets defects, and mitochondria enhance the budding of mitochondrial-derived vesicles (MDVs). MDV formation reflects an evolutionarily conserved mechanism reminiscent of bacterial outer membrane vesicle biogenesis. Structural proteomics analysis by mass spectrometry corroborates this microscopy observation by identifying changes in multiple proteins that regulate cristae structure, MDV formation, and trafficking. Our results suggest that α-syn may promote MDV generation, and support an important link between α-syn and mitochondria which will be important for future mechanistic studies. The processes we detected could be of interest for diagnostics and potential therapeutic interventions.

DOI: https://doi.org/10.1073/pnas.2604082123
Cancer Res. 2026 Jun 06.

Lactate-Activated GPR132 Signaling Drives a Tumor Microenvironmental Autocrine Metabolic Loop in Kidney Cancer.

Dazhi Wang, Timothy M Horton, Kyutae David Lee, Ifeanyichukwu Chinedu Ogobuiro, Fatemeh Vatankhah, Isadora de Andrade, John C Pisano, Vijay S Thakur, Mia K Gurevich, Sam Taylor, Mohammad Alyamani, Durga Prasad Gannamedi, Daniel G Isom, David B Lombard, Anthony J Griswold, Nima Sharifi, Vanina T Tcheuyap, James Brugarolas, Mark L Gonzalgo, Oleksandr N Kryvenko, Scott M Welford.

Despite the presence of oxygen, tumors frequently preferentially perform fermentative glycolysis, producing lactate and acidifying the tumor microenvironment. Although studies have observed that high concentrations of lactate in the tumor microenvironment help tumors gain a proliferative advantage, a detailed understanding of the molecular mechanisms is needed to uncover strategies to overcome lactate-mediated growth. Here, we investigated how lactate exerts pro-growth effects in clear cell renal cell carcinoma (ccRCC), a highly glycolytic tumor primarily caused by alterations in the von Hippel-Lindau tumor suppressor and constitutive activation of HIF signaling. High lactate concentrations activated GPR132, a lactate sensor highly expressed by ccRCC, which conferred pro-tumor growth signaling by elevating mitochondrial respiration through the ERK/STAT3/JAK2 pathway. Furthermore, GPR132 facilitated the uptake of lactate through elevation of HIF signaling downstream of AKT/mTOR to fuel mitochondrial respiration in a feed-forward manner. Treatment with a small molecule GPR132 antagonist demonstrated the essentiality of GPR132 to support ccRCC growth in vivo. Together, these findings reveal that GPR132 signaling promotes ccRCC by sustaining mitochondrial integrity and elevating lactate import. The crosstalk between lactate and tumor cells is a metabolic vulnerability that can be disrupted by targeting GPR132, providing a potential treatment strategy for ccRCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3236
Nat Commun. 2026 Jun 10.

A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.

Sarin Segev-Nakar, Itay Koren.

Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.

DOI: https://doi.org/10.1038/s41467-026-74117-6
J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02116-2. [Epub ahead of print] 113244

Mitochondrial permeability transition in redox homeostasis and ferroptosis.

Lishu Guo.

  Mitochondria are major sources of intracellular reactive oxygen species (ROS), and act as central signaling hubs in maintaining homeostasis of cellular oxidative states. Mitochondrial permeability transition (MPT) is coordinately mediated by mitochondrial outer membrane permeabilization (MOMP) and opening of the permeability transition pore (PTP). MPT is highly sensitive to ROS, and serves as a critical checkpoint in redox balances and cell death. This review will summarize the regulatory systems of mitochondrial and intracellular redox homeostasis, as well as the recent advances in understanding of MPT regulatory mechanisms. Furthermore, this review highlights the functional roles of MPT in redox homeostasis and ferroptosis, a form of iron-dependent, lipid peroxidation-driven cell death. The PTP is a critical molecular switch, which can convert from a defender against mitochondrial redox stress and cell death processes, including specifically iron-dependent, lipid peroxidation-driven cell death, known as ferroptosis, into a ROS amplifier and cell death promoter depending on its open states. MOMP causes the uncoupling of the mitochondrial respiratory chain, and increases ROS production, leading to oxidative stress. The most recent work suggests that the interplay between MTCH2 and F-ATP synthase coordinates MOMP and the PTP opening to mediate the occurrence of MPT. This review provides insight on molecular switches that regulate MPT, determining redox state and cell death.

