bims-mihora 2026-03-08 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–03–08
33 papers selected by
Lisa Patel, Istesso

The Yin-Yang of Stress and Senescence: Integrated Stress Response and SASP Crosstalk in Stem Cell Fate, Regeneration, and Disease.
Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.
Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.
Function and regulation of the mitochondrial stress response.
Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
Inhibition of mitochondrial integrated stress response ameliorates ibuprofen-induced endothelial dysfunction in neonatal hyperoxia-induced lung injury.
YAP in synovial macrophages mitigates mechanically-induced osteoarthritis by preserving mitochondrial fusion.
MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.
Fueling the Fire: Metabolic Dysfunction and Senescence as Drivers of Lung Aging and Disease.
Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.
Unconventional model organisms bend our view on mitochondrial cristae.
Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.
Single-cell aging trajectories reveal a dynamic coupling between nuclear size and proteasome concentration.
Mitochondrial Resilience: Unraveling the Triadic Interplay of Phosphocreatine, Cyclophilin D, and STAT3 in Heart Failure.
Design, Synthesis, and Preliminarily Biological Evaluations of Derivatives of the PARP-1 Inhibitor AZD2461 With Mitochondria-Protecting Activities.
Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.
Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.
ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.
Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.
Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
Mitochondrial ORF188 confers salt stress tolerance in rapeseed via an ATP-dependent enhancement of antioxidant capacity.
Melatonin as a radioprotectant against mitochondrial damage.
Neuropilin-2 Deficiency Promotes Mitochondrial Dysfunction and NAD⁺-Dependent Cellular Senescence in Retinal Degeneration.
Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.
Tet2 modulates ER stress responses related to β-cell death and autoimmunity in diabetes.
Piezoelectric Ceramic Nanofiber Aerogels Direct Neutrophil Fate for Diabetic Tissue Regeneration.
Inhibiting cGAS-STING to Preserve Mitochondrial-Nuclear Communication and Stemness in Young Tendon Stem Cells: A Hydrogel Strategy against Age-Related Tendinopathy.

Biocell. 2026 ;pii: 2. [Epub ahead of print]50(1):

The Yin-Yang of Stress and Senescence: Integrated Stress Response and SASP Crosstalk in Stem Cell Fate, Regeneration, and Disease.

Douglas M Ruden.

  Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs: the integrated stress response (ISR) and the senescence-associated secretory phenotype (SASP). These pathways act as a Yin-Yang system, balancing beneficial and detrimental outcomes across development, tissue homeostasis, and disease. On the yin (protective) side, transient ISR activation and acute SASP signaling foster adaptation, embryonic patterning, wound healing, and regeneration. On the yang (maladaptive) side, chronic ISR signaling and unresolved SASP output drive stem cell exhaustion, fibrosis, inflammation, and tumorigenesis. This duality highlights their roles as both guardians and disruptors of stem cell integrity. Mechanistically, ISR regulates translational control via eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and activating transcription factor 4 (ATF4)-dependent transcription, while SASP reprograms the extracellular milieu through cytokines, growth factors, and proteases. Their crosstalk creates feedback loops that shape tissue niches and long-term stem cell potential. Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline, to offer new insights into regenerative medicine, anti-aging interventions, and cancer therapeutics.

Keywords:  Integrated stress response (ISR); activating transcription factor 4 (ATF4); cancer; eukaryotic initiation factor 2 alpha (eIF2α); inflammation; senescence-associated secretory phenotype (SASP); stem cells

DOI:  https://doi.org/10.32604/biocell.2025.072273
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123

Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.

Rebecca Cornell, Ava Handley, Roger Pocock.

  The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.

Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide

DOI:  https://doi.org/10.1073/pnas.2525619123
Front Cell Dev Biol. 2026 ;14 1745201

Hepatic mitochondrial signaling as a systemic hub: inter-organ communication networks in aging and aging-related diseases.

Yishuo Ji, Ying Wang, Xiaowei Yu, Yi Jin, Kai Zhao, Yue Hu, Zhenglin He.

  Aging and aging-related diseases are increasingly viewed as systemic disorders arising from disrupted inter-organ communication, yet the mechanisms linking local metabolic stress to organism-wide dysfunction remain unclear. The liver occupies a central position in this network, but how hepatic mitochondrial stress is translated into circulating signals that remodel distant tissues is incompletely understood. Here, we synthesize evidence identifying hepatic mitochondria as a systemic signaling hub that integrates metabolic and inflammatory stress and disseminates blood-borne cues during aging. We focus on three major classes of mitochondrial outputs: UPRmt-driven mitokines, including fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15); metabolites generated through mitochondrial metabolic reprogramming; and mitochondrial danger signals such as mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (mtDNA). These signals act through endocrine, metabolic, and immune pathways to reshape mitochondrial function, inflammation, and energy homeostasis across multiple organs. We further discuss how aging shifts hepatic mitochondrial signaling from adaptive to maladaptive states and emphasize that liver-centered regulation operates within bidirectional networks involving the gut, skeletal muscle, and immune system. Finally, we outline translational challenges and potential strategies for modulating hepatic mitochondrial outputs to restore systemic homeostasis in aging and aging-related diseases.

Keywords:  UPRmt; aging; diseases; hepatic mitochondria; inter-organ communication; mitokines; mtDNA; mtROS

DOI:  https://doi.org/10.3389/fcell.2026.1745201
Eur J Neurosci. 2026 Mar;63(5): e70449

Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.

Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.

  Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.

Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles

DOI:  https://doi.org/10.1111/ejn.70449
Am J Physiol Cell Physiol. 2026 Mar 04.

MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.

Mireille Khacho, Yan Burelle.

  Muscle stem cells (MuSCs) are essential for muscle regeneration, but their function declines with aging 1-4, neuromuscular disorders5-8 , and non-genetic muscle-wasting conditions9 . Their regenerative capacity is also influenced by environmental factors, including dietary changes such as high-fat diets and diabetes 10-12, impacting their ability to restore muscle integrity. Understanding the mechanisms that regulate MuSC function is thus crucial for developing strategies to preserve muscle health and improve regenerative potential in both physiological and pathological contexts. Recent advances have unveiled a crucial role for mitochondria in controlling MuSC quiescence, fate decisions, and differentiation into myofibers. Several studies have now shown that disruption of mitochondrial function, through genetic or pharmacological means, leads to dysregulation of MuSC functions and impaired myogenic lineage progression. Mitochondrial abnormalities in MuSCs have also been shown to contribute to the loss of regenerative capacity observed in conditions such as aging, sepsis, in myopathies. Together, this evidence and others have sparked great interest for understanding how these organelles regulate MuSC behavior and exploring the therapeutic potential of mitochondria targeted therapies to improve or maintain muscle regeneration. This review aims to provide a comprehensive overview of the role of mitochondria in regulating MuSC quiescence, fate decisions and myogenesis under both normal and diseased conditions. It summarizes current knowledge, highlights existing gaps, and explores emerging areas related to bioenergetic properties and metabolic signaling, mitochondrial network dynamics, quality control, and inter-organelle cross-talk across different MuSC states. It also discusses potential therapeutic strategies targeting mitochondrial function to enhance MuSC regenerative capacity and counteract muscle degeneration.

Keywords:  Muscle stem cells; metabolism; mitochondrial dynamics; mitophagy; stem cell fate

DOI:  https://doi.org/10.1152/ajpcell.00027.2026
Cell Biochem Funct. 2026 Mar;44(3): e70190

Disruption of Cytoskeleton Induces Physiologically and Morphologically Dysfunctional Mitochondria in B-ALL Cells.

Bhanu Priya Awasthi, Bhanupriya Tanwar, Akshi Shree, Sumedha Saluja, Jayanth Kumar Palanichamy, Sameer Bakhshi, Archna Singh.

  The interaction of cellular organelles is crucial for maintaining intracellular homeostasis, particularly highlighting the impact of the cytoskeleton on mitochondrial dynamics. The aim of our study is to find direct molecular connections between cytoskeletal disturbance and mitochondrial failure which are inadequately characterized particularly in B-ALL. We investigated the effects of cytoskeleton inhibition on mitochondria in B-ALL using Pironetin (an alpha-tubulin inhibitor) and Latrunculin B (an actin inhibitor). Our findings indicate that these inhibitors caused mitochondrial fragmentation, characterized by smaller, rounder mitochondria with disordered cristae, increased Drp1 expression (fission protein), and decreased Mfn 1/2 and OPA 1 (fusion proteins) together with significantly modified the expression of essential mitochondrial transporters, such as VDAC and ANT2. These alterations were linked to increased mitochondrial membrane depolarization & mitochondrial reactive oxygen species and gradual mtDNA depletion, indicative of impaired oxidative phosphorylation (increased non-mitochondrial oxygen consumption, decreased mitochondrial reserve capacity) and diminished mitochondrial functionality. These mitochondrial alterations indicate that communication between the cytoskeleton and mitochondria is essential for preserving mitochondrial homeostasis. This study potentially enhances our understanding of how cancer cells modulate mitochondrial function during progression or therapeutic interventions.

Keywords:  cytoskeleton; latrunculin B; leukemia; mitochondria; pironetin

DOI:  https://doi.org/10.1002/cbf.70190
Nat Struct Mol Biol. 2026 Mar 05.

Function and regulation of the mitochondrial stress response.

Joshua B Sheetz, Srividya Chandrasekhar, Michael Rapé.

As mitochondria have crucial roles in metabolism and signaling, their structure and function must be continuously monitored and rapidly adjusted to meet cellular demands. Critical to this regulation is a conserved stress response that detects and alleviates challenges to mitochondrial integrity. Recent work has shown that mitochondrial stress often elicits simultaneous protective reactions that act in a coordinated and tightly regulated fashion to preserve this essential organelle. Here we review components, coordination and control within this comprehensive stress response and discuss how increased understanding of mitochondrial stress signaling is beginning to inform therapeutic approaches directed against diseases of high unmet need.

DOI: https://doi.org/10.1038/s41594-026-01769-9
Mol Biol Cell. 2026 Mar 04. mbcE25110560

Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.

Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.

Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.

DOI: https://doi.org/10.1091/mbc.E25-11-0560
Biochem Pharmacol. 2026 Mar 02. pii: S0006-2952(26)00189-9. [Epub ahead of print] 117857

Inhibition of mitochondrial integrated stress response ameliorates ibuprofen-induced endothelial dysfunction in neonatal hyperoxia-induced lung injury.

Xuan Wang, Bingchun Lin, Lingling Yang, Xiaoyan Huang, Zhanfeng Li, Haimei Yang, Junyan Zhong, Chuanzhong Yang, Xueyu Chen.

