bims-celmim 2025-12-28 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–12–28
sixteen papers selected by
Marc Segarra Mondejar, AINA

Maintenance and Decline of Neuronal Lysosomal Function in Aging.
Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.
Multi-omics approach to dissect the significance of lipid metabolism in helper T cell subset.
The ACSL family: Bridging fatty acid metabolism and cell death in cancer progression.
A role for Fis1 in dendritic development.
Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.
Biosensors reveal subcellular redox status in live cells.
Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.
Mitochondrial control of fuel switching via carnitine biosynthesis.
Emerging nano-delivery systems for targeting mitochondria.
PIP2 corrects an endothelial Piezo1 channelopathy.
Targeting Ogt in ADPKD mitigates metabolic reprogramming and renal cystogenesis, extending survival.
Sirtuin 3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells by regulating macrophage polarization under high glucose.
The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
Mitochondrial VHL rewires cell metabolism in hypoxia.
LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson's disease.

Cells. 2025 Dec 12. pii: 1976. [Epub ahead of print]14(24):

Maintenance and Decline of Neuronal Lysosomal Function in Aging.

Ruiling Zhong, Claire E Richardson.

  Lysosomes are central effectors of cellular maintenance, integrating the degradation of damaged organelles and protein aggregates with macromolecule recycling and metabolic signaling. In neurons, lysosomes are particularly crucial due to the cells' long lifespan, polarized architecture, and high metabolic demands. Proper regulation of lysosomal function is essential to sustain proteostasis, membrane turnover, and synaptic integrity. Although lysosomal dysfunction has been extensively studied in neurodegenerative diseases, far less is known about how lysosomal capacity and function are maintained-or fail to be maintained-with age in non-diseased neurons. In this review, we summarize current understanding of neuronal lysosomal dynamics, discuss methodological challenges in assessing lysosomal capacity and function, and highlight recent advances that reveal age-associated decline in neuronal lysosomal competence.

Keywords:  TFEB; aging; autolysosome; autophagy; endolysosome; lysosome; neuron

DOI:  https://doi.org/10.3390/cells14241976
bioRxiv. 2025 Dec 10. pii: 2025.12.07.692828. [Epub ahead of print]

Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.

Jonathan K Yan, Ying Yang, Wenqi Wang.

Cancer metastasis is a leading cause of cancer-related deaths, while its underlying mechanisms remain incompletely understood. To colonize distant organs, cancer cells reprogram their metabolism to adapt to diverse environmental challenges. Therefore, elucidating the metabolic pathways that drive cancer metastasis will uncover novel biomarkers and therapeutic targets. In this study, we integrated published datasets and systematically analyzed metabolites across multiple cancer cell lines. This large-scale bioinformatic analysis revealed distinct metabolites and metabolic pathways associated with organ-specific metastasis, and underscored the crucial role of tissue of origin in shaping the metabolic landscape of metastatic tumors. Notably, the transsulfuration pathway (also known as the cysteine and methionine metabolism) was strongly enriched in cancer cells with high metastatic potential. We validated this finding in pancreatic cancer, where the pathway enzyme cystathionine β-synthase (CBS) and its metabolic products were highly expressed in metastatic cancer cells. Targeting the transsulfuration pathway either by methionine deprivation or pharmacological inhibition of CBS significantly impaired the migration and invasion of metastatic pancreatic cancer cells. Taken together, our study not only provides a global view of the altered metabolic landscape in metastasis, but also identifies the transsulfuration pathway as an oncogenic driver and a therapeutic target for pancreatic cancer metastasis.

DOI: https://doi.org/10.64898/2025.12.07.692828
Front Immunol. 2025 ;16 1708616

Multi-omics approach to dissect the significance of lipid metabolism in helper T cell subset.

Toshio Kanno, Keiko Nakano, Yukie Iwao, Yusuke Endo.

  The immunometabolism has fundamentally reshaped our understanding of T cell biology. Recent advances have demonstrated that metabolic reprogramming is not merely a consequence of T cell activation but a central driver of lineage specification and effector function. For example, quiescent naïve T cells primarily rely on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to meet baseline energy needs, whereas activation triggers a metabolic shift toward anabolic pathways dominated by aerobic glycolysis and de novo biosynthesis of macromolecules. Concurrently, the lipid metabolism confers extensive remodeling: activated T cells upregulate the pathways for de novo fatty acid synthesis and cholesterol biosynthesis, uptake, and storage to sustain membrane biogenesis and signal transduction. Conversely, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. This review reports recent advances by integrating experimental findings and methodological developments, highlighting how metabolic programs across distinct stages of T cell differentiation-with particular emphasis on the lipid metabolism-govern their specialized functions.