Keywords:  ferroptosis; mitochondria; mitochondrial permeability transition; redox homeostasis; the permeability transition pore

DOI:  https://doi.org/10.1016/j.jbc.2026.113244
Elife. 2026 Jun 10. pii: RP111544. [Epub ahead of print]15

Cell size modulates ferroptosis susceptibility.

Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.

  Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.

Keywords:  biochemistry; cell biology; cell death; cell size; chemical biology; erastin2; ferroptosis; glutathione; heterogeneous response; human; scaling

DOI:  https://doi.org/10.7554/eLife.111544
Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00162-1. [Epub ahead of print] 102951

Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.

Rahul Kumar Verma, Atharva Bhingare, Dnyanesh Dubal, Richa Rikhy.

  Mitochondrial fusion and electron transport chain complex I are each essential for differentiation in Drosophila neuroblasts, but the mechanism by which they interact to mediate differentiation is unknown. We found that complex I subunit depletion did not affect type II neuroblast numbers but reduced their proliferation and decreased their lineage cells. Complex I depletion decreased the mitochondrial membrane potential and cristae numbers, increased fragmentation and ROS, and inhibited Notch signaling in lineage cells. Similarly, antioxidant enzyme depletion increased ROS and reduced lineage cells. Both complex I and antioxidant proteins promoted the G1/S transition and nuclear cyclin E levels. Additional mitochondrial fusion via Drp1 mutants restored ROS levels, proliferation, and differentiation defects in complex I and antioxidant protein-depleted neuroblasts. Overexpression of antioxidant proteins and an increase in Notch signaling alleviated ROS and the complex I depletion-driven defect in neuroblast proliferation and differentiation. Complex I and mitochondrial fusion together restrict ROS to support neuroblast proliferation and differentiation.

Keywords:  Drosophila; Drp1; Notch; complex I; differentiation; mitochondria; mitochondrial fragmentation; mitochondrial fusion; neural stem cells; neuroblasts

DOI:  https://doi.org/10.1016/j.stemcr.2026.102951
J Cell Sci. 2026 Jun 08. pii: jcs.264795. [Epub ahead of print]

Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.

Ranran Mao, Jiaqi Zhai, Chunfang Tong, Wenfeng Fu, Dong Li, Jia-Jia Liu.

  In eukaryotic cells, organelles communicate through membrane contact sites-specialized regions where their membranes come into close apposition without fusing. Among these, contacts between the endoplasmic reticulum (ER) and the Golgi apparatus are critical for lipid trafficking and polarized sorting of protein cargoes, yet their regulation and physiological roles remain poorly understood due to limited research tools. Here, we developed genetically encoded biosensors that selectively label ER-Golgi contact sites by building upon split GFP/YFP systems. These fluorescent probes reliably detect ER-Golgi contacts whose formation depends on Golgi-enriched phosphatidylinositol 4-phosphate and the lipid transfer activity of Oxysterol-Binding Protein, and reveal the dynamic remodeling of these structures in live cells. Notably, the biosensors captured alterations in ER-Golgi contacts during cell division and ER stress, as well as their developmental loss in mammalian neurons. We propose these biosensors as powerful tools for investigating ER-Golgi interactions in response to physiological cues or pathological perturbations across diverse cell types.

Keywords:  Biosensor; Endoplasmic reticulum; Golgi; Membrane contact sites; Split GFP

DOI:  https://doi.org/10.1242/jcs.264795
J Cell Biol. 2026 Aug 03. pii: e202507174. [Epub ahead of print]225(8):

Mitochondria limit coenzyme Q export under cholesterol biosynthetic stress.

Marjana Ndoci, Sharanya Bhattacharya, Ishita Agrawal, Yvonne Hinze, Kathrin Lemke, Anna-Lena Schumacher, Esther Uijttewaal, Ulrich Elling, Steffen Lawo, Patrick Giavalisco, Thomas Langer, Soni Deshwal.