  Ibuprofen is a nonsteroidal anti-inflammatory drug with promising activity against patent ductus arteriosus (PDA) in premature infants, but its adverse effect on angiogenesis has hampered the clinical benefit and contributed to development of bronchopulmonary dysplasia (BPD). However, the molecular mechanisms underlying its anti-angiogenic effect have remained incompletely understood. Here we show that ibuprofen compromised mitochondrial function in human endothelial cells, and when used in combination with oxygen therapy-the life-saving respiratory support that preterm infants rely on, ibuprofen and hyperoxia cooperated to activate a heightened mitochondrial integrated stress response (ISR) which resulted in mitochondrial dysfunction and subsequent endothelial defect. In contrast, human endothelial cells pretreated with ISR inhibitor (ISRIB) show significantly enhanced mitochondrial bioenergetics and improved endothelial angiogenic capacity following combination treatment of ibuprofen and hyperoxia. Furthermore, prophylactic ISRIB treatment in vivo reduced ISR signaling in lung endothelial cells and partially improved angiogenesis in ibuprofen-treated BPD mouse lungs. Our findings demonstrate the prophylactic effectiveness of ISRIB against pathologic ISR in driving endothelial dysfunction, thus offering an attractive preventive approach for PDA patients undergoing treatment with ibuprofen and hyperoxia.

Keywords:  Adverse effect; Bronchopulmonary dysplasia; Integrated stress response; Mitochondria; Umbilical vein

DOI:  https://doi.org/10.1016/j.bcp.2026.117857
Cell Signal. 2026 Feb 26. pii: S0898-6568(26)00080-X. [Epub ahead of print]143 112430

YAP in synovial macrophages mitigates mechanically-induced osteoarthritis by preserving mitochondrial fusion.

Yi Cheng, Zhi-Liang Guo, Yi-Fei Gu, Wen-Lei Li, Wei-Bing Zhang.

   BACKGROUND: Osteoarthritis (OA) is a prevalent and progressive degenerative joint disease resulting from abnormal loading; however, the mechanisms by which load induces OA remain incompletely understood. The Hippo/YAP signaling pathway is crucial for cellular mechanosensation, yet its effects on synovial macrophages-key players in joint inflammation-have not been documented. This study aims to investigate whether YAP regulates mitochondrial homeostasis to influence macrophage function in the context of mechanically induced OA.
METHODS: We generated anterior cruciate ligament transection (ACLT) mice to induce OA and administered bone marrow-derived macrophages (BMDMs) subjected to cyclic tensile strain (CTS). We employed micro-computed tomography (micro-CT), histological analysis, immunofluorescence, and Western blotting to assess joint damage and molecular alterations. DCFH-DA and JC-1 staining were conducted to investigate mitochondrial function, followed by transmission electron microscopy for further analysis. Functional enhancement and deficiency studies were performed using Yap1 overexpression and small interfering RNAs (siRNAs), with rescue experiments conducted using AAV5-YAP1 in macrophages.
RESULTS: ACLT induced joint instability, activated the Hippo pathway, and inhibited YAP in synovial macrophages, which is associated with OA progression. Pathological mechanical stress (12% CTS) directly inhibited YAP's nuclear localization and promoted M1 polarization in BMDMs. Mechanistically, YAP maintained mitochondrial homeostasis through TEAD1-dependent transcriptional regulation of Mfn1, a crucial mitochondrial fusion protein. Inhibition of YAP disrupted mitochondrial dynamics, leading to a decrease in mitochondrial membrane potential, an increase in mitochondrial ROS, and a reduction in ATP content. Overexpression of YAP1 rescued mitochondrial dysfunction, suppressed M1 polarization, and protected chondrocytes from catabolic effects. In vivo, specific macrophage overexpression of YAP1 significantly alleviated OA progression by restoring the YAP-MFN1 axis.
CONCLUSION: This study identifies YAP as a mechanosensitive regulator of synovial macrophages that modulates mitochondrial homeostasis to inhibit inflammatory polarization. The YAP-MFN1 axis emerges as a novel therapeutic target for mechanical stress-induced osteoarthritis and elucidates the interplay between cellular mechanosensing and joint inflammation.

Keywords:  Hippo/YAP pathway; Macrophage polarization; Mechanical stress; Mitochondrial dynamics; Osteoarthritis; Synovial inflammation

DOI:  https://doi.org/10.1016/j.cellsig.2026.112430
Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2524659123

MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.

Erin L Ramsey, Stephanie Dobersch, Brian Freie, Nan Hyung Hong, Xiaoying Wu, Sita Kugel, Robert N Eisenman, Patrick A Carroll.

  MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of messenger RNA (mRNA). MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Reestablishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Last, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.

Keywords:  MYC network; MondoA inhibitor; MondoA/MLXIP; pancreatic cancer; stress response

DOI:  https://doi.org/10.1073/pnas.2524659123
Physiol Rev. 2026 Mar 06.

Fueling the Fire: Metabolic Dysfunction and Senescence as Drivers of Lung Aging and Disease.

Corrine R Kliment, Aditi U Gurkar, Nayra Cárdenes, Richard Ramonell, Toren Finkel, Melanie Königshoff.

  With a rapidly expanding human population at advanced ages and age as the main driver for chronic diseases, we face the challenge of understanding tissue aging and devising new therapeutic interventions. Cellular senescence is an important hallmark of all aging tissues and has emerged as a potential key driver of chronic lung diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and asthma. This comprehensive review recapitulates current knowledge of pathways and processes involved in cellular senescence with emphasis on the role of mitochondrial dysfunction and the "4 Ms" (morphology, mitophagy, metabolism, and metabolites). We review our current knowledge of healthy lung aging, discuss which pathomechanisms in chronic lung disease are characterized by senescence, and summarize current target therapeutics and their impact on lung disease. Within this exponentially growing field, we propose emerging concepts and current gaps in knowledge which need to be addressed to develop better opportunities for therapeutic strategies and future investigations.