Keywords:  Acc1; T cell; Th17 and Treg cells; acetyl-CoA carboxylase 1; lipid metabolism; memory T cell; multi-omics

DOI:  https://doi.org/10.3389/fimmu.2025.1708616
Metabolism. 2025 Dec 18. pii: S0026-0495(25)00340-3. [Epub ahead of print]176 156470

The ACSL family: Bridging fatty acid metabolism and cell death in cancer progression.

Ziqi Yu, Lifeng Zhang, Bo Jiang, Lu Zhang, Minghui Chen, Mei Song.

  Fatty acids (FAs) are indispensable for cellular homeostasis and centered in anabolic and catabolic pathways that are tightly governed by long-chain acyl-CoA synthetases (ACSLs). These enzymes drive fatty acid β-oxidation (FAO) to generate energy, remodel cell membrane phospholipid composition to dictate ferroptosis susceptibility, coordinate steroidogenesis and eicosanoid biosynthesis, and mediate metabolic reprogramming, thus acting as a central nexus between FAs metabolism and cell death. Dysregulation of ACSLs across malignancies fosters oncogenic dependency on metabolic reprogramming, influencing tumor progression, immune modulation, and therapy resistance, offering a rationale for anticancer therapeutic opportunities. Here, we delineate the decisive roles of ACSLs in the metabolic fate of FAs and cell death execution. We dissect their tumorigenic mechanisms through metabolic rewiring and cell death modulation, with an emphasis on ACSLs-mediated crosstalk between ferroptosis and cancer immunity. Furthermore, we discuss the potential of ACSLs-targeted agents in tumor therapy and the treatment of ferroptosis-associated pathologies, offering actionable insights for clinical translation.

Keywords:  ACSL; Cancer therapy; Fatty acid metabolism; Ferroptosis; Regulated cell death

DOI:  https://doi.org/10.1016/j.metabol.2025.156470
Sci Rep. 2025 Dec 23.

A role for Fis1 in dendritic development.

Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.

Mitochondrial ATP production and calcium handling are critical for metabolic regulation and neurotransmission. Thus, the formation and maintenance of the mitochondrial network is a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously revealed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Therefore, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo, and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 activity regulates mitochondrial morphological and functional features that influence dendritic tree arborization and connectivity.

DOI: https://doi.org/10.1038/s41598-025-33557-8
bioRxiv. 2025 Dec 16. pii: 2025.12.12.693842. [Epub ahead of print]

Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.

Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.

Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains the highest energy phosphate bond above ATP, and has diverse biological functions, including glycolysis, gluconeogenesis, and glyceroneogenesis. Although PEP is generally considered a cytosolic intermediate, it can also be synthesized within mitochondria by the mitochondria-localized carboxykinase (PCK2, also known as M-PEPCK). However, the mechanism by which mitochondrial PEP is delivered to the cytosolic compartment and caters to cell-specific requirements remains elusive. Here, we identify SLC25A35, a previously uncharacterized mitochondrial inner-membrane protein, as the long-sought carrier responsible for mitochondrial PEP efflux. SLC25A35 is highly expressed in lipogenic cells, such as adipocytes, which employ the mitochondrial pyruvate-to-PEP bypass, and is upregulated by lipogenic stimuli. Reconstitution studies by proteo-liposomes, together with structural analyses, demonstrated specific PEP transport by SLC25A35 in a pH gradient-dependent manner. Importantly, loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, the glycerol backbone in triglyceride, resulting in reduced glycerolipid synthesis while preserving substrate oxidation in the TCA cycle. Furthermore, blockade of SLC25A35 in the liver of obese mice markedly decreased glycerolipid accumulation, ameliorated hepatic steatosis, and improved systemic glucose homeostasis. Together, the present study identifies mitochondrial PEP transport via SLC25A35 as a metabolic checkpoint of fatty acid esterification, offering a selective target for "lipogenic mitochondria" to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.

DOI: https://doi.org/10.64898/2025.12.12.693842
J Mol Cell Cardiol. 2025 Dec 20. pii: S0022-2828(25)00235-4. [Epub ahead of print]212 1-9

Biosensors reveal subcellular redox status in live cells.

