bims-mihora 2025-12-28 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–12–28
twenty-one papers selected by
Lisa Patel, Istesso

Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.
Targeting mitochondrial autophagy for anti-aging.
Metabolic-stress-induced mitochondrial calcium dysregulation: a central hub in diabetic cardiomyopathy pathogenesis and treatment.
The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.
SIRT3-mediated mitochondrial reprogramming: emerging therapeutic paradigms in peripheral neuropathy and neuropathic pain.
Mitochondrial polarization and redox homeostasis couple glycolysis-to-OXPHOS metabolic rewiring to lifespan extension in C. elegans.
Prohibitin 2 ameliorates cisplatin-induced acute kidney injury by modulating mitochondrial homeostasis.
Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.
Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging.
Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.
Metabolic Stress and Adaptation in Pancreatic β-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation.
Current Knowledge of the Integrated Stress Response in the Development and Management of Acute Myeloid Leukemia: A Novel Target with Encouraging Progress.
LL37-induced mitochondrial stress activates the mtDNA/cGAS/STING pathway to promote mast cell-mediated rosacea inflammation.
Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
Defective Mitochondrial Unfolded Protein Response in Cancer Acts as a Lifeline for Tumor Growth and Survival.
Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.
Mitochondrial biogenesis modulation by silicon-stimulated mesenchymal stem cells-derived extracellular vesicles drives angio- and lymphangiogenesis in chronic wound healing.
Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.
Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States.

Environ Pollut. 2025 Dec 19. pii: S0269-7491(25)01936-0. [Epub ahead of print] 127562

Trifloxystrobin induces oxidative stress-dependent activation of the OMA1-DELE1-HRI integrated stress response leading to apoptosis in human neuroblastoma cells.

Hanen Chaabani, Imen Ayed, Karima Rjiba, Salwa Abid, Joel Eyer, Damien Arnoult.

  Trifloxystrobin (TFX), a potent inhibitor of complex III in the mitochondrial respiratory chain, is a widely used strobilurin fungicide whose neurotoxic mechanisms remain poorly defined. This study investigated the molecular pathways underlying TFX-induced toxicity in human SH-SY5Y neuronal-like neuroblastoma cells, with particular emphasis on oxidative stress, mitochondrial dysfunction, and activation of the Integrated Stress Response (ISR). TFX exposure (24 h) exhibited an IC50 of approximately 100 μM, induced G0/G1 cell cycle arrest, and triggered mitochondria-mediated apoptosis, as evidenced by loss of mitochondrial membrane potential (ΔΨm), Bax activation, cytochrome c release, DNA fragmentation, phosphatidylserine exposure, and caspase-3 activation. These effects were accompanied by increased mitochondrial superoxide levels and decreased ATP production, indicating profound mitochondrial impairment. Pretreatment with N-acetylcysteine (NAC) markedly restored cell viability, reduced ROS accumulation, prevented ΔΨm dissipation, and diminished apoptotic damage. Mechanistically, TFX activated the ISR through the OMA1-DELE1-HRI mitochondrial stress signaling axis, as confirmed by loss-of-function experiments targeting these proteins. Importantly, both NAC and the ISR inhibitor ISRIB (Integrated Stress Response InhiBitor) significantly attenuated ISR activation and the resulting apoptosis, demonstrating that oxidative stress serves as an upstream trigger for ISR engagement and cell death. Collectively, these findings reveal that TFX induces oxidative stress-dependent activation of the OMA1-DELE1-HRI ISR pathway, linking mitochondrial dysfunction to apoptosis in human neuroblastoma cells. To our knowledge, this is the first report identifying ISR activation as a mechanistic component of strobilurin fungicide-induced neurotoxicity.

Keywords:  ISR; SH-SY5Y cells; Trifloxystrobin; apoptosis; oxidative stress

DOI:  https://doi.org/10.1016/j.envpol.2025.127562
Cell Death Discov. 2025 Dec 24.

Targeting mitochondrial autophagy for anti-aging.

Wenjun Shan, Yuling Liu, Ruying Tang, Longfei Lin, Hui Li, Hongjun Yang.

