bims-mihora 2025-12-07 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–12–07
fourteen papers selected by
Lisa Patel, Istesso

Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.
Photobiomodulation stimulates mitochondrial function and cell proliferation in meniscus-derived stem cells (MeSCs) via activation of TRPV1 channel.
Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan.
Sequential Mitochondrial Transplantation for Myocardial Ischemia-Reperfusion Injury Treatment.
Protective Effects of Standardized Peucedanum Japonicum Thunb. Extract Against UVB-Induced Corneal Epithelial Apoptosis via Mitochondrial Regulation.
Exposure to polystyrene nanoparticles induce disruption of mitochondrial homeostasis and impairs trophoblast cell invasion and migration via MDM2/ROCK1 pathway.
Critical role of mitochondrial aconitase in skeletal muscle maturation.
Integrated multi-omics and machine learning elucidate the pathogenic role of mitophagy in osteoarthritis and identify novel therapeutic strategies.
Identification of Mitochondrial Unfolded Protein Response-Related Genes and Diagnostic Biomarkers in Atherosclerosis by Integrative Multidimensional Analysis and Experimental Validation.
Mechanisms and treatment modalities related to premature ovarian insufficiency in mitochondria: literature review.
Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
Mitochondria in pyroptosis: Mechanisms and implications.
Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.

J Clin Invest. 2025 Dec 01. pii: e187571. [Epub ahead of print]135(23):

Dysfunctional LHX6 pallido-subthalamic projections mediate epileptic events in a mouse model of Leigh syndrome.

Laura Sánchez-Benito, Melania González-Torres, Irene Fernández-González, Laura Cutando, María Royo, Joan Compte, Miquel Vila, Sandra Jurado, Elisenda Sanz, Albert Quintana.

  Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease, a group of untreatable and usually fatal disorders. Refractory epileptic events are a common neurological presentation of mitochondrial disease, including Leigh syndrome, a severe form of mitochondrial disease associated with epilepsy. However, the neuronal substrates and circuits for mitochondrial disease-induced epilepsy remain unclear. Here, using mouse models of Leigh syndrome that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrated that mitochondrial dysfunction leads to a reduction of GABAergic neurons in the rostral external globus pallidus (GPe) and identified a specific affectation of pallidal Lhx6-expressing inhibitory neurons contributing to altered GPe excitability. Our findings revealed that viral vector-mediated Ndufs4 reexpression in the GPe effectively prevented seizures and improved survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in epilepsy development in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with mitochondrial disease, providing promising leads in the quest to identify effective treatments.

Keywords:  Epilepsy; Inflammation; Mitochondria; Mouse models; Neuroscience

DOI:  https://doi.org/10.1172/JCI187571
Sci Rep. 2025 Dec 04. 15(1): 43131

Photobiomodulation stimulates mitochondrial function and cell proliferation in meniscus-derived stem cells (MeSCs) via activation of TRPV1 channel.

Jiabei Tong, Xiaoyun Wu, Zifan Wang, Xiujuan Li, Yang Yu, Zhong Zhang, Zhaohui Zheng, Tan Huang, Zhijie Ma.

  The meniscus is a crescent-shaped knee structure that helps stabilize the joint. This study investigates the molecular mechanism of photobiomodulation (PBM) at various wavelengths (400-405, 500-505, 700-710 and 1064 nm) and energy densities (3, 15, 30 and 60 J/cm2) affects mitochondrial function and cell proliferation in Meniscus-derived stem cells (MeSCs). We used LED light to irradiate human MeSCs and assessed intracellular calcium (Ca2⁺), cytochrome C oxidase (CCO) activity, nitric oxide (NO) concentrations, cell viability, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and cell proliferation. The results showed that intracellular Ca2⁺ levels and ROS production increased as PBM energy density increased, whereas CCO activity and NO concentration remained unchanged. Irradiation at 700-710 and 1064 nm with energy densities of 3, 15, and 30 J/cm2 improved proliferation and of MeSCs, with the most significant effect at 15 J/cm2. However, all other PBM conditions reduced mitochondrial function and proliferative capacity. Inhibition of transient receptor potential vanilloid 1 (TRPV1) Ca2+ channel reduced PBM-induced elevations in Ca2+ and ROS at all wavelengths and prevented the associated changes in proliferation. These findings establish a dose-dependent effect of PBM on MeSCs mediated by TRPV1-Ca2⁺-ROS signaling and support its potential application in cytotherapy.