Keywords:  Aging; Lung; Metabolism; Mitochondria; senescence

DOI:  https://doi.org/10.1152/physrev.00024.2025
Sci Adv. 2026 Mar 06. 12(10): eaed3579

Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.

Kenneth Ehses, Jorge P López-Alonso, Odetta Antico, Yannik Lang, Till Rudack, Abdussalam Azem, Miratul M K Muqit, Iban Ubarretxena-Belandia, Rubén Fernández-Busnadiego.

Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo-electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo-electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.

DOI: https://doi.org/10.1126/sciadv.aed3579
Acta Histochem. 2026 Feb 28. pii: S0065-1281(26)00016-4. [Epub ahead of print]128(2): 152331

Mesenchymal stem cell mitochondrial transfer effectively protects Leber's Hereditary Optic Neuropathy (LHON) mutant cells from mitochondrial damage.

Aswathy P Nair, Aishwarya Janaki P, Janani Gopalarethinam, Abishek Kumar B, Balachandar Vellingiri, Mohana Devi Subramaniam.

  Leber's Hereditary Optic Neuropathy (LHON) is the most prevalent mitochondrial inherited disorder, primarily caused by primary mitochondrial mutations. Clinically, LHON is characterized by degeneration of optic nerves that leads to acute or subacute sudden or painless central vision loss. Currently no effective treatment has been established for LHON. Recent studies have highlighted the significance of intercellular mitochondrial transfer, which facilitates communication between cells and presents a novel therapeutic avenue. In this study, we investigated the formation of tunnelling nanotubes (TNTs) and the subsequent mitochondrial transfer between Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and LHON ND4 mutant cells within the coculture system. Our findings demonstrated that mitochondrial transfer from BM-MSCs to LHON mutant cells via TNTs effectively rescued the mutant LHON cells by reducing apoptosis, restoring mitochondrial membrane potential and reducing reactive oxygen species (ROS) generation. These results provide compelling evidence of cell-cell communication between mesenchymal stem cells and LHON mutant cells, indicating a potential regenerative capacity through the reduction in mitochondrial mutation load. This study would help to implement further research in this area for the protective effect of mitochondria transfer and future cell-based treatment approaches for LHON.

Keywords:  Leber’s Hereditary Optic Neuropathy; Mitochondria transfer; Mitochondrial disease; Stem cells; Tunneling Nanotubes

DOI:  https://doi.org/10.1016/j.acthis.2026.152331
J Cell Sci. 2026 Mar 01. pii: jcs264310. [Epub ahead of print]139(5):

Unconventional model organisms bend our view on mitochondrial cristae.

Silvia Tassan-Lugrezin, Silje A C A Debets, Laura van Niftrik, Taco W A Kooij, Irina Bregy.

  Cristae, convolutions of the inner mitochondrial membrane, provide an extended surface area for respiratory chain complexes and ATP synthases. Crista structure has been extensively researched in opisthokont model organisms, such as yeast and various animals; however, the vast majority of eukaryotic cristae diversity has been largely unexplored. Here, we provide a comprehensive overview of crista formation and maintenance in Euglenozoa and Alveolata, two highly divergent eukaryotic clades that include parasites of clinical and veterinary importance. Within these clades, cristae have been studied primarily in the kinetoplastid Trypanosoma brucei and the apicomplexan Toxoplasma gondii. We also discuss the apicomplexan Plasmodium falciparum, the deadliest human parasite and etiological agent of malaria, in which de novo formation of cristae occurs naturally following an apparently acristate life cycle stage. We compare findings from these divergent and disease-relevant organisms with those from more traditional model organisms, highlighting conserved and unique traits across the eukaryotic kingdom. In this Review, we focus on the roles of three key players in crista curvature - ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS) and cardiolipin, a lipid specific to the inner mitochondrial membrane. By comparing distantly related organisms, we synthesize a broadly applicable model of the general principles of crista formation.

Keywords:   Plasmodium falciparum ; Toxoplasma gondii ; Trypanosoma brucei ; ATP synthase; Apicomplexa; Cardiolipin; Kinetoplastida; MICOS; Mitochondrial cristae

DOI:  https://doi.org/10.1242/jcs.264310
Mol Genet Metab Rep. 2026 Mar;46 101302

Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.

Gerardo G Piroli, Rebecca Myers, Lynda Holloway, Andrew Hayek, Ellen Linebaugh, Julie R Jones, Cindy Skinner, Steven A Skinner, Norma Frizzell, Richard Steet.

  Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.

Keywords:  Complex III; Mitochondria; Mitochondrial transplantation; Respiration; UQCRC1; UQCRC2

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101302
iScience. 2026 Mar 20. 29(3): 114736

Single-cell aging trajectories reveal a dynamic coupling between nuclear size and proteasome concentration.

Michael Mobaraki, Changhui Deng, Jiashun Zheng, Hao Li.

  Yeast replicative aging is cell autonomous and thus a good model for mechanistic study from a dynamic systems perspective. Utilizing an engineered strain and a high-throughput microfluidic device, we analyzed the dynamic trajectories of thousands of single yeast mother cells throughout their lifespan, using fluorescent reporters that cover a wide range of biological processes. We found that proteostasis markers are the strongest predictors of the lifespan of individual cells. We observed that proteasome concentration in the nucleus shows dynamics distinct from those in the cytoplasm, with much more rapid decrease during aging; such behavior can be accounted for by the increase of nuclear size in a simple mathematical model of transport. We hypothesize that nuclear enlargement may dilute key nuclear factors, potentially contributing to aging. Our large-scale single-cell dynamics dataset provides a valuable resource for analyzing relationships among aging hallmarks.