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

DOI: https://doi.org/10.1038/s41420-025-02913-y
Front Endocrinol (Lausanne). 2025 ;16 1696344

Metabolic-stress-induced mitochondrial calcium dysregulation: a central hub in diabetic cardiomyopathy pathogenesis and treatment.

Siqi Deng, Fatemeh Tayefi, Yunpeng Jin.

  Diabetic cardiomyopathy (DCM), as a devastating complication of diabetes mellitus (DM), arises from a complex interplay between systemic metabolic derangements and myocardial vulnerability. While hyperglycemia, lipotoxicity, and insulin resistance are established drivers of cardiac dysfunction, the precise mechanisms linking these metabolic insults to cardiac dysfunction remain elusive. Recent evidence suggests that the dysregulation of mitochondrial calcium homeostasis plays a critical role in integrating diabetic metabolic stress and cardiomyocyte fate. This review synthesizes recent advances in understanding how mitochondrial calcium mishandling-encompassing impaired uptake, excessive release, and buffering failure-orchestrates the pathological triad of bioenergetic deficit, oxidative stress, and cell death in DCM. We delve into the molecular mechanisms underpinning this dysregulation, highlighting its interplay with the diabetic metabolic milieu. Furthermore, we critically evaluate novel therapeutic strategies targeting mitochondrial calcium fluxes, including the inhibition of the mitochondrial calcium uniporter (MCU), the activation of the mitochondrial Na+/Ca2+/Li+ exchanger (NCLX), and the modulation of the mitochondrial permeability transition pore (mPTP), discussing their clinical translation potential and existing challenges. By reframing DCM through the lens of mitochondrial calcium homeostasis, this review not only synthesizes current knowledge but also provides a critical comparison of emerging therapeutic strategies and evaluates the formidable challenges in their clinical translation, thereby bridging the gap between endocrine metabolism and cardiac pathophysiology and offering nuanced perspectives for biomarker discovery and stage-specific interventions.

Keywords:  calcium homeostasis; diabetic cardiomyopathy; heart failure; mitochondrial calcium; mitochondrial dysfunction; therapeutic targets

DOI:  https://doi.org/10.3389/fendo.2025.1696344
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
Free Radic Biol Med. 2025 Dec 22. pii: S0891-5849(25)01452-2. [Epub ahead of print]

SIRT3-mediated mitochondrial reprogramming: emerging therapeutic paradigms in peripheral neuropathy and neuropathic pain.

Yogesh Mishra, Ashutosh Kumar.

  Peripheral neuropathy is a debilitating condition resulting from peripheral nerve damage or dysfunction, primarily caused by aging, obesity, diabetes, cancer chemotherapy, HIV infection, ischemia, or trauma. It manifests as sensory, motor, and autonomic impairments, with symptoms such as numbness, tingling, weakness, and pain, most commonly affecting the hands and feet. Among these, neuropathic pain is the most debilitating, often worsening at night and contributing to insomnia, mood disturbances, depression, and reduced quality of life. Mitochondrial dysfunction is a key pathological hallmark in the onset and progression of peripheral neuropathy and neuropathic pain. Sirtuin 3 (SIRT3), a NAD+-dependent mitochondrial deacetylase, plays a crucial role in maintaining mitochondrial homeostasis by deacetylating >250 lysine residues across ∼115 mitochondrial proteins. Through this mechanism, SIRT3 regulates mitochondrial energy metabolism, oxidative phosphorylation, calcium buffering, redox balance, membrane integrity, DNA repair, proteostasis, biogenesis, dynamics, mitophagy, and autophagy. Emerging evidence suggests that reduced SIRT3 expression and activity contribute to mitochondrial dysfunction associated with peripheral neuropathy and neuropathic pain. Conversely, its restoration has been shown to improve mitochondrial health, suppress nitro-oxidative and inflammatory nerve damage, and alleviate neuropathic symptoms. This review critically examines the role of mitochondrial dysfunction in the pathogenesis of peripheral neuropathy and neuropathic pain. Furthermore, we summarize recent advances in SIRT3 biology, regulation, and acetylproteome, highlighting their implications for mitochondrial function and neuroprotection. Lastly, we provide a comprehensive analysis of literature supporting SIRT3 as a promising therapeutic target, discussing strategies to enhance its expression or activity through lifestyle modifications, natural compounds, small molecules, and genetic approaches. These insights may pave the way for novel therapeutic interventions in peripheral neuropathy and neuropathic pain.