Haoqi Li, Huimin Li, Yufan Chao, Yaozhao Li, Zijie Cheng, Yuqing Li, Yun Yin, Tao Chen, Xin Dong, Dan Wu, Qingxun Hu.

  Redox homeostasis is crucial for cellular function and signaling, with its disruption linked to various diseases. Given the compartment-specific nature of redox regulation, we employed highly responsive genetically encoded fluorescent sensors, including Hyper7, iNap, and roGFP2, to achieve real-time in situ tracking of the redox dynamics of H2O2, NADPH and GSH in the cytoplasm and mitochondria. It revealed that glycolysis and oxidative phosphorylation differentially modulate redox metabolites across subcellular domains, demonstrating metabolic pathway-specific regulation of redox equilibrium. Pathological modeling (cardiac hypertrophy, ischemia-reperfusion and cuproptosis) characterized mitochondrial redox systems exhibit superior stress-responsive regulation versus cytoplasmic counterparts, displaying enhanced dynamic responses during injury progression. These results suggest that precise subcellular redox mapping delivers critical insights into dynamic signal transduction mechanisms and proposes targeted therapeutic avenues for redox-associated pathologies through compartment-specific interventions.

Keywords:  Biosensors; Live-cell imaging; Pathophysiological conditions; Redox metabolism

DOI:  https://doi.org/10.1016/j.yjmcc.2025.12.009
bioRxiv. 2025 Dec 19. pii: 2025.12.18.695286. [Epub ahead of print]

Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.

Dengbao Yang, Gemma Molinaro, Nadine Nijem, Chuanhai Zhang, Dylen Penny, Meijuan Bai, Mei-Jung Lin, Xiaodong Wen, Salvador Pena, Janaka Wansapura, Maria Gaitanou, Rebecca Matsas, Boyuan Wang, Hamid Baniasadi, Yan Han, Jay Gibson, Kimberly Huber, Xing Zeng.

Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo . Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.

DOI: https://doi.org/10.64898/2025.12.18.695286
bioRxiv. 2025 Dec 20. pii: 2025.12.16.694762. [Epub ahead of print]

Mitochondrial control of fuel switching via carnitine biosynthesis.

Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Anthony Verkerke, Alexander Banks, Sheng Tony Hui, Lijun Sun, Jin-Seon Yook, Rose Witte, Shingo Kajimura.

Metabolic adaptation to environmental changes, such as fasting and cold exposure, involves a dynamic shift in fuel utilization from glucose to fatty acid oxidation, a process that relies on carnitine-mediated fatty acid oxidation in mitochondria. While dietary sources of animal origin (e.g., red meat) contribute to the carnitine pool, de novo carnitine synthesis from trimethyllysine (TML) is essential, particularly for those whose dietary sources are vegetables and fruits that contain negligible amounts of carnitine. However, the molecular pathway of de novo carnitine synthesis and its physiological significance remain poorly understood. Here, we showed that SLC25A45 is a mitochondrial TML carrier that controls de novo carnitine biosynthesis in vivo. Genetic loss of SLC25A45 results in systemic carnitine and acylcarnitine deficiency, leading to impaired fatty acid oxidation and thermogenesis during cold adaptation, while promoting glucose catabolism. Notably, Slc25a45-deficient mice maintained a high respiratory exchange ratio and impaired lipid mobilization following treatment with a GLP1 receptor agonist (GLP-1RA), rendering them resistant to GLP-1RA-induced adipose tissue loss. Together, the present study identifies SLC25A45 as a regulatory checkpoint in fuel switching during adaptation, with implications for systemic energy balance and response to GLP-1RA-mediated anti-obesity therapy.

DOI: https://doi.org/10.64898/2025.12.16.694762
Nanoscale. 2025 Dec 22.

Emerging nano-delivery systems for targeting mitochondria.

Agata N Burska, Kristina E Raish, Dinmukhamet Bayandy, Vesselin N Paunov.

This review aims to provide a comprehensive analysis of the potential of mitochondria-targeting nanosystems as a novel therapeutic approach for treating a wide range of diseases. It explores the underlying mechanisms of mitochondrial dysfunction in disease progression and shows how nanotechnology offers an innovative platform for delivering targeted therapies directly to mitochondria. We also highlight the role of mitochondria in cellular function and disease pathology particularly in cancer, followed by a consideration of the therapeutic potential of targeting these organelles. We explore the recent development and design principles of mitochondria-targeting nanosystems, assessing their applications and challenges and finally outline future research directions, emphasizing the importance of overcoming current limitations to expand the use of these nanosystems in medicine. This is intended to provide valuable insights into the promising connection of mitochondrial biology and nanotechnology, with the goal of advancing innovative treatments for various diseases.