Coenzyme Q (CoQ) is a hydrophobic lipid primarily synthesized in the mitochondria, though it is also present in non-mitochondrial membranes. However, the metabolic pathways that regulate intracellular CoQ distribution are unknown. This study identifies a key role for the mevalonate pathway in regulating CoQ distribution. The mevalonate pathway synthesizes isopentenyl pyrophosphate (IPP) as the precursor metabolite for both CoQ and cholesterol. We show that CoQ synthesis remains stable regardless of whether the mevalonate pathway is upregulated or downregulated. Upregulation of HMG-CoA reductase (HMGCR), indicative of increased mevalonate flux, enhances cholesterol ester synthesis without altering CoQ levels. When the pathway is downregulated, cholesterol synthesis declines, yet mitochondrial CoQ levels are preserved. Under these limiting conditions, mitochondria reduce CoQ export to maintain their internal CoQ pool. While this adaptation sustains mitochondrial respiration, it diminishes extramitochondrial CoQ availability and sensitizes cells to ferroptosis. These findings uncover a mitochondria-driven mechanism that preserves respiratory function by prioritizing CoQ retention during metabolic stress.

DOI: https://doi.org/10.1083/jcb.202507174
bioRxiv. 2026 Jun 06. pii: 2026.06.04.730191. [Epub ahead of print]

Metformin Redirects Autophagy from Bulk Turnover to Mitochondrial Clearance.

Thuraya M Mutawi, Shweta R Malvankar, Andrea Graziani, Udita Shah, Khanh Nguyen, David G Broadbent, Zachary Clark, Michaella J Rekowski, Susan M Lunte, Carlo Barnaba.

Metformin is the most widely prescribed antidiabetic drug and an active candidate for repurposing in oncology. How it engages autophagy - a pathway central to both its metabolic and its anti-tumor effects - has remained unresolved, with reports of induction, suppression, and no effect. Here we show that metformin reroutes rather than induces or inhibits autophagy in human cancer cells: at therapeutic concentrations, it suppresses bulk cytosolic turnover by selectively blocking WIPI2-mediated phagophore tethering, while the ULK1 initiation complex relocates toward mitochondria and engages selective mitochondrial clearance. We trace this redirection to mitochondrial complex I inhibition, registered as a shift in the NAD + /NADH ratio before any change in the adenylate pool, and to a non-canonical reprogramming of the ULK1 complex that operates independently of mTORC1 and of the proposed PEN2-lysosomal route. AMPK is engaged in a subunit-specific manner that restrains ATG13 at initiation and enables WIPI2 displacement at maturation. The ULK1 complex is therefore the node at which metformin sets autophagic substrate selection, with direct implications for combination therapy in diabetes and cancer.

DOI: https://doi.org/10.64898/2026.06.04.730191
J Cell Biol. 2026 Aug 03. pii: e202603129. [Epub ahead of print]225(8):

Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.

Soumya Bhattacharyya, Jose Wojnacki, Nathalie Brouwers, Vivek Malhotra.

Procollagen I (PC1) is assembled into a trimer within the lumen of the endoplasmic reticulum (ER). In vitro, collagen trimers form rigid molecules reaching lengths of up to 400 nm, and this conformation is presumed to represent their assembled state in vivo. Here, we demonstrate that endogenous PC1 assembles into biomolecular condensates in the ER of activated human hepatic stellate cells. PC1 condensates form in response to increased collagen synthesis and are part of a multicomponent system enriched in the chaperones Hsp47 and calreticulin, as well as the disulfide isomerases PDIA1 and PDIA6, but notably lacking the unfolded protein sensor BiP. PC1 condensates localize to ER exit sites, a process mediated by TANGO1, and dissipate upon ER stress. We propose that this organization enables the accommodation of large quantities of PC1 in the ER lumen without triggering degradation. Furthermore, we suggest that PC1 within condensates is exported in a manner resembling liquid extrusion rather than as a rigid trimer.

DOI: https://doi.org/10.1083/jcb.202603129
Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515

STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.

Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.

  The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.

Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy

DOI:  https://doi.org/10.1016/j.celrep.2026.117515
Nature. 2026 Jun 10.

Mitochondria directly interact with the nuclear pore complex.

Ivan Menendez-Montes, Consuelo Marin-Vicente, Shibani Mukherjee, Mahmoud Salama Ahmed, Manuel Jose Gomez, Chukwuemeka George Anene-Nzelu, Chang Jie Mick Lee, Svenja Koslowski, Ashley Solmonson, Tara Tassin, Shah R Ali, Pedro Pessoa, Abdallah Elnwasany, Nicholas T Lam, Suwannee Thet, Enrique Calvo, Alisson C Cardoso, Ana Helena M Pereira, Feng Xiao, Ping Wang, Asim Mohamed, Hamed El-Feky, Ahmed Elghamry, Gonzalo Gancedo-Alonso, Ngoc Uyen Nhi Nguyen, Ching-Cheng Hsu, Aundrea K Westfall, Ralph DeBerardinis, Roger Sik-Yin Foo, Michael Kinter, Steve Pressé, Chao Xing, Luke Szweda, Asaithamby Aroumougame, Fatima Sanchez-Cabo, Jose Antonio Enriquez, Miguel Torres, Jesus Vazquez, Hesham A Sadek.

Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria-nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2-VDAC1 interacting amino acids resulted in reduced mitochondria-nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.

DOI: https://doi.org/10.1038/s41586-026-10588-3
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2523612123

A pericyte chloride clamp mechanism governs capillary control of cerebral blood flow.

Liuruimin Xiang, Ashwini Hariharan, Dominic Isaacs, Nick Weir, Thomas A Longden.

  Thin-strand pericytes cover the deepest reaches of the brain's capillary network, and their fine processes are intimately associated with adjacent endothelial cells (ECs). Recent work has revealed that thin-strand pericytes contribute to electrical signaling throughout the brain's vasculature by generating hyperpolarizing signals that can be transmitted over long distances to relax remote ensheathing pericytes around proximal branches of the capillary bed and smooth muscle cells (SMCs) around arterioles, thereby eliciting blood flow increases. Resetting hyperpolarizing events in thin-strand pericytes must involve the engagement of ion channels that carry depolarizing currents, but the channels that mediate such conductances are unknown. Here, we reveal that thin-strand pericytes of the mouse cortex express functional TMEM16A calcium (Ca2+)-activated chloride (Cl-) channels (CaCCs) encoded by the Ano1 gene, and we demonstrate that these are controlled by endoplasmic reticulum (ER) Ca2+ release through ryanodine receptors (RyRs) and inositol-1,4,5-trisphosphate (IP3) receptors (IP3Rs), and Ca2+ entry via plasmalemmal L- and T-type voltage-dependent Ca2+ channels (VDCCs). We show that the activity of thin-strand pericyte CaCCs plays a key role in tethering membrane potential close to ECl to regulate upstream arteriole diameter in vivo. We term this mechanism the pericyte "Cl- clamp," and we show that this functions to oppose hyperpolarizing electrical signaling and dilation under basal conditions and conversely opposes constriction under depolarizing conditions. We suggest that the operation of this VDCC-ER-CaCC unit is thus essential for optimal management of energy substrate delivery to local neurons.

Keywords:  Ano1; TMEM16A; capillaries; cerebral blood flow; pericytes

DOI:  https://doi.org/10.1073/pnas.2523612123
Biochem J. 2026 Jul 08. 483(7): 1193-1220

Mitophagy: an emerging therapeutic target in mitochondrial diseases.

Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.

  Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.

Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins

DOI:  https://doi.org/10.1042/BCJ20260161
FASEB J. 2026 Jun 15. 40(11): e71990

WNK4 Enhances Anti-PD-1 Resistance and Promotes Tumor Progression in Hepatocellular Carcinoma by Reprogramming Cysteine Metabolism in Cancer-Associated Fibroblasts.

Ge Yu, Yun-Long Cui, Han Mu, Dong-Ming Liu, Xu Bao, Hong-Yuan Zhou, Hui-Kai Li.