Keywords:  Intracellular calcium; Meniscus-derived stem cells; Photobiomodulation; Proliferation; Reactive oxygen

DOI:  https://doi.org/10.1038/s41598-025-27040-7
Nat Commun. 2025 Dec 04. 16(1): 10909

Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.

Cindy Dong, Alison Finigan, Nichola Figg, Benjamin Jenkins, Albert Koulman, Suvagata R Chowdhury, Anne-Marie Tricolici, Jordi Lambert, Sebnem Oc, Helle F Jørgensen, Julien Prudent, Michael P Murphy, Martin Bennett, Emma Yu.

Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth's Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.

DOI: https://doi.org/10.1038/s41467-025-65873-y
bioRxiv. 2025 Nov 17. pii: 2025.04.14.648769. [Epub ahead of print]

Engineering ATP Import in Yeast Uncovers a Synthetic Route to Extend Cellular Lifespan.

Naci Oz, Hetian Su, Vedat Sari, Praveen Patnaik, Rohil Hameed, Jong Hee Song, Derek C Prosser, Vyacheslav M Labunskyy, Vadim N Gladyshev, Nan Hao, Alaattin Kaya.

Aging results from the gradual accumulation of molecular damage as a result of cellular processes and is characterized by impaired functions, most notably an age-related decline in ATP production. However, the causal relationship between cellular ATP homeostasis and aging has not been established. In this study, we used a novel approach by harnessing a nucleotide transporter from a eukaryotic intracellular parasite to facilitate the direct import of extracellular ATP into budding yeast cells, enabling us to effectively manipulate their intracellular ATP levels. We found that depletion of ATP significantly reduces lifespan, while the supplementation of ATP in the growth medium fully restores it thereby extending lifespan. Moreover, gene expression analysis revealed that elevated ATP levels inhibit catabolic processes, indicating a suppression of glucose metabolism. Overall, our study revealed the direct impact of cellular ATP homeostasis on lifespan regulation that has never been directly tested before. This work offers new insights into the bioenergetic control of aging and positions energy metabolism as a promising target for longevity interventions.
Significance: Cellular energy homeostasis is a crucial factor in determining the health and longevity of organisms. While intracellular ATP levels are tightly regulated, the idea that cells can directly take in extracellular ATP to influence metabolism has not been thoroughly explored. In this study, we engineered yeast cells to import external ATP and demonstrated that this approach significantly alters mitochondrial function, metabolic flow, and aging processes. Our findings show that ATP uptake inhibits catabolic pathways and enhances mitochondrial maintenance, thereby extending cellular lifespan through a novel and non-traditional mechanism. This research reveals an unexpected degree of metabolic flexibility and introduces a synthetic biology-based method to reprogram energy metabolism and longevity. The principles established in this study provide a new framework for understanding the role of cellular bioenergetics in aging, highlighting how the modulation of ATP availability can impact metabolic states and lifespan regulation.

DOI: https://doi.org/10.1101/2025.04.14.648769
ACS Nano. 2025 Nov 30.

Sequential Mitochondrial Transplantation for Myocardial Ischemia-Reperfusion Injury Treatment.

Ziyu Wu, Zichun Zhao, Ronghuang Yu, Yuning Sun, Wenyan Guo, Jun Wang, Chun Mao, Mimi Wan, Min Zhou.