Keywords:  Lysine deacetylation; Mitochondrial function; Neuropathic pain; Peripheral neuropathy; SIRT3; SIRT3 activator; Therapeutic target

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.035
MicroPubl Biol. 2025 ;2025

Mitochondrial polarization and redox homeostasis couple glycolysis-to-OXPHOS metabolic rewiring to lifespan extension in C. elegans.

Anwaar Ali, Shanmuganathan Balakrishnan, Jiayu Xiang, Haesoo Bae, Minou Tsujishita, Amina Abulimiti, Bence Nemeth, Michalis Barkoulas, Kambiz N Alavian.

Mitochondria are essential for maintaining cellular homeostasis throughout life. Here, we investigated the differential effects of glucose and galactose, as well as glycolytic inhibition, on C. elegans lifespan in relation to mitochondrial membrane potential and reactive oxygen species (ROS) levels. Our results show that long-term treatment with glucose reduces both lifespan and mitochondrial membrane potential, whereas galactose increases them. The increase in mitochondrial membrane potential and lifespan is inversely correlated with mitochondrial ROS levels, suggesting a role for mitohormesis in lifespan extension.

DOI: https://doi.org/10.17912/micropub.biology.001858
Front Physiol. 2025 ;16 1658685

Prohibitin 2 ameliorates cisplatin-induced acute kidney injury by modulating mitochondrial homeostasis.

Qi Zhang, Xiaoyu Shi, Lu Yao, Ping Zhou, Wei Ding.

  Acute kidney injury (AKI), associated with a major health burden globally, is frequently caused by nephrotoxic agents, specifically cisplatin. Prohibitin (PHB) 2, a highly conserved mitochondrial protein localized at the inner mitochondrial membrane, is key to maintaining mitochondrial respiration, cristae morphogenesis, and regulating cell death. Despite being extensively assessed in chronic kidney disease models, the role of PHB2 in AKI, particularly cisplatin-induced AKI, warrants further exploration. Here, we investigated the protective effects of PHB2 in cisplatin-induced AKI in in vitro and in vivo models. The results demonstrated that cisplatin upregulated PHB2 expression both in vitro and in vivo. Mechanistically, PHB2 deficiency exacerbated cisplatin-induced cell apoptosis and mitochondrial dysfunction, indicated by increased caspase-3 activity and reactive oxygen species (ROS) production, as well as mitochondrial membrane potential loss, in vitro. Our Western blot analysis results further validated PHB2's involvement in autophagy processes within renal tubular cells. Nevertheless, PHB2 overexpression mitigated these detrimental effects, suggesting the protective role of PHB2 in cisplatin-induced AKI. In vivo, adeno-associated virus-mediated PHB2 overexpression reduced cisplatin-induced renal tubular injury and enhanced mitochondrial ultrastructure, supporting its potential therapeutic benefits. Taken together, our findings underscore the protective role of PHB2 in cisplatin-induced AKI, highlighting its potential as a therapeutic target for mitigating renal injury. Future studies elucidating the mechanisms underlying the protective effects of PHB2 and exploring its clinical implications in AKI management are warranted.

Keywords:  acute kidney injury; cisplatin; mitochondrial dysfunction; prohibitin 2; renal protection

DOI:  https://doi.org/10.3389/fphys.2025.1658685
bioRxiv. 2025 Dec 12. pii: 2025.12.09.693285. [Epub ahead of print]

Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.

Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.

