bims-nenemi 2025-02-23 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–02–23
seventeen papers selected by
Marco Tigano, Thomas Jefferson University

Compositionally unique mitochondria in filopodia support cellular migration.
How are mitochondrial nucleoids trafficked?
Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Elevated expression of Piezo1 activates the cGAS-STING pathway in chondrocytes by releasing mitochondrial DNA.
Deciphering Phase-Separated Mitochondrial RNA Granules under Stress Conditions with the Mitoribosome-Targeting Small Molecule.
Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.
Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
A novel biosensor for the spatiotemporal analysis of STING activation during innate immune responses to dsDNA.
Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia.
Necrosis drives susceptibility to Mycobacterium tuberculosis in PolgD257A mutator mice.
Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.
Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.

Curr Biol. 2025 Feb 14. pii: S0960-9822(25)00125-3. [Epub ahead of print]

Compositionally unique mitochondria in filopodia support cellular migration.

Madeleine Marlar-Pavey, Daniel Tapias-Gomez, Marcel Mettlen, Jonathan R Friedman.

  Local metabolic demand within cells varies widely, and the extent to which individual mitochondria can be specialized to meet these functional needs is unclear. We examined the subcellular distribution of the mitochondrial contact site and cristae organizing system (MICOS) complex, a spatial and functional organizer of mitochondria, and discovered that it dynamically enriches at the tip of a minor population of mitochondria in the cell periphery. Based on their appearance, we term these mitochondria "METEORs". METEORs have a unique composition, and MICOS enrichment sites are depleted of mtDNA and matrix proteins and contain high levels of the Ca2+ uniporter MCU, suggesting a functional specialization. METEORs are also enriched for the myosin MYO19, which promotes their trafficking to a small subset of filopodia. We identify a positive correlation between the length of filopodia and the presence of METEORs and show that elimination of mitochondria from filopodia impairs cellular motility. Our data reveal a novel type of mitochondrial heterogeneity and suggest compositionally specialized mitochondria support cell migration.

Keywords:  MCU; MICOS; MYO19; calcium; cristae; filopodia; migration; mitochondria; organelle

DOI:  https://doi.org/10.1016/j.cub.2025.01.062
Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]

How are mitochondrial nucleoids trafficked?

Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.

  Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.

Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence

DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
Nature. 2025 Feb 19.

Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.

Kate McArthur, Michael T Ryan.



Keywords:  Cell biology

DOI:  https://doi.org/10.1038/d41586-025-00303-z
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.

Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.

  Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
Nat Commun. 2025 Feb 17. 16(1): 1696

Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype.

Joae Joung, Yekang Heo, Yeonju Kim, Jaejin Kim, Haebeen Choi, Taerang Jeon, Yeji Jang, Eun-Jung Kim, Sang Heon Lee, Jae Myoung Suh, Stephen J Elledge, Mi-Sung Kim, Chanhee Kang.

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU. Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.

DOI: https://doi.org/10.1038/s41467-025-56929-0
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Osteoarthritis Cartilage. 2025 Feb 18. pii: S1063-4584(25)00818-0. [Epub ahead of print]

Elevated expression of Piezo1 activates the cGAS-STING pathway in chondrocytes by releasing mitochondrial DNA.

Lin Sun, Yao Wang, Tianyou Kan, Han Wang, Junqi Cui, Liao Wang, Chenglei Liu, Hanjun Li, Zhifeng Yu, Mengning Yan.