Keywords:  cellular physiology; dynamical system; integrative aspects of cell biology; model organism

DOI:  https://doi.org/10.1016/j.isci.2026.114736
J Cardiovasc Transl Res. 2026 Mar 06. pii: 34. [Epub ahead of print]19(1):

Mitochondrial Resilience: Unraveling the Triadic Interplay of Phosphocreatine, Cyclophilin D, and STAT3 in Heart Failure.

Eskandar Qaed, Wu Liu, Waleed Aldahmash, Mueataz A Mahyoub, Haya A Elshafei, Zeyao Tang.

  Heart failure remains a major global health burden, with mitochondrial dysfunction recognized as a key contributor to its onset and progression. This review highlights three critical regulators of mitochondrial integrity phosphocreatine (PCr), cyclophilin D (CypD), and signal transducer and activator of transcription 3 (STAT3) and their coordinated roles in cardiac function. PCr is vital for sustaining myocardial energy balance, particularly under metabolic stress. CypD controls the mitochondrial permeability transition pore, regulating cell death pathways that contribute to cardiac injury. Beyond its classical nuclear actions, STAT3 supports mitochondrial respiration, biogenesis, and resistance to oxidative damage. Evidence reveals a functional interplay among these regulators, forming a protective network that preserves mitochondrial performance. Disruption of this network promotes energetic failure, mitochondrial injury, and heart failure progression. Targeting PCr metabolism, CypD activity, and STAT3 signaling may represent a promising therapeutic approach to enhance mitochondrial resilience and improve clinical outcomes in heart failure patients.

Keywords:  Cyclophilin D; Heart failure; Mitochondrial; Phosphocreatine; STAT3

DOI:  https://doi.org/10.1007/s12265-026-10756-w
Chem Biodivers. 2026 Mar;23(3): e02633

Design, Synthesis, and Preliminarily Biological Evaluations of Derivatives of the PARP-1 Inhibitor AZD2461 With Mitochondria-Protecting Activities.

Xiong Zhang-E, Yu Lin, Jinglong Liu, Xunping Li, Zhenli Min.

  Poly (ADP-ribose) polymerase-(PARP)-1 repairs the damaged DNA to maintain genome integrity, with nicotinamide adenine dinucleotide (NAD)+ being a substrate. Hyperactivation of PARP-1 causes the depletion of NAD+ pool and inhibits ATP production in mitochondria, ultimately leading to mitochondrial dysfunction, energy failure and cell death. These processes are involved in the pathological mechanisms of a range of neurodegenerative diseases. Inhibiting PARP-1 activity may therefore be valuable in the treatment of these diseases. As NAD+ is most highly distributed within mitochondria, direct inhibition of PARP-1 activity in the organelle may be more efficacious. Therefore, three mitochondrial-targeting compounds 4a-4c were synthesized by coupling the triphenylphosphonium (TPP+) moiety with the ─OH derivative of the PARP-1 inhibitor AZD2461 through various linkers. A fourth compound 4d, was synthesized by coupling the ─OH derivative with the enol form of the antioxidant edaravon. The compounds 4a-4d were tested for protective activity in PC12 cells injured by D-galactose (D-gal) at 60 mM, and the results showed that compound 4c prevented the PC12 cell impairment. Further assays indicated that 4c could restore the loss of mitochondrial membrane potential triggered by D-gal in PC12 cells. This study demonstrated that a mitochondria-targeting PARP-1 inhibitor could improve mitochondrial function and prevent PC12 cell death caused by excessive oxidative stress induced by D-gal.

Keywords:  AZD2461; PARP‐1; mitochondria‐targeting; neuroprotection

DOI:  https://doi.org/10.1002/cbdv.202502633
Cell. 2026 Feb 27. pii: S0092-8674(26)00115-7. [Epub ahead of print]

Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle.

Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley.

  The tricarboxylic acid (TCA) cycle couples nutrient oxidation with the generation of reducing equivalents that power oxidative phosphorylation. Nevertheless, the requirement for components of the TCA cycle is context-specific, raising the question of which TCA cycle outputs support cell fitness. Here, we demonstrate that citrate clearance is an essential function of the TCA cycle. As citrate production increases, so do TCA cycle activity and dependence upon aconitase 2 (ACO2), the enzyme that initiates citrate catabolism in the TCA cycle. Disrupting citrate catabolism activates the integrated stress response and impairs cell fitness, and these effects are reversed by preventing citrate production or promoting mitochondrial citrate efflux. In vivo, ACO2 deficiency induces citrate accumulation and triggers tubular degeneration in the kidney, a tissue that physiologically takes up circulating citrate. Thus, intracellular citrate accumulation can be a metabolic liability, and citrate clearance is a major function of ACO2 in the TCA cycle.

Keywords:  ACO2; TCA cycle; cell metabolism; citrate; integrated stress response

DOI:  https://doi.org/10.1016/j.cell.2026.01.028
Biochim Biophys Acta Mol Basis Dis. 2026 Mar 03. pii: S0925-4439(26)00060-8. [Epub ahead of print] 168211

Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.

Sandra A Niño, Oskar Barrios-Camus, Eduardo Silva-Pavez, J César Cárdenas, Christian González-Billault.

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.

Keywords:  APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL

DOI:  https://doi.org/10.1016/j.bbadis.2026.168211
Redox Biol. 2026 Mar 03. pii: S2213-2317(26)00107-2. [Epub ahead of print]92 104109

ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.