  The treatment of myocardial ischemia-reperfusion injury (IRI) requires urgent improvement of mitochondrial dysfunction and sustained energy supply to restore cardiac function, but currently, there is a lack of effective strategies to meet these needs. Here, we transplanted mitochondria to treat myocardial IRI by a sequential administration approach. First, nanomotors with chemotactic target ability are modified on the surface of mitochondria to obtain engineered mitochondrial nanomotors. Then, denatured bovine serum albumin is modified outside the nanomotor, enabling mitochondria to hitchhike on activated neutrophils to accumulate in the damaged heart. During reperfusion, immediate intramyocardial injection of these mitochondria can stabilize energy supply and rescue dying cardiomyocytes from IRI. In the subsequent tissue repair stage, the mitochondria injected intravenously can achieve stepwise targeting to the damaged heart by hitchhiking on activated neutrophils and chemotactic behavior of nanomotors, thereby continuously supplementing energy to cardiomyocytes and enhancing cardiac function. In addition, in vivo results show that sequential administration reduces adverse reactions such as arrhythmia caused by high-dose mitochondrial transplantation. Compared with existing treatment methods, this design of sequential administration is a special strategy targeting the specific needs and inflammatory microenvironment of myocardial IRI, better promoting the clinical translation of mitochondrial transplantation.

Keywords:  mitochondrial transplantation; myocardial ischemia-reperfusion injury; nanomotor; neutrophil hitchhiking; sequential therapy

DOI:  https://doi.org/10.1021/acsnano.5c10203
Front Biosci (Landmark Ed). 2025 Nov 27. 30(11): 46498

Protective Effects of Standardized Peucedanum Japonicum Thunb. Extract Against UVB-Induced Corneal Epithelial Apoptosis via Mitochondrial Regulation.

Hye-Sun Lim, Young-Sik Yoo, Gunhyuk Park, Sunoh Kim.

   BACKGROUND: Ultraviolet B (UVB) irradiation is a major environmental factor causing corneal epithelial cell apoptosis, leading to ocular surface damage and vision impairment.
OBJECTIVE: This study aimed to investigate whether the standardized extract of Peucedanum japonicum Thunb. (SBP) protects corneal cells from UVB-induced apoptosis and explore its mitochondrial regulatory mechanisms.
METHODS: Corneal epithelial cells were exposed to UVB irradiation, with or without treatment with SBP extract or its fractions. Nicotinamide adenine dinucleotide dehydrogenase activity, mitochondrial membrane potential, and mitochondrial morphology were assessed, and apoptosis-related proteins were analyzed using a cytokine antibody array kit. In vivo mouse models were also used to evaluate corneal damage following UVB exposure.
RESULTS: The SBP extract, particularly the n-butanol (n-BuOH) fraction, significantly attenuated UVB-induced mitochondrial dysfunction and reduced apoptosis. Treatment restored mitochondrial membrane potential and improved corneal morphology in UVB-exposed mice. Chlorogenic acid, a major active compound, exhibited similar protective effects. The n-BuOH fraction demonstrated protective effects comparable to those of chlorogenic acid.
CONCLUSIONS: SBP protects corneal cells from UVB-induced apoptosis through mitochondrial stabilization, suggesting its potential as a therapeutic agent for ocular surface disorders.

Keywords:  apoptosis; corneal diseases; mitochondria; peucedanum japonicum; ultraviolet rays

DOI:  https://doi.org/10.31083/FBL46498
PLoS One. 2025 ;20(12): e0337568

Exposure to polystyrene nanoparticles induce disruption of mitochondrial homeostasis and impairs trophoblast cell invasion and migration via MDM2/ROCK1 pathway.

Dongdong Hao, Tengteng Ma, Xiaoping Li, Fengchun Gao.