   OBJECTIVE: Abnormal mechanical stress is a key factor in osteoarthritis (OA) pathogenesis. This study aims to investigate the role of the mechanosensitive ion channel Piezo1 in activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and its contribution to cartilage degradation in OA.
METHODS: We conducted both in vivo and in vitro experiments. In vitro, chondrocytes were subjected to mechanical stress, and Piezo1 expression, calcium ion (Ca2+) influx, and mitochondrial permeability changes were analyzed. In vivo, Piezo1 conditional knockout (Col2a1CreERT; Piezo1flox/flox) mice were used to assess the activation of the cGAS-STING pathway and cartilage degradation. Additionally, the effects of STING inhibitors on inflammation and OA progression were evaluated.
RESULTS: Mechanical stress significantly increased Piezo1 expression and Ca2+ influx in chondrocytes, leading to mitochondrial Ca2+ overload and mtDNA release. This triggered activation of the cGAS-STING pathway (9.35[95%CI 1.378 to 18.032], n=3 biologically independent samples), resulting in inflammatory responses (4.185[95%CI 0.411 to 8.168], n=3 biologically independent samples). In Piezo1 knockout mice, cGAS-STING activation (-7.23[95%CI -10.52 to -3.89], n=6) and cartilage degradation (OARSI grade; -3.651[95%CI -5.562 to -1.681] n=6) were reduced. STING inhibitors effectively decreased inflammation (-8.95[95%CI -17.24 to -1.31], n=3 biologically independent samples) and slowed OA progression (OARSI grade; -2.76 [95%CI -4.37 to -1.08], n=6) in both in vivo and in vitro models.
CONCLUSIONS: Mechanical stress induces mtDNA release via Piezo1 activation, which triggers the cGAS-STING pathway and exacerbates cartilage degradation. Targeting Piezo1 or the cGAS-STING pathway may offer a promising therapeutic strategy to reduce inflammation and protect cartilage in OA.

Keywords:  Piezo1; cGAS-STING pathway; mechanical stress; mitochondrial DNA; osteoarthritis

DOI:  https://doi.org/10.1016/j.joca.2025.02.778
Anal Chem. 2025 Feb 19.

Deciphering Phase-Separated Mitochondrial RNA Granules under Stress Conditions with the Mitoribosome-Targeting Small Molecule.

Gui-Xue Tang, Shu-Tang Zeng, Jian Wang, Jia-Tong Yan, Shuo-Bin Chen, Zhi-Shu Huang, Xiu-Cai Chen, Jia-Heng Tan.

RNA granules are liquid-liquid-phase-separated condensates comprising RNA and proteins. Despite growing insights into their biological functions, studies have predominantly relied on biological methodologies lacking adequate chemical tools. Here, we introduce ICP-CHARGINGS, a concept for efficiently identifying chemical probes to characterize RNA granules of interest among nucleic acid-targeting agents. Focusing on mitochondrial RNA granules (MRGs), whose functions remain elusive, we developed a methodology within this framework and identified NATA, a new fluorescent molecule that, following mechanistic studies, was found to bind to the mitoribosome, enabling MRG labeling and recognition. Using NATA to reveal the potential buffering roles of MRGs, we demonstrated a close correlation between MRG maintenance and assembly and cellular survival and proliferation under cold shock and hypoxic stress. Overall, the introduction and implementation of the ICP-CHARGINGS strategy provide a specialized chemical tool for advancing our comprehension of MRG biology and establish a paradigm for elucidating RNA structures within RNA granules that can be targeted by small molecules, paving the way for developing tailored chemical probes for diverse RNA granules in future research.

DOI: https://doi.org/10.1021/acs.analchem.4c05506
bioRxiv. 2025 Feb 08. pii: 2025.02.07.637120. [Epub ahead of print]

Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production.

Kimberly S Huggler, Carlos A Mellado Fritz, Kyle M Flickinger, Gavin R Chang, Meghan F McGuire, Jason R Cantor.

Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.

DOI: https://doi.org/10.1101/2025.02.07.637120
Nature. 2025 Feb 19.

Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.

Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.

Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.

DOI: https://doi.org/10.1038/s41586-025-08590-2
EMBO J. 2025 Feb 21.

A novel biosensor for the spatiotemporal analysis of STING activation during innate immune responses to dsDNA.

Steve Smarduch, Sergio David Moreno-Velasquez, Doroteja Ilic, Shashank Dadsena, Ryan Morant, Anja Ciprinidis, Gislene Pereira, Marco Binder, Ana J García-Sáez, Sergio P Acebrón.