Yosuke Nagai, Keiichiro Matoba, Rimei Nishimura.

  Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) serve as central molecular switches that couple cytoskeletal dynamics with redox regulation and mitochondrial quality control. Dysregulated ROCK signaling promotes mitochondrial fragmentation, oxidative stress, and metabolic inflexibility, thereby linking nutrient overload to multi-organ dysfunction in diabetes, obesity, and cardiometabolic disease. Recent advances have identified ROCK1 as a key regulator of mitochondrial dynamics and bioenergetics: ROCK1 directly phosphorylates the fission protein Drp1 and suppresses the AMPK-PGC-1α pathway, resulting in impaired fatty acid oxidation, decreased mitochondrial biogenesis, and enhanced oxidative injury. Pharmacological or genetic inhibition of ROCK restores mitochondrial structure, energy metabolism, and redox balance across the heart, kidney, and liver, underscoring its therapeutic relevance. In contrast, ROCK2 plays more complementary roles in immune regulation and fibrotic remodeling, as evidenced by the clinical success of selective ROCK2 inhibition. In addition, metabolic drugs such as statins and GLP-1 receptor agonists can indirectly attenuate ROCK activity, suggesting feasible translational strategies for cardiometabolic disease. Despite these advances, isoform-specific mechanisms remain incompletely defined, and selective ROCK1 inhibitors have not yet been developed. Future studies should focus on clarifying ROCK1-specific signaling in mitochondrial homeostasis, developing tissue-targeted inhibitors, and combining ROCK modulation with metabolic or antioxidant therapies. A further understanding of the ROCK-mitochondria axis will enable the design of precise interventions to restore redox equilibrium and prevent progression of metabolic and cardiovascular disorders.

Keywords:  Cardiometabolic diseases; Metabolic remodeling; Mitochondrial dynamics; ROCK1; Redox signaling

DOI:  https://doi.org/10.1016/j.redox.2026.104109
Sci Rep. 2026 Mar 17.

β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.

Mari Saida, Noritaka Saeki, Hiroshi Sakai, Jun Iwanami, Atsushi Yokoyama, Shun Sawatsubashi, Motoi Kanagawa, Norio Sato, Yuuki Imai.

  Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit-acquired weakness (ICU-AW) as part of post-intensive care syndrome. To identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed the 'sirtuin signaling pathway' and 'mitochondrial dysfunction' significantly enriched and Sirt3, a major mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, was downregulated. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among these proteins, mass spectrometry detected several proteins in the acetylated band, including multiple complex I subunits. Whether these are direct SIRT3 targets remains to be determined. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with β-nicotinamide mononucleotide (β-NMN) partially rescued energy production. In vivo, acute-phase administration of β-NMN preserved mitochondrial morphology and skeletal muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness associated with Sirt3 downregulation, and highlights β-NMN supplementation as a promising NAD⁺-targeted therapeutic strategy for mitigating ICU-AW.

Keywords:   β-NMN; Mitochondrial respiration; Sepsis; Sirt3; Skeletal muscle weakness

DOI:  https://doi.org/10.1038/s41598-026-43172-w
J Alzheimers Dis. 2026 Mar 06. 13872877261418994

Region-specific ups and downs in mitochondrial numerical densities during Alzheimer's disease progression: A pilot study in human brains.

Anna-Lena Balsliemke, Barbara Ahlemeyer, Eugen Schmidl, Till Acker, Anne Schänzer, Eveline Baumgart-Vogt.

  BackgroundMitochondrial dysfunction is an important pathogenic factor in Alzheimer´s disease (AD) progression. Most studies analysed disturbances in the mitochondrial metabolism and oxidative stress or focussed on mitochondrial dynamics such as mitochondrial trafficking, fusion-fission and mitophagy.ObjectiveVery limited data exist regarding changes in the mitochondrial numerical density at different levels of AD neuropathologic changes (ADNC) in human brains.MethodsMitochondrial numerical densities were analysed by morphometry using the marker protein ATP5B in sections of 13 brain areas of 8 patients with either low, mid or high ADNC, 6 patients with tauopathy and 10 control patients. Patient samples were classified according to the ABC score.ResultsIn comparison to control patients, we detected increases in mitochondrial densities at low (not in all cases), mid and high ADNC in neurons of the frontal (25%) and temporal (11%) neocortices, pontine nuclei (30%) and Purkinje neurons of the cerebellum (30%). Contrarily, mitochondrial densities decreased by 20% in hippocampal neurons of the entorhinal cortex and CA3 region at mid and high ADNC. Only minor changes occurred in other brain regions investigated (e.g., parietal and occipital neocortices, inferior olive, substantia nigra, striatum). In tauopathy patients, changes in mitochondrial densities were comparable to those in AD patients, except for a stronger decrease in the entorhinal cortex (40%) and a greater increase in the temporal neocortex (30%).ConclusionsIn the neocortex, primarily affected by extracellular amyloid-β (Aβ) deposits, mitochondrial densities in neurons increased, whereas they decreased in the hippocampus, at first enriched in intracellular neurofibrillary tangles.

Keywords:  Alzheimer's disease; amyloid-β; energy metabolism/oxidative stress; fatty acids; hippocampus; immunocytochemistry; lipidmetabolism; mitochondria; mitochondrial numerical density; neurofibrillary tangles; tauopathies

DOI:  https://doi.org/10.1177/13872877261418994
Autophagy Rep. 2026 ;5(1): 2635914

Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.

  Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.

Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy

DOI:  https://doi.org/10.1080/27694127.2026.2635914
Plant Cell Rep. 2026 Mar 03. pii: 72. [Epub ahead of print]45(3):

Mitochondrial ORF188 confers salt stress tolerance in rapeseed via an ATP-dependent enhancement of antioxidant capacity.

Shi-Hang Fan, Zi-Hong Huang, Jun Li, Xiang Ji, Wei Hua, Zheng-Wei Fu.

   KEY MESSAGE: The mitochondrial gene ORF188 enhances salt stress tolerance in rapeseed by boosting ATP synthesis, thereby fueling antioxidant defense systems and maintaining cellular homeostasis. Soil salinity severely impairs crop productivity by inducing osmotic stress, ionic toxicity, and oxidative damage. An energy deficit, arising from impaired mitochondrial ATP production under stress, represents a critical bottleneck that compromises the plant's antioxidant capacity. Here, we report that the mitochondrial gene ORF188, a homolog of the ATP synthase F0 subunit, significantly enhances salt stress tolerance in rapeseed. ORF188-overexpressing lines exhibited superior growth and reduced oxidative damage under salt stress, which was underpinned by constitutively elevated ATP synthase activity and cellular ATP levels. This energy surplus enhanced the antioxidant system, maintained favorable Na+/K+ ratio and orchestrated a homeostasis-oriented stress transcriptome. Crucially, treatment with the ATP synthase inhibitor Oligomycin A abolished both the salt-tolerant phenotype and the associated transcriptional reprogramming, thereby confirming the essential role of enhanced ATP synthesis. Our findings demonstrate that ORF188 as a key genetic determinant of salt stress tolerance via ATP-dependent antioxidant activation, and representing a promising target for breeding salt-resilient crops.

Keywords:   ORF188 ; ATP synthesis; Mitochondrial; Rapeseed; Salt stress tolerance

DOI:  https://doi.org/10.1007/s00299-026-03759-z
Int J Radiat Biol. 2026 Mar 03. 1-11

Melatonin as a radioprotectant against mitochondrial damage.

Tsutomu Shimura, Jiayu Wu, Maho Aizawa, Yui Takahashi, Megumi Sasatani, Asako J Nakamura, Akira Ushiyama.

   PURPOSE: Conventional radioprotectants are designed to be administered before radiation exposure, while few have been identified that are effective when administered post-exposure. Irradiation generates intracellular reactive oxygen species (ROS) that induce mitochondrial damage, causing the release of mitochondrial contents into the cell cytoplasm and ensuing cell death. This mitochondrial damage occurs a few hours after radiation exposure, so mitochondria-targeted radioprotection can be effective when administered post-exposure. Here, we examined the efficacies of the glutathione (GSH) peroxidase activators melatonin and mitoEbselen-2 against radiation-induced mitochondrial damage.
MATERIALS AND METHODS: Human TIG-3 fibroblasts were exposed to ionizing radiation (IR), and cGAS-positive cytosolic DNA was detected by immunostaining with double-strand DNA and cGAS antibodies as an indicator of mitochondrial (mt)DNA leakage. Mitochondrial membrane potential (Δψm) was also measured using JC-1, while radiation-induced senescence was detected by β-gal staining. Mice were exposed to whole-body irradiation with or without melatonin treatment to assess radioprotective efficacy in vivo.
RESULTS: Radiation exposure induced mitochondrial damage in TIG-3 cells as evidenced by cytosolic mtDNA leakage, Δψm depolarization, and accelerated cellular senescence. Melatonin and mitoEbselen-2 protected against both irradiation-induced and H2O2-induced mitochondrial damage, suggesting that these agents act as ROS scavengers. Melatonin also maintained Δψm after irradiation and inhibited cellular senescence. However, prolonged mitoEbselen-2 treatment indicated potential cytotoxicity as shown by Δψm loss. Melatonin mitigated the release of exosome mtDNA into the plasma of mice, as well as radiation-induced damage to blood cells and testicular tissue.
CONCLUSIONS: Melatonin can protect against irradiation-induced mitochondrial damage, suggesting utility for mitigating the health effects of accidental radiation exposure.

Keywords:  Melatonin; Nrf2; cytosolic DNA; mitochondria; radiation protection

DOI:  https://doi.org/10.1080/09553002.2026.2636299
Invest Ophthalmol Vis Sci. 2026 Mar 02. 67(3): 11

Neuropilin-2 Deficiency Promotes Mitochondrial Dysfunction and NAD⁺-Dependent Cellular Senescence in Retinal Degeneration.

Lechun Ou, Baoyue Cui, Linbin Zhou, Keli Liu, Le Shi, Tian Zhou, Lei Zeng, Hong Zhou, Huiyi Xu, Yingfeng Zheng, Xiaolai Zhou, Xuri Li, Chang He, Wei Yi, Feng Zhang, Rong Ju, Xialin Liu.