BACKGROUND: Polystyrene nanoparticles (PS-NPs) are recognized as environmental pollutants with potential reproductive toxicity. This study delves into the impacts of PS-NPs exposure on trophoblast cells, specifically examining mitochondrial dysfunction, cell invasion and migration.
METHODS: Trophoblast cells were exposed to PS-NPs to evaluate the effects on cell proliferation, apoptosis, mitochondrial function (including mitochondrial membrane potential, intracellular ROS levels, and gene expression), autophagy, inflammatory responses and cell motility. Co-immunoprecipitation and Western blotting analyses were employed to assess the expressions and interactions of MDM2 and ROCK1 under PS-NPs exposure conditions.
RESULTS: We observed that PS-NPs exposure impaired trophoblast cell proliferation, promoted apoptosis, and disrupted mitochondrial function, evident by ROS elevation, mitochondrial membrane potential reduction, and altered gene expression. Increased autophagy activity and inflammatory cytokine release indicated cellular stress. Moreover, PS-NPs impeded cell migration and invasion, with exacerbated effects upon MDM2 knockdown and ROCK1 inhibition.
CONCLUSION: The study elucidates the intricate connections among mitochondrial dysfunction, autophagy, inflammation, and cell motility in response to PS-NPs, suggesting that targeting the MDM2-ROCK1 pathway could offer a promising approach to alleviate PS-NP-induced toxicity in trophoblast cells and support placental health.

DOI: https://doi.org/10.1371/journal.pone.0337568
Sci Rep. 2025 Dec 02. 15(1): 42957

Critical role of mitochondrial aconitase in skeletal muscle maturation.

Tomoya Fukawa, Miho Takata, Kota Kishida, Kosuke Sugiura, Minori Suzuki, Haruka Tsuda, Iori Sakakibara, Takayuki Uchida, Md Mizanur Rahman, Anayt Ulla, Koichi Sairyo, Takahiko Sato, Madoka Ikemoto-Uezumi, Akiyoshi Uezumi, Takeshi Nikawa.

  Skeletal muscle dynamically regulates protein synthesis and degradation through metabolic responses to external stimuli. In the absence of mechanical load, this normal metabolic response is impaired, leading to muscle atrophy. Previous studies have suggested that mitochondrial dysfunction occurs under unloaded conditions. In this study, we focused on aconitase 2 (Aco2), a mitochondrial protein known to contain an iron-sulfur cluster and function as a metabolic sensor. We generated skeletal muscle-specific Aco2 knockout (cKO) mice to investigate its role in muscle function. Although these mice appeared grossly normal, they died shortly after birth. Analysis of the diaphragm muscle revealed signs of muscle fiber atrophy and impaired muscle maturation. Besides these signs of immaturity, abnormal muscle cells exhibiting disrupted sarcomere structures were frequently observed. Furthermore, these cells showed a marked increase in the apoptotic marker Active Caspase-3, indicating that Aco2 deficiency induces muscle cell death. These findings suggest that Aco2 plays a critical role in skeletal muscle maturation and maintenance of muscle homeostasis. Moreover, these findings highlighted the potential involvement of Aco2 in disuse muscle atrophy and its utility as a therapeutic target.

Keywords:  Aconitase 2-knockout mice; Apoptosis; Mitochondrial dysfunction; Sarcomere disruption; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-25560-w
Int Immunopharmacol. 2025 Dec 01. pii: S1567-5769(25)01904-6. [Epub ahead of print]168(Pt 2): 115916

Integrated multi-omics and machine learning elucidate the pathogenic role of mitophagy in osteoarthritis and identify novel therapeutic strategies.

Qiu Dong, Hao Huang, Ying Feng, Longteng Chao, Zelin Wu, Zhengang Zha, Ruobin Li, Junyuan Chen.