Cells dynamically regulate chromatin in response to nutrient flux which promotes the transcriptional changes necessary for adaptation. The mechanistic target of rapamycin complex 1 (mTORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin stability feeds back to mTORC1 activation and stress adaption remains unknown. We previously identified histone H3 at lysine 37 (H3K37) as essential for the response to mTORC1 stress such that mutation of H3K37 to alanine (H3K37A) causes cell death upon mTORC1 inhibition. Herein, we show that H3K37-dependent chromatin stability prevents proteasome-mediated histone degradation, restricts mTORC1 signaling, and safeguards mitochondrial homeostasis during mTORC1 stress. Genetic interaction analyses reveal that H3K37A combined with mutants that destabilize chromatin, including loss of the Set2 H3K36 methyltransferase, Rpd3S histone deacetylase, or multiple histone deposition pathways, causes synthetic lethality when mTORC1 is inhibited. Transcriptome analysis indicates that H3K37A misregulates the mitochondrial transcriptome during mTORC1 stress, which increases mitochondrial reactive oxygen species (ROS) and triggers lethal mitochondrial retrograde signaling. Inactivation of retrograde signaling, or ROS neutralization, rescues viability of H3K37A and chromatin stability mutants during mTORC1 stress. These findings establish chromatin stability as a key safeguard that restrains mTORC1 activity and prevents toxic mitochondrial stress during metabolic adaptation.

DOI: https://doi.org/10.64898/2025.12.09.693285
Aging Dis. 2025 Dec 21.

Mitochondrial Dysfunction in Alzheimer's disease: Focus on Dynamics and Electron Transport Chain.

Jiehui Li, Gajendra Kumar, Yuqing Yan, Mengmeng Wang, Ling Xu, Haige Wu, Ye Gao, Yi Wang, Yingyi Fan, Ying Bai.

Alzheimer's disease (AD) is a progressive neurological disease characterized by a decline in cognitive abilities and memory loss. Mitochondrial dysfunction is a major factor in early pathological changes; however, its precise pathogenic mechanisms are not yet fully understood. Mitochondria are essential for neuronal energy generation, calcium ion balance regulation, apoptosis control, and production of reactive oxygen species. Among the various mitochondrial changes, the imbalance between fission and fusion is closely linked to β-amyloid deposition and tau pathology, forming a vicious cycle. The electron transport chain (ETC) produces more than 90% of cellular ATP and is damaged in AD. However, most studies simply refer to "mitochondrial dysfunction" in general terms without detailing specific changes in ETC complexes and their subunits. This review aims to provide a detailed overview of the dynamics and ETC complex dysfunction observed in AD for therapeutic targets.

DOI: https://doi.org/10.14336/AD.2025.1046
Genes Dis. 2026 Mar;13(2): 101719

Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging.

Tingting Liu, Jingwen Li, Haojie Wu, Junbo Qiao, Jianshe Wei.

  Parkinson's disease (PD) is a complex neurodegenerative disorder that poses significant burden on patients and families. Its exact cause is unknown, resulting in limited effective treatments. Mitochondrial dysfunction, linked to genetics, aging, oxidative stress, and environmental factors, is central to PD. Healthy elderly individuals have a compensatory mitochondrial DNA (mtDNA) mechanism in brain cells, but this mechanism is impaired in PD patients, leading to mtDNA reduction, respiratory chain dysfunction, decreased adenosine triphosphate (ATP) synthesis, and inadequate neuron energy. Aging increases oxidative stress, impairing mitochondrial function. Mitochondrial dysfunction in the dopaminergic neurons of the substantia nigra causes neuronal loss and disease progression. Aging microglia also play a crucial role, with a reduced capacity to clear neurotoxic substances, especially in the substantia nigra. A decrease in triggering receptor expressed on myeloid cells 2 (TREM2) gene expression shifts microglia to a pro-inflammatory phenotype, exacerbating neuroinflammatory responses and protein deposition. Down-regulation of the C-X3-C motif chemokine ligand 1 (CX3CL1)/C-X3-C chemokine receptor 1 (CX3CR1) signaling pathway increases the expression of pro-inflammatory cytokines, accelerating neuronal loss and disease progression. Recent research has identified a new astrocyte aging regulatory mechanism involving the cyclic GMP‒AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway, promoting astrocyte aging and exacerbating dopamine neuronal loss and motor dysfunction. Understanding PD pathogenesis, especially mitochondrial dysfunction, aging, and glial cell changes, is crucial for developing effective treatments.