  Hepatocellular carcinoma (HCC) is the most prevalent subtype of primary liver cancer. Immunotherapy, particularly targeting immune checkpoints such as programmed cell death protein 1 (PD-1), has shown considerable therapeutic promise. Bioinformatic analysis of Gene Expression Omnibus datasets demonstrated significant upregulation of WNK lysine deficient protein kinase 4 (WNK4) expression in HCC tissues obtained from untreated patients or anti-PD-1 non-responders, suggesting a potential role for WNK4 in HCC progression and immunotherapy resistance. Through a series of experiments, we confirmed that WNK4 promoted the proliferative and migrative abilities of HCC cells and enhanced the resistance of HCC model mice to anti-PD-1 therapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), critically influences immunotherapy efficacy. The current study uncovered that WNK4 was transferred by HCC cell-derived exosomes into CAFs and promoted the cysteine metabolic reprogramming. Moreover, WNK4-mediated promotional effects of CAFs on the malignant phenotypes of HCC cells and anti-PD-1 resistance were in a cysteine-dependent manner. According to mechanism investigation, WNK4 could bind high mobility group box 1 (HMGB1) and induce its phosphorylation and cytoplasmic retention, thus reducing nuclear HMGB1-p53 interaction to enhance cystathionine gamma-lyase (CTH) expression. In summary, this study unveils a novel WNK4-HMGB1-p53 axis in CAFs that promotes HCC progression and modulates cysteine metabolism to foster immunotherapy resistance, offering potential therapeutic targets for HCC.

Keywords:  WNK lysine deficient protein kinase 4; anti‐PD‐1 resistance; cancer‐associated fibroblasts; exosome; hepatocellular carcinoma

DOI:  https://doi.org/10.1096/fj.202502777R
Biosens Bioelectron. 2026 Jun 06. pii: S0956-5663(26)00536-1. [Epub ahead of print]311 118904

Responsive NIR fluorescent probes targeting PKM2 with enzyme-activating properties for precision cancer diagnosis.

Yaling Zeng, Zujiang He, Shuangpeng Li, Wenfeng Liu, Qingjian Zou, Li-She Gan, Shuai Zha, Hongguang Li.

  Pyruvate kinase M2 (PKM2) serves as a crucial metabolic biomarker for tumor progression; however, distinguishing PKM2 from its highly homologous isoform PKM1 and dynamically monitoring its oligomeric state in living systems remain formidable challenges. Herein, we present two novel near-infrared (NIR) fluorescent probes, YL1 and YL2, designed by conjugating the PKM2-specific allosteric activator TEPP-46 with a green fluorescent protein (GFP)-chromophore-derived molecular rotor. Operating through a twisted intramolecular charge transfer (TICT) mechanism, these probes exhibit a highly sensitive "turn-on" NIR fluorescence response upon specific binding within the hydrophobic allosteric pocket of PKM2, which restricts their intramolecular rotation. Both probes demonstrate exceptional isoform selectivity over PKM1 and various biological interferents, boasting low detection limits (180 nM for YL1 and 210 nM for YL2) alongside ultra-fast, second-scale binding kinetics. Significantly, YL1 and YL2 function as potent fluorogenic agonists, effectively promoting the allosteric re-assembly of tumor-associated, inactive PKM2 dimers into active tetramers, thereby restoring pyruvate kinase activity. In live-cell imaging, the probes selectively illuminate PKM2-overexpressing cancer cells (HeLa, A549, and 4T1) with high contrast while remaining virtually silent in normal cells (HK-2, MCF-10A). Furthermore, their integration with flow cytometry facilitates rapid, quantitative, and high-throughput screening of malignant cell populations. Finally, in vivo imaging successfully visualizes tumor lesions in mouse models with high signal-to-noise ratios and deep tissue penetration. This multifunctional probe platform seamlessly integrates precision imaging, enzyme activation, and high-throughput cytometric screening, offering a powerful theranostic strategy for tracking metabolic reprogramming and facilitating early cancer diagnosis.

Keywords:  Flow cytometry; Fluorescent probe; High-throughput screening; Live-cell imaging; PKM2; Turn-on probe

DOI:  https://doi.org/10.1016/j.bios.2026.118904
PLoS One. 2026 ;21(6): e0350129

Lipid droplet associated protein HILPDA promotes hypoxia-induced ferroptosis by driving LPCAT3-mediated polyunsaturated phospholipids enrichment.