DOI: https://doi.org/10.1039/d5nr03935e
Proc Natl Acad Sci U S A. 2025 Dec 30. 122(52): e2522750122

PIP2 corrects an endothelial Piezo1 channelopathy.

Ahmed M Hashad, Mohammad M Abd-Alhaseeb, Xin Rui Lim, Natalia M Mathieu, Osama F Harraz.

  Brain capillaries are sensors of neural activity. When a brain region is active, capillary endothelial cells (ECs) sense neuron-derived mediators and elicit a local increase in blood flow (functional hyperemia) to support the rise in metabolic needs. This hyperemic response involves a rapid electrical component and a slower chemical component that involves Gαq PCR (GqPCR) activation by agonists released from neurons. The intravascular forces associated with hyperemia engage mechanosensitive Piezo1-mediated signaling that serves a mechano-feedback control function to facilitate the return of elevated blood flow to basal levels. Whether GqPCR activity influences Piezo1 mechanosensitive signaling has not been explored, despite the potential significant implications of such crosstalk. Using patch-clamp electrophysiology and freshly isolated brain capillary ECs, we demonstrate that prostanoid or muscarinic GqPCR activation facilitates Piezo1 activity. Pharmacological studies revealed the involvement of Gαq and phospholipase C stimulation, as well as downstream phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis in Piezo1 activation, but not signaling triggered by metabolites of PIP2 hydrolysis. Exogenous application of nanomolar-to-micromolar PIP2 suppressed Piezo1 open probability. Brain capillary ECs from mouse models of Alzheimer's disease, cerebral small vessel disease, or Piezo1 gain-of-function mutation exhibited higher Piezo1 activity, that was corrected by exogenous ex vivo PIP2 application. We finally tested in vivo the hypothesis that systemic PIP2 administration restores functional hyperemia in EC-specific Piezo1 gain-of-function mutant mice suffering impaired blood flow. Our findings provide insights into Piezo1 channel regulation and how it affects neurovascular coupling and cerebral blood flow.

Keywords:  GqPCR; PIP2; Piezo1; cerebral blood flow; neurovascular coupling

DOI:  https://doi.org/10.1073/pnas.2522750122
bioRxiv. 2025 Dec 16. pii: 2025.12.14.693989. [Epub ahead of print]

Targeting Ogt in ADPKD mitigates metabolic reprogramming and renal cystogenesis, extending survival.

Matthew A Kavanaugh, Saleem Ahmad, Dona Greta Isai, Heather A L Riddell, Amanda P Assis, Chadhve Ranganathan, Aakriti Chaturvedi, Vincent Lam, Nikhitha Muthineni, Rayyan Abid, Jenna E Jurgensmeyer, Casey Blades, Michele T Pritchard, Madhulika Sharma, Darren P Wallace, Stephen C Parnell, Chad Slawson, Pamela V Tran.

Aberrant cell metabolism drives autosomal dominant polycystic kidney disease (ADPKD). O-GlcNAcylation, a metabolically regulated post-translational modification, is elevated in ADPKD kidneys. Using rapidly and slowly progressive ADPKD mouse models, we demonstrate that deleting O-GlcNAc transferase ( Ogt ) reduces renal cystogenesis and extends survival in a rapidly progressive model from postnatal day 21 to over a year. Pharmacological OGT inhibition similarly reduced cyst formation of patient-derived renal epithelial cells in vitro . In Pkd1 conditional knockout kidneys, Ogt deletion maintained phosphorylated AMPK and mitochondrial respiratory chain complex levels, preserving cellular energy sensing and production. Further, metabolomic analysis revealed normalization of glycolysis and of the hexosamine and hyaluronic acid biosynthesis pathways. In contrast, dysregulation of these pathways in Pkd1 conditional knockout kidneys culminated in increased tricarboxylic acid cycle entry, increased O-GlcNAc, and increased hyaluronic acid in the extracellular matrix, respectively. These findings identify Ogt as a central metabolic regulator and therapeutic target, linking metabolism to intracellular and extracellular mechanisms of cyst formation.

DOI: https://doi.org/10.64898/2025.12.14.693989
Sci Rep. 2025 Dec 25.