Keywords:  Aging; Astrocytes; Microglia; Mitochondrial dysfunction; Parkinson's disease

DOI:  https://doi.org/10.1016/j.gendis.2025.101719
Nat Commun. 2025 Dec 26.

Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.

Yanan Chen, Rejani B Kunjamma, Karin Lin, Li Kai, Maria Dima, Kody Bruce, Ian Steckler, Young Hyun Che, Jason Chan-Zervas, Jaime Eugenin von Bernhardi, Caitlin Connelly, Sude Ece, Grace Newell, Dwight E Bergles, Carmela Sidrauski, Brian Popko.

The leukodystrophy Pelizaeus-Merzbacher disease (PMD) is caused by myelin protein proteolipid protein gene (PLP1) mutations. PMD is characterized by oligodendrocyte death and CNS hypomyelination; thus, increasing oligodendrocyte survival and enhancing myelination could provide therapeutic benefit. Here, we use the PMD mouse model Jimpy to determine the impact of the integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression. Male Jimpy animals in which the ISR-triggering eukaryotic initiation factor (eIF) 2α kinase, protein kinase-like endoplasmic reticulum kinase (PERK), is inactivated have an extended lifespan that correlates with increased oligodendrocyte survival and enhanced CNS myelination. Inactivation of downstream components of the ISR pathway, in contrast, does not rescue oligodendrocytes or myelin. Phosphorylated eIF2α inhibits the exchange factor eIF2B, resulting in diminished protein synthesis. Treatment with small molecule eIF2B activators 2BAct and ISRIB increases oligodendrocyte survival, CNS myelination, and doubled the Jimpy lifespan. These results suggest that ISR modulation could provide therapeutic benefit to PMD patients.

DOI: https://doi.org/10.1038/s41467-025-68045-0
Cells. 2025 Dec 17. pii: 2014. [Epub ahead of print]14(24):

Metabolic Stress and Adaptation in Pancreatic β-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation.

Jannat Akram, Prianna Menezes, Noorul Ibtesam Idris, Joanna Eliza Thomas, Radwan Darwish, Afrin Tania, Alexandra E Butler, Abu Saleh Md Moin.

  Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin-NFAT or oxygen-binding globins-offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell-derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation.

Keywords:  diabetes pathogenesis; glycolysis; hypoxia; hypoxia-inducible factor-1α (HIF-1α); ischemic preconditioning; islet transplantation; mitochondrial dysfunction; pancreatic β-cells; reactive oxygen species (ROS); β-cell apoptosis

DOI:  https://doi.org/10.3390/cells14242014
Drug Des Devel Ther. 2025 ;19 11269-11288

Current Knowledge of the Integrated Stress Response in the Development and Management of Acute Myeloid Leukemia: A Novel Target with Encouraging Progress.

Wanzhi Jiang, Yaonan Hong, Peicheng Wang, Xiawan Yang, Keding Shao, Man Li, Dijiong Wu.

  Primary or acquired resistance to standard chemotherapy and novel targeted therapies remains a common cause of relapsed/refractory acute myeloid leukemia (AML). The five-year overall survival rate for AML patients remains poor. Exploring novel therapeutic pathways may offer effective strategies to address this challenge. The Integrated Stress Response (ISR) is a signaling pathway that maintains cellular homeostasis by reducing global protein synthesis in response to external and internal stressors. Recent studies have demonstrated that ISR exerts a dual role in AML. Moderate activation of ISR supports hematopoietic and leukemia stem cell maintenance and promotes AML progression, whereas hyperactivation of ISR induces apoptosis and reduces myeloid cell leukemia-1 (MCL-1) expression. MCL-1 overexpression contributes to venetoclax resistance. However, MCL-1 inhibitors have shown disappointing cardiac toxicity in clinical studies. Hyperactivation of the ISR can indirectly suppress MCL-1 and help reverse venetoclax (ABT-199) resistance, as reported in previous studies. Our previous study also indicates that ISR activation can reverse venetoclax resistance in AML cells. These findings support the ISR as a novel therapeutic target in AML. However, the mechanisms by which ISR influences stemness and resistance are not yet fully understood. This review integrates current mechanistic insights and preclinical evidence to highlight the ISR as both a key driver of leukemogenesis and a promising target for overcoming drug resistance in AML. We searched the literature up to October 2025 in PubMed, Google Scholar, and ClinicalTrials.gov using terms related to AML, ISR signaling, venetoclax, and ISR kinases.