Zhenmei Song, Wenli Li, Jie Zeng, Xuexin Wang, Dezhi Wang, Xingchen Liao.

Each year, tens of millions of individuals sojourn to high-altitude environments (>2500 m), where they face the significant physiological challenge of hypoxia, a condition that often induces a range of gastrointestinal disorders. While our prior studies linked this damage to ferroptosis, the role of hypoxia-inducible lipid droplet-associated protein (HILPDA), a hypoxia inducible factor-1α/2α (HIF-1α/2α) downstream regulator, in this process remains unclear. This study aimed to explore the role and mechanism of HILPDA in regulating ferroptosis of normal human gastric and small intestinal epithelial cells (NGEC and HIEC) under hypoxic conditions. Our results found that overexpression of HIF-1α, HIF-2α, and HILPDA exacerbated hypoxia-induced cell death, which was reversed by the ferroptosis inhibitor ferrostatin-1. Knockdown of HIF-1α/2α inhibited HILPDA expression. Furthermore, knockdown of HILPDA led to a reduction of the hypoxia-induced lipid peroxidation, and the ferroptotic characteristics of cellular mitochondria observed under transmission electron microscopy. Conversely, HILPDA overexpression reversed the protective effects of HIF-1α/2α knockdown. Lipidomic analysis further revealed that HILPDA knockdown significantly decreased the levels of polyunsaturated fatty acid-phosphatidylcholines (PUFA-PCs) and phosphatidylethanolamines (PEs) under hypoxia. Compared to HIF-1α knockdown, HILPDA knockdown led to a slight difference in PUFA-PEs without significant difference in PCs and phosphatidylinositols (PIs) under hypoxia. Compared to HIF-2α knockdown, HILPDA knockdown resulted in negligible differences in PEs, PCs, and PIs. In addition, HILPDA knockdown downregulated Lysophosphatidylcholine Acyltransferase 3 (LPCAT3), and overexpression of LPCAT3 significantly attenuated the inhibitory effect of HILPDA knockdown on hypoxia-induced ferroptosis. In conclusion, HILPDA enhanced susceptibility to hypoxia-induced ferroptosis in NGEC and HIEC by enriching PUFA-containing phospholipids through LPCAT3. These findings identified the HIF-1α/2α-HILPDA-LPCAT3 axis as a pivotal pathway driving hypoxia-induced ferroptosis, therefore providing potential therapeutic targets for gastric and small intestinal mucosal injury associated with hypoxia.

DOI: https://doi.org/10.1371/journal.pone.0350129
Immunity. 2026 Jun 09. pii: S1074-7613(26)00218-9. [Epub ahead of print]59(6): 1493-1511

Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities.

Mingyang Yin, Tao Liang, Yumeng Zhang, Guangchuan Wang, Wei Yang, Chenqi Xu.

  All immune cells engage in cholesterol metabolism, which generates a spectrum of bioactive metabolites that mainly include cholesterol itself, its biosynthetic intermediates, and oxidized or sulfated derivatives. These metabolites regulate not only cellular metabolism but also immune signaling. In addition, several functional proteins within cholesterol metabolic pathways exert non-canonical signaling functions that shape immune cell responses. Distinct immune cell types adopt specialized cholesterol metabolic programs tailored to their functional demands, and these programs are further influenced by physiological factors such as diet and aging. In human disease, immune cell cholesterol metabolism is frequently dysregulated, which highlights metabolic intervention as a promising therapeutic strategy. Accordingly, the repurposing of established metabolic drugs such as statins and PCSK9 inhibitors is gaining momentum, alongside the identification of additional therapeutic targets. A deeper understanding of how cholesterol metabolism governs immune responses will advance fundamental immunology and accelerate the development of next-generation immunotherapies.

Keywords:  cholesterol metabolism; human diseases; immune cells; metabolic reprograming; therapeutic strategies

DOI:  https://doi.org/10.1016/j.immuni.2026.05.007