  The cGAS-STING signalling pathway has a central role in the innate immune response to extrinsic and intrinsic sources of cytoplasmic dsDNA. At the core of this pathway is cGAS-dependent production of the intra- and extra-cellular messenger cGAMP, which activates STING and leads to IRF3-dependent expression of cytokines and interferons. Despite its relevance to viral and bacterial infections, cell death, and genome instability, the lack of specific live-cell reporters has precluded spatiotemporal analyses of cGAS-STING signalling. Here, we generate a fluorescent biosensor termed SIRF (STING-IRF3), which reports on the functional interaction between activated STING and IRF3 at the Golgi. We show that cells harbouring SIRF react in a time- and concentration-dependent manner both to STING agonists and to microenvironmental cGAMP. We demonstrate that the new biosensor is suitable for single-cell characterisation of immune responses to HSV-1 infection, mtDNA release upon apoptosis, or other sources of cytoplasmic dsDNA. Furthermore, our results indicate that STING signalling is not activated by ruptured micronuclei, suggesting that other cytosolic pattern recognition receptors underlie the interferon responses to chromosomal instability.

Keywords:  Biosensor; Innate Immune Response; Micronuclei; cGAMP; cGAS-STING Signalling

DOI:  https://doi.org/10.1038/s44318-025-00370-y
bioRxiv. 2025 Jan 31. pii: 2024.12.21.629919. [Epub ahead of print]

Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.

Jorge L Cueva-Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.

DOI: https://doi.org/10.1101/2024.12.21.629919
Metabolism. 2025 Feb 15. pii: S0026-0495(25)00030-7. [Epub ahead of print]166 156161

Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia.

Feng-Qing Huang, Hong-Fei Wang, Tong Yang, Dai Yang, Peian Liu, Raphael N Alolga, Gaoxiang Ma, Baolin Liu, An Pan, Shi-Jia Liu, Lian-Wen Qi.

  The brain is rich in lipids, and disorders or abnormalities in lipid metabolism can induce neurotoxicity. Ceramides are the central intermediates of sphingolipid metabolism. This study was designed to investigate the potential lipotoxicity of ceramides in brain ischemia. First, a pseudo-targeted lipidomics analysis of plasma samples from stroke patients found significantly elevated levels of long-chain ceramides. A similar observation was made in mice subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. In cultured cells, it was found that the altered ceramides were mainly derived from astrocytes via de novo pathway, and SPTLC2 was a key regulator because Sptlc2 knockdown largely blocked ceramide production. Ceramides induced astrocyte activation and triggered oxidative stress to impair mitochondrial homeostasis by increasing mitochondrial permeabilization. Moreover, ceramides triggered the formation of voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane, through which mtDNA was released into the cytoplasm. Similar to oxygen and glucose depletion treatment, ceramides also increased cGAS activity and STING protein expression. However, this activity was diminished in the presence of the mitochondrial ROS scavenger SKQ1, indicating the involvement of oxidative stress in ceramide action. By facilitating cGAS/STING signaling cascades, ceramides resultantly induced interferon response to aggravate inflammatory damage in the ischemic brain. To address the impact of ceramides on brain ischemic injury in vivo, ceramide generation was blocked in the brain by injection of AAV9-Sptlc2 shRNA in pMCAO mice. Sptlc2 knockdown in the brain reduced ceramide generation and attenuated brain ischemic damage with astrocyte inactivation. As expected, Sptlc2 deficiency effectively blocked cGAS/STING pathway-dependent interferon responses. Together, these findings suggest a new therapeutic strategy for pharmacological intervention to attenuate neuroinflammation.

Keywords:  Astrocytes; Brain ischemia; Ceramides; Oxidative stress; cGAS/STING pathway

DOI:  https://doi.org/10.1016/j.metabol.2025.156161
Infect Immun. 2025 Feb 19. e0032424

Necrosis drives susceptibility to Mycobacterium tuberculosis in PolgD257A mutator mice.

C J Mabry, C G Weindel, L W Stranahan, J J VanPortfliet, J R Davis, E L Martinez, A P West, K L Patrick, R O Watson.

  The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity, and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection time point, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected PolgD257A mice, and PolgD257A mutator macrophages are hypersusceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

Keywords:  Mycobacterium tuberculosis; Polg; innate immunity; necrosis

DOI:  https://doi.org/10.1128/iai.00324-24
J Mol Neurosci. 2025 Feb 17. 75(1): 23

Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.

Gengxin Lu, Junyu Wu, Zhihui Zheng, Zhezhi Deng, Xue Xu, Xintian Li, Xiaoqiu Liang, Weiwei Qi, Shifeng Zhang, Yuemin Qiu, Minping Li, Junjie Guo, Haiwei Huang.