Keywords:  ATF4; acute myeloid leukemia; eIF2α; integrated stress response; resistance

DOI:  https://doi.org/10.2147/DDDT.S573043
Free Radic Biol Med. 2025 Dec 18. pii: S0891-5849(25)01442-X. [Epub ahead of print]244 422-434

LL37-induced mitochondrial stress activates the mtDNA/cGAS/STING pathway to promote mast cell-mediated rosacea inflammation.

Rui Sun, Huiping Fan, Qingsong Ma, Xiaojin Li, Jiayun Liu, Chen Xu, Chengqi Liu, Dong Zhang, Weiyuan Ma.

   BACKGROUND: Rosacea is a chronic inflammatory skin disease characterized by persistent facial erythema and telangiectasia. The antimicrobial peptide LL37 is a key initiator in rosacea, with mast cells serving as critical inflammatory mediators. However, the precise mechanism underlying LL37-induced mast cell degranulation remains unclear.
METHODS: The rosacea RNA-seq dataset GSE65914 was downloaded from the Gene Expression Omnibus (GEO) database and subjected to transcriptome analysis. DCFH-DA staining was performed to detect oxidative stress. Mitochondrial function was evaluated using MitoSOX and JC-1 staining. Calcein AM/Co2+ quencher staining was employed to assess mitochondrial permeability transition pore (mPTP) opening. Transmission electron microscopy was utilized to observe mitochondrial ultrastructure. Cytosolic mitochondrial DNA (mtDNA) was evaluated via immunofluorescence and qPCR. Western blotting and CUT&RUN assays were conducted to detect activation of the cGAS/STING/NF-κB axis. Mast cell degranulation was assessed using ELISA. N-acetylcysteine (NAC) was administered to scavenge reactive oxygen species (ROS). Cyclosporin A (CsA) was used to inhibit mPTP opening. SP23 was applied for chemical degradation of STING. A LL37-induced rosacea-like dermatitis mouse model was established and topically treated with applied CsA/SP23 cream.
RESULTS: Transcriptomic profiling reveals significant enrichment of the cGAS/STING signaling pathway in rosacea lesions. LL37 induces oxidative stress-driven mitochondrial damage in mast cells, resulting in the leakage of mtDNA. Cytosolic mtDNA activates the cGAS/STING/NF-κB signaling pathway, inducing mast cell degranulation. ROS scavenging, blockade of mPTP or targeted degradation of STING significantly reduced mast cell activation. Animal experiments demonstrated that topical administration of CsA or SP23 suppressed cGAS/STING/NF-κB signaling in dermal mast cells and alleviated rosacea-like dermatitis.
CONCLUSION: LL37 promotes mast cell-driven inflammation through mitochondrial stress and innate immune activation and suggest that targeting the mtDNA/cGAS/STING pathway may offer a promising therapeutic strategy for rosacea.

Keywords:  Mast cell; Mitochondrial DNA; Oxidative stress; Rosacea; cGAS/STING pathway

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.026
Autophagy. 2025 Dec 26.

Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.

Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.

  Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.

Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons

DOI:  https://doi.org/10.1080/15548627.2025.2610450
Cell Stress Chaperones. 2025 Dec 19. pii: S1355-8145(25)00088-4. [Epub ahead of print] 100143

Defective Mitochondrial Unfolded Protein Response in Cancer Acts as a Lifeline for Tumor Growth and Survival.