   INTRODUCTION: Osteoarthritis (OA), the most prevalent degenerative joint disease, is characterized by chronic synovial inflammation, cartilage degradation, and disrupted cellular homeostasis. Impaired mitophagy has been implicated in OA pathogenesis, yet effective therapeutic strategies remain limited. This study aims to elucidate the role of mitophagy in OA and to identify cordycepin as a novel therapeutic agent that activates mitophagy, highlighting its potential clinical significance.
METHOD: Mitophagy alterations in clinical OA samples were assessed using immunohistochemistry and validated with public bulk transcriptomic data. Differences in mitophagy pathways were characterized, followed by machine learning to identify pivotal genes for a diagnostic nomogram. Single-cell gene set analysis and computational drug repositioning identified potential mitophagy-modulating therapeutics. In vitro, qPCR and Western blot measured inflammation and mitophagy markers, while autophagic flux dynamics were analyzed using JC-1 staining and tandem fluorescent LC3 (mRFP-GFP) transduction. In vivo efficacy and safety were evaluated in OA animal models.
RESULTS: We found significantly reduced mitophagy scores in OA synovium through integrated multi-omics approach. Machine learning identified seven pivotal mitophagy regulators: ULK1, ATG12, MAP1LC3B, UBB, UBC, TOMM40, and CSNK2B. Computational drug repositioning nominated cordycepin as a candidate therapeutic. In vitro, cordycepin demonstrated potent anti-inflammatory effects, attenuated cellular oxidative stress, inhibited mitochondrial outer membrane depolarization, and activated mitophagic flux. In vivo, cordycepin promoted LC3-TOMM20 co-localization, confirming mitophagy activation. This resulted in significant amelioration of synovitis and attenuation of cartilage degradation.
CONCLUSION: Our findings establish mitophagy impairment as a critical factor in OA pathogenesis and present cordycepin as a promising therapeutic option that targets mitochondrial quality control. This study lays the groundwork for future precision therapies aimed at degenerative joint disorders.

Keywords:  Cordycepin; Mitochondrial metabolism; Mitophagy; Multi-omics bioinformatics analysis; Osteoarthritis

DOI:  https://doi.org/10.1016/j.intimp.2025.115916
J Inflamm Res. 2025 ;18 16637-16665

Identification of Mitochondrial Unfolded Protein Response-Related Genes and Diagnostic Biomarkers in Atherosclerosis by Integrative Multidimensional Analysis and Experimental Validation.

Shuguang Wu, Yanhong Liu, Yu Li, Junyu Lai, Qiang Wan, Jianguang Wu, Yirong Ma.

   Background: Atherosclerosis (AS) is a common cardiovascular disease worldwide. The mitochondrial unfolded protein response (UPRmt) is a defense mechanism that enhances protein folding and degradation to maintain mitochondrial function and cellular homeostasis under stress. Research suggests a strong link between mitochondrial dysfunction and AS, particularly related to oxidative stress and inflammation. However, the exact relationship between UPRmt and AS is unclear. Identifying biomarkers associated with UPRmt is crucial for improving AS diagnosis and treatment.
Methods: Microarray datasets related to AS were retrieved from the Gene Expression Omnibus (GEO) database. After integrating these datasets and eliminating batch effects, we obtained 101 AS and 67 control samples. Based on the expression levels of UPRmt-related genes (MRGs), the samples were classified into two subtypes and subjected to differential analysis, weighted correlation network analysis, and immune infiltration analysis. A predictive model was built using 12 machine learning algorithms to identify hub genes associated with UPRmt. Additionally, single-cell RNA-seq data and the CellChat algorithm were used to explore intercellular communication mechanisms mediated by these hub genes in AS. Mendelian randomization analysis was performed to identify biomarkers linked to AS. Molecular simulation techniques assessed the therapeutic potential of Iloprost. Finally, the expression and distribution of core genes were analyzed by RT-qPCR, Western blot, and immunofluorescence.
Results: We identified seven hub genes at the intersection of UPRmt dysregulation and atherosclerosis. These genes showed consistent differential expression across cohorts and formed coherent mitochondria-stress modules. Their expression correlated with multiple immune-cell infiltration scores, including macrophage and T-cell signatures, and with inflammatory mediators. A classifier based on the seven-gene panel distinguished atherosclerotic from non-atherosclerotic samples across external datasets and remained robust after accounting for clinical covariates. Experimental assays confirmed altered expression of selected genes and their modulation under mitochondrial stress. Molecular simulation suggested that Iloprost can bind to the APOC1 protein's active pocket.
Conclusion: ARHGAP25, CYTH4, ITGB7, APOC1, WDFY4, MARCO and PLCB2 are pivotal genes intimately linked to AS and the UPRmt. They potentially play crucial roles in mitochondrial dysfunction and immune regulation. As such, these genes may be promising biomarkers and therapeutic targets for AS.