  Radiation brain injury (RBI) is a complication of cranial tumor radiotherapy that significantly impacts patients' quality of life. Astrocyte-secreted vascular endothelial growth factor (VEGF) disrupts the blood-brain barrier (BBB) in RBI. However, further studies are required to elucidate the complex molecular mechanisms involved. Reactive oxygen species (ROS) are closely linked to VEGF pathway regulation, with excessive ROS potentially disrupting this pathway. Mitochondria, the primary ROS-producing organelles, play a crucial role under irradiation. Our findings suggest that irradiation activates astrocytes with altered polarity, generating both cellular and mitochondrial ROS. Concurrently, mitochondrial morphology and function are disrupted, leading to defective mitophagy and an accumulation of damaged mitochondria, which further exacerbates ROS damage. Urolithin A (UA) is a natural activator of mitophagy. We found that UA promoted mitophagy in irradiated astrocytes, reduced cellular and mitochondrial ROS, restored mitochondrial morphology and function, reversed VEGF overexpression, and attenuated the disruption of endothelial tight junction proteins in endothelial cells cultured with irradiated astrocyte supernatants. In conclusion, our study identifies a connection between impaired mitophagy and VEGF overexpression in radiation-induced astrocytes. We also demonstrated UA may serve as a therapeutic strategy for protecting the tight junction protein in RBI by enhancing mitophagy, reducing ROS accumulation, and downregulating VEGF expression.

Keywords:  Astrocyte; Mitophagy; Radiation-induced brain injury; Urolithin A; VEGF

DOI:  https://doi.org/10.1007/s12031-024-02302-7
Cell Death Dis. 2025 Feb 19. 16(1): 116

Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.

Mengfei Yao, Xingming Zhang, Tianqi Wu, Tao Feng, Xiaojie Bian, Mierxiati Abudurexiti, Wenfeng Wang, Guohai Shi, Gong-Hong Wei, Qin Zhang, Xiangyun Li, Gang Feng, Leilei Du, Jianhua Wang.

Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors; however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.

DOI: https://doi.org/10.1038/s41419-025-07449-8
Cell Prolif. 2025 Feb 21. e70002

Mitochondrial Mutation Leads to Cardiomyocyte Hypertrophy by Disruption of Mitochondria-Associated ER Membrane.

Miao Yu, Min Song, Manna Zhang, Shuangshuang Chen, Baoqiang Ni, Xuechun Li, Wei Lei, Zhenya Shen, Yong Fan, Jianyi Zhang, Shijun Hu.

  m.3243A>G is the most common pathogenic mtDNA mutation. High energy-demanding organs, such as heart, are usually involved in mitochondria diseases. However, whether and how m.3243A>G affects cardiomyocytes remain unknown. We have established patient-specific iPSCs carrying m.3243A>G and induced cardiac differentiation. Cardiomyocytes with high m.3243A>G burden exhibited hypertrophic phenotype. This point mutation is localised in MT-TL1 encoding tRNALeu (UUR). m.3243A>G altered tRNALeu (UUR) conformation and decreased its stability. mtDNA is essential for mitochondrial function. Mitochondria dysfunction occurred and tended to become round. Its interaction with ER, mitochondria-associated ER membrane (MAM), was disrupted with decreased contact number and length. MAM is a central hub for calcium trafficking. Disrupted MAM disturbed calcium homeostasis, which may be the direct and leading cause of cardiomyocyte hypertrophy, as MAM enforcement reversed this pathological state. Considering the threshold effect of mitochondrial disease, mito-TALENs were introduced to eliminate mutant mitochondria and release mutation load. Mutation reduction partially reversed the cellular behaviour and made it approach to that of control one. These findings reveal the pathogenesis underlying m.3243A>G from perspective of organelle interaction, rather than organelle. Beyond mitochondria quality control, its proper interaction with other organelles, such as ER, matters for mitochondria disease. This study may provide inspiration for mitochondria disease intervention.

Keywords:  cardiomyocyte hypertrophy; induced pluripotent stem cell; mitochondrial mutation; mitochondria‐associated ER membrane

DOI:  https://doi.org/10.1111/cpr.70002