Uttam Sharma, Vaishnavi Vishwas, Rajiv Ranjan Kumar, Nikita Agarwal, Akshi Shree, Jaya Kanta Gorain, Archana Sasi, Surender K Sharawat, Archna Singh, Jayanth Kumar Palanichamy, Sameer Bakhshi.

  Defective mitochondrial unfolded protein response (UPRmt plays an important role in driving tumor growth and treatment resistance. Under physiological conditions, UPRmt preserves mitochondrial protein homeostasis and structure by inducing chaperones such as heat shock proteins (HSP60, HSP70, HSP10) and proteases like caseinolytic peptidase ATP-dependent, proteolytic subunit (ClpP), and Lon peptidase 1 (LONP1). However, dysfunctional UPRmt in cancer cells may allow them to tolerate mitochondrial damage and metabolic dysregulation, and avoid cell death, thus promoting therapy resistance. Our current understanding of how transcriptional regulators such as activating transcription factor 5 (ATF5), C/EBP homologous protein (CHOP), and forkhead box protein O3a (FOXO3a), along with signaling circuits including ATF5-ATF4-CHOP, SIRT3-FOXO3a and AKT-ERα, coordinate detrimental forms of UPRmt activation in cancer cells remains limited. This review describes known interactions among mediators of the UPRmt pathway and how they may be dysregulated in cancer cells. We also explore how this altered stress response may provide avenues for therapeutic targeting.

Keywords:  Cancer; Chaperones; Mitochondrial unfolded protein response; Proteases; UPRmt

DOI:  https://doi.org/10.1016/j.cstres.2025.100143
Commun Biol. 2025 Dec 22.

Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.

Yvan Campos, Gustavo Palacios, Elida Gomero, Diantha van de Vlekkert, Krishnan Venkataraman, Jaison John, Jason Andrew Weesner, Randall Wakefield, Xiaohui Qiu, Ricardo Rodriguez-Enriquez, Stephanie Rockfield, Jeroen Demmers, Joseph T Opferman, Cam Robinson, Khaled Khairy, Tulio Bertorini, Gerard C Grosveld, Alessandra d'Azzo.

High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz-/- or Alix-/- mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers.

DOI: https://doi.org/10.1038/s42003-025-09363-3
Biochemistry (Mosc). 2025 Dec;90(12): 1957-1969

Mitochondrial Reticulum in Skeletal Muscles: Proven and Hypothetical Functions.

Lora E Bakeeva, Valeriya B Vays, Irina M Vangeli, Chupalav M Eldarov, Vasily A Popkov, Ljubava D Zorova, Savva D Zorov, Dmitry B Zorov.

  The mitochondrial reticulum of skeletal muscles has been characterized in the 1970-80s. It has been suggested and then proven its role is delivering energy in a form of transmembrane potential on the mitochondrial inner membrane throughout the cell volume, followed by ATP synthesis by the mitochondrial ATP synthase. However, the data on the mitochondrial ultrastructure still remains a subject to criticism. To exclude the possibility of artifacts caused by the sample preparation for electron microscopy, we compared the structure of mitochondria in the ultrathin sections of muscle fibers observed by electron microscopy and in intact fibers stained with a membrane potential-dependent dye and visualized by confocal microscopy. The comparison was carried out for mice and naked mole rats known for their superior longevity. The obtained results confirmed previous findings regarding the structure of mitochondrial reticulum. A model suggesting the functioning of giant mitochondria as intracellular structures preventing tissue hypoxia was proposed.

Keywords:  hypoxia; membrane potential; mitochondria; mouse; naked mole rat; oxygen transport; reticulum; ultrastructure

DOI:  https://doi.org/10.1134/S000629792560190X
Mater Today Bio. 2025 Dec;35 102629

Mitochondrial biogenesis modulation by silicon-stimulated mesenchymal stem cells-derived extracellular vesicles drives angio- and lymphangiogenesis in chronic wound healing.

Min-Hua Yu, Yen-Hong Lin, En-Wei Liu, Tai-Yi Hsu-Jiang, Der-Yang Cho, Jian-Jr Lee, Ming-You Shie.