Keywords:  atherosclerosis; immune infiltration; machine learning; mitochondrial unfolded protein response; molecular dynamics; single-cell sequencing analysis

DOI:  https://doi.org/10.2147/JIR.S562903
J Ovarian Res. 2025 Dec 06.

Mechanisms and treatment modalities related to premature ovarian insufficiency in mitochondria: literature review.

Huihui Li, Xinyu Zhu, Ruotong Ju, Puhua Zhang, Tingting Xue, Shu Wang, Ruixiang Zhu, Jiali Luo, Xuan Jing, Xiangrong Cui.

  Premature ovarian insufficiency (POI) is a common, heterogeneous disorder that affects up to 3.5% of women under 40 years of age and is defined by oligo/amenorrhoea, hypo-oestrogenism, and markedly elevated gonadotrophin levels. POI substantially increases risks for infertility, osteoporosis, cardiovascular disease, and psychological morbidity; however, its precise aetiology remains elusive, and current therapies rarely restore lasting ovarian function. This review synthesizes recent molecular, cellular, and animal data to clarify how six facets of mitochondrial dysregulation: oxidative stress, imbalanced dynamics (fusion/fission/mitophagy), defective biogenesis, altered mitochondrial DNA (copy-number and mutation), mitochondrial membrane potential, and disrupted electron-transport-chain activity-contribute to accelerated oocyte apoptosis, granulosa-cell dysfunction, and premature follicle loss. We further evaluate emerging mitochondria-targeted interventions, including small-molecule antioxidants, modulators of mitochondrial dynamics, biogenesis activators, autophagy regulators, mtDNA-protective agents, and innovative strategies such as mitochondrial transplantation. This article aims to systematically elaborate the mechanism of mitochondrial dysfunction in POI, summarize the treatment strategies for mitochondria, and provide a theoretical basis for clinical intervention.

Keywords:  Mechanism; Mitochondria; Premature ovarian insufficiency (POI); Prevention and treatment

DOI:  https://doi.org/10.1186/s13048-025-01915-9
Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1
Mol Immunol. 2025 Dec 03. pii: S0161-5890(25)00277-9. [Epub ahead of print]189 98-105

Mitochondria in pyroptosis: Mechanisms and implications.

Basmah M Eldakhakhny, Wesam H Abdulaal, Johra Khan, Amir Ajoolabady, Domenico Pratico, Suhad Bahijri, Jaakko Tuomilehto, Anwar Borai, Bonglee Kim, Jun Ren.

  Pyroptosis is an inflammatory, necrotic, and lytic form of programmed cell death, involving activation of inflammasome complexes, inflammatory caspases, and the cleavage of gasdermins. Gasdermins are a large family of pore-forming proteins with critical implications in key cellular processes and inflammatory disease contexts. These gasdermins subsequently oligomerize to form pores in the plasma membrane, releasing cellular contents and inflammatory mediators. Mechanistically, pyroptosis can occur via either caspase-1-dependent canonical pathway or the caspase-1-independent non-canonical pathway, both ultimately resulting in similar forms of pyroptotic cell death. While the underlying mechanisms of pyroptosis are broad and complex, certain key processes simplify the understanding of these mechanisms. One such critical process is the role of mitochondria and mitochondrial dysfunction in mediating pre-pyroptotic signaling. This review aims to provide a brief overview of the general mechanisms of pyroptosis, followed by a discussion of the latest findings on the functional and regulatory roles of mitochondria in pyroptosis. Moreover, we aimed to discuss and decipher emerging concepts such as the interaction between gasdermin D and cardiolipin, the role of mitochondrial DNA and its associated signaling pathways, as well as perspectives on the clinical relevance of these findings in conditions like sepsis, cardiotoxicity, and other diseases.

Keywords:  Caspases; Cell signaling; Gasdermins; Inflammasomes; Inflammation; Mitochondria; Pyroptosis

DOI:  https://doi.org/10.1016/j.molimm.2025.12.002
Nat Commun. 2025 Dec 05.

Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.

Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.

The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.

DOI: https://doi.org/10.1038/s41467-025-66901-7