Sirtuin 3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells by regulating macrophage polarization under high glucose.

Linni Lin, Yijie Ren, Xia Wang, Hengxing Liang, Qianqian Yao.



Keywords:  Autophagy; Macrophage polarization; Mesenchymal stem cells; Osteogenic differentiation; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-025-33483-9
bioRxiv. 2025 Dec 16. pii: 2025.12.13.693635. [Epub ahead of print]

The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.

Bryanna Shao, Bartosz Kula, Han Le, Prasanna Venkhatesh, Prasanna Katti, Andrea G Marshall, Siddharth Chittaranjan, Suraj Thapilyal, Namdar Hari Kalpana, C Nivedya, Adam Roszczyk, Harrison Mobley, Mason Killion, Emelina St John, Pamela Martin, Benjamin Rodrigiuez, Markis' Hamilton, LaCara Bell, Sunjay M Wyckoff, Laurent A Moran, Mark Philips, David Hubert, Briar Tomeau, Jeremiah M Afolabi, Annet Kirabo, Ismary Blanco, Samantha Reasonover, Lauren E Drake, Ethan S Lippmann, Chantell Evans, Monica M Santisteban, Taneisha G Cheairs, Sepiso Mesenga, Celestine Wanjalla, Jennifer Gaddy, Ronald McMillan, Calixto P Hernandez Perez, Htet Htet Paing, Jenny C Schafer, Bret Mobley, Julia Berry, Amber Crabtree, Oleg Kovtun, Shawn Goodwin, Edgar Garza Lopez, Chandravanu Dash, Dao-Fu Dai, Tyne W Miller-Fleming, Antentor Hinton, Nathan A Smith.

Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.

DOI: https://doi.org/10.64898/2025.12.13.693635
Cell Metab. 2025 Dec 22. pii: S1550-4131(25)00527-3. [Epub ahead of print]

Mitochondrial VHL rewires cell metabolism in hypoxia.

Guobang Li, Wenfeng Pan, Long Wu, Zhiliang Cai, Haoming Chen, Xingui Wu, Tiantian Yu, Kun Liao, Hui Zhang, Xingqiao Wen, Bo Li.

  Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated α subunits of hypoxia-inducible factors (HIFs) for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here, we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits 3-methylcrotonyl-coenzyme A carboxylase subunit 2 (MCCC2), an essential subunit of the leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and protein arginine methyltransferase 5 (PRMT5)-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of ischemic injury and functionally associated with VHL mutations in cancer. Our study highlights VHL as a bona fide regulator of hypoxic metabolism within mitochondria, rather than a solely "standby adaptor" for HIFs under hypoxia.

Keywords:  VHL; hypoxia; leucine; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.11.013
Brain Res. 2025 Dec 19. pii: S0006-8993(25)00682-1. [Epub ahead of print] 150119

LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson's disease.

Jinzhao Gao, Kunpeng Qin, Wenke Xian, Jiwen Ren, Anmu Xie, Binghui Hou.

  Leucine-rich repeat neuronal protein 3 (LRRN3) is a multifunctional transmembrane protein with a crucial role in intracellular signal transduction. It is expressed at high levels in neurons. LRRN3 expression has been shown to be associated with Parkinson's disease (PD) and aging. It is involved in regulating cellular energy metabolism. However, the specific mechanism involved remains undetermined. In this study, we investigated whether LRRN3 can regulate the expression of the key glycolytic enzymes HK2 and LDHA as well as lactate levels. We also studied the expression of the apoptosis-related regulatory factors Bax and Bcl-2 and the mitochondrial structure. We found that LRRN3 can inhibit the expression of HK2 and LDHA and reduce lactate levels in PD models. LRRN3 rescued apoptotic cells, reversed mitochondrial structure damage, and alleviated motor deficits in PD mice. When glycolysis was inhibited in mice treated with 2-deoxy-D-glucose, apoptosis, mitochondrial structure damage, and motor deficits were reversed. Mechanistically, LRRN3 targets and inhibits glycolytic enzymes to enhance lactate homeostasis, ultimately exerting a protective effect on dopaminergic (DA) neurons. Our data indicate that LRRN3 can protect DA neurons by suppressing glycolysis. It holds promise as a potential therapeutic target for PD.

Keywords:  Aerobic glycolysis; Apoptosis; LRRN3; Lactate; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.brainres.2025.150119