  Diabetic wounds are characterized by chronic inflammation, reduced angiogenesis, and insufficient collagen deposition, leading to impaired healing. Extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSC) offer a promising cell-free therapeutic strategy; however, their efficacy and immunomodulation can be enhanced through bioactivation. In this study, we incorporated calcium silicate-stimulated ADSC-derived EVs (CSEVs) into collagen hydrogels to create a sustained-release system to promote diabetic wound healing. CSEVs exhibit enhanced protein content, surface marker expression, and bioactive cargo enriched with proangiogenic and anti-inflammatory factors. In addition, the suppression of proinflammatory signaling, polarization of M2 macrophages, stimulation of angiogenesis and lymphangiogenesis, and activation of mitochondrial function in dermal fibroblasts were among the many effects of CSEVs on the wound microenvironment. Moreover, miR-31 in CSEVs demonstrated an important factor in promoting difficult wound repair. These results highlight the potential of collagen scaffolds incorporated with CSEVs as strong acellular substrates for improving wound healing in diabetic environments. CSEVs and miRNA-mediated cues work together to overcome regeneration constraints of chronic wounds.

Keywords:  Calcium silicate; Diabetic wound healing; Extracellular vesicles; Immunomodulation; miR-31

DOI:  https://doi.org/10.1016/j.mtbio.2025.102629
Cells. 2025 Dec 09. pii: 1956. [Epub ahead of print]14(24):

Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging.

Surim Bang, So-Hyun Choi, Seung Min Jeong.

  Mitochondrial fatty acid oxidation (FAO) has long been recognized as a central pathway for energy production, providing acetyl-CoA, NADH, and FADH2 to sustain cellular growth and survival. However, recent advances have revealed that FAO exerts far broader roles beyond bioenergetics. FAO contributes to redox balance by generating NADPH for antioxidant defense, regulates protein acetylation through acetyl-CoA availability, and modulates stress signaling pathways to support cellular adaptation under nutrient or genotoxic stress. These emerging insights establish FAO as a metabolic hub that integrates energy homeostasis with redox regulation, epigenetic modification, and stress responses. Dysregulation of FAO has been increasingly implicated in aging and diverse pathologies, including cellular senescence, obesity, cancer and fibrosis. In this review, we highlight recent findings and provide an updated perspective on the expanding roles of mitochondrial FAO in stress responses and aging, with particular emphasis on its potential as a therapeutic target in age-associated diseases.

Keywords:  acetylation; age-related diseases; fatty acid oxidation; redox homeostasis; stress response

DOI:  https://doi.org/10.3390/cells14241956
bioRxiv. 2025 Dec 15. pii: 2025.12.12.694052. [Epub ahead of print]

Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States.

Helena Yu, Yoon Joon Kim, Katelyn Chen, Andrea Z Liu, Mary Jean Sunshine, Robert A J Signer.

Hematopoietic stem cells (HSCs) must preserve protein homeostasis (proteostasis) despite dramatic changes in proliferative and biosynthetic demands during development, yet how proteostasis is regulated across these transitions is poorly understood. Here, we show that fetal and neonatal HSCs operate through distinct, stage-specific proteostasis programs that differ fundamentally from those in adulthood. Using quantitative in vivo assays spanning embryonic through adult stages, we uncover an unanticipated decoupling between protein synthesis and protein quality control during development, revealing that fetal and neonatal HSCs employ specialized mechanisms to safeguard proteome integrity under developmental stress. Developing HSCs experience a distinctive proteostasis landscape characterized by elevated protein synthesis, increased unfolded protein burden, and selective engagement of stress-buffering and protein degradation pathways that are largely dispensable in young adult HSCs. Disruption of these pathways compromises early life HSC function and long-term fitness, establishing proteostasis control as a key regulator of stem cell maturation. These findings define previously unrecognized mechanisms by which HSCs manage the proteome during early life and reveal fundamental principles governing stem cell proteostasis across ontogeny.

DOI: https://doi.org/10.64898/2025.12.12.694052