Purpose: Retinal pigment epithelial (RPE) dysfunction is a central pathological feature of retinal degenerative diseases, leading to irreversible vision loss. RPE dysfunction is substantially driven by mitochondrial impairment and senescence. However, the upstream regulators of these processes remain largely undefined. This study investigated the role of neuropilin-2 (NRP2) in RPE homeostasis and explored mitochondrial-targeted therapy with echinacoside (ECH) as a potential intervention for retinal degeneration.
Methods: RPE-specific Nrp2 conditional knockout mice were generated using AAV-VMD2-Cre and retinal morphology and function were assessed by fundus imaging, optical coherence tomography, histology, and electroretinogram (ERG). Cellular and metabolic phenotypes were examined in NRP2-deficient ARPE-19 cells and validated in vivo. RPE senescence, mitochondrial function, NAD⁺ metabolism, and sirtuin activity were analyzed, and the effects of ECH treatment were evaluated both in vitro and in vivo.
Results: RPE-specific Nrp2 deletion resulted in progressive RPE atrophy, photoreceptor loss, and impaired ERG responses. NRP2 deficiency led to mitochondrial elongation, elevated ROS, membrane depolarization, and reduced NAD⁺/NADH ratios. Decreased NAD⁺ levels were accompanied by downregulation of SIRT1/SIRT3 and increased protein acetylation, promoting RPE senescence. Restoring NAD⁺ levels or ECH treatment rescued mitochondrial dysfunction and reduced senescence markers in vitro. Furthermore, in vivo ECH administration preserved retinal structure and visual function in NRP2-deficient mice.
Conclusions: NRP2 is a critical regulator of mitochondrial integrity and NAD⁺ metabolism in the RPE. Its loss disrupts metabolic homeostasis, promoting RPE senescence and retinal degeneration. Targeting the NRP2-mitochondria-NAD⁺ axis with echinacoside represents a promising therapeutic strategy for preventing retinal degenerative diseases.

DOI: https://doi.org/10.1167/iovs.67.3.11
NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3
Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627

Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.

Akriti Prashar, Rosa Puertollano.

Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.

DOI: https://doi.org/10.1016/j.ceb.2026.102627
iScience. 2026 Mar 20. 29(3): 114818

Tet2 modulates ER stress responses related to β-cell death and autoimmunity in diabetes.

Jinxiu Rui, Madhav Kothari, Romy Kursawe, Mahsa Nouri Barkestani, Romi Genosar, Pamela Clark, Michael L Stitzel, Kevan C Herold.

  We found that beta cells from Tet2-deficient mice were protected from killing in a model of autoimmune Type 1 diabetes, but the mechanism of protection and specific cell types affected by Tet2 loss were unknown. Herein we show that in Tet2-deficient NOD mice transplanted with wild-type bone marrow, there are fewer islet infiltrating lymphocytes beginning 8-10 weeks after transplant, which was seen primarily among CD4+ T-cells. Transcription factor binding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To determine whether there were similar effects in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2 (TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.

Keywords:  cell biology; immunology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.114818
Adv Mater. 2026 Mar 06. e20475

Piezoelectric Ceramic Nanofiber Aerogels Direct Neutrophil Fate for Diabetic Tissue Regeneration.

Jibing He, Yinghao Wu, Mengqi Cheng, Haihan Gao, Hongwei Lu, Zihao Lin, Yuhan Jiang, Zhipeng Zou, Yiwei Pan, Wen Gong, Ke Wang, Jiaxing Wang, Fangzhou Yao, Xin Ma, Xiaochun Peng.

  The dysregulation of neutrophil death pathways constitutes a critical barrier to diabetic tissue regeneration, in which pyroptosis perpetuates chronic inflammation while apoptosis promotes tissue homeostasis. However, achieving reliable control over neutrophil death patterns to tune inflammation and repair processes remains a major challenge. Here, we develop a multifunctional aerogel scaffold based on piezoelectric ceramic nanofibers to synergistically direct neutrophil fate. Specifically, (K,Na)NbO3 piezoceramics are incorporated into gelatin/polylactic acid nanofiber membranes, homogenized via high-speed fragmentation, and freeze-dried to form a porous aerogel scaffold. Conjugation with the retinoid derivative peretinoin yields the final piezoelectric ceramic nanofiber aerogel (KAP). Peretinoin released from KAP suppresses caspase-3-mediated cleavage of gasdermin E (GSDME), switching neutrophil death from pyroptosis to apoptosis. Meanwhile, upon ultrasound activation, KAP generates surface potentials to enhance macrophage phagocytic capacity via calcium influx and lysosomal acidification. This dual mechano-chemical approach promotes efferocytosis and reprograms macrophages toward a pro-regenerative phenotype, thereby breaking the cycle of chronic inflammation in diabetic microenvironments. In diabetic rodent models, KAP significantly accelerates the healing of both soft and hard tissues. This study presents a piezoelectric ceramic nanofiber aerogel that offers a potential therapeutic approach for diabetic tissue regeneration.

Keywords:  drug delivery; immunomodulation; neutrophils; piezoelectric material; tissue regeneration

DOI:  https://doi.org/10.1002/adma.202520475
Adv Sci (Weinh). 2026 Mar 02. e20941

Inhibiting cGAS-STING to Preserve Mitochondrial-Nuclear Communication and Stemness in Young Tendon Stem Cells: A Hydrogel Strategy against Age-Related Tendinopathy.

Zhuo Zhang, Weiyong Song, Heng Yin, Yi Wang, Yi Zou, Yuling Li, Yue Luo, Chao Xiang, Xiaoqin Liu, Yan Xiong, Yong Wang, Ke Jiang.

  Age-related tendinopathy is common in the elderly. Their refractory nature is linked to low cellular density and poor blood supply of tendons. Key pathological features in aged tendons include the accumulation of senescent tendon-derived stem cells (TDSCs), a decrease in young TDSCs, and an imbalance in the inflammatory microenvironment caused by reactive oxygen species (ROS). Among these, impaired mitochondria-nucleus communication is a central mechanism in disease progression. This study develops a ROS-responsive dual-targeted hydrogel (P/H@Lipo) loaded with selenium nanocatalysts (HPSe) and the STING inhibitor H-151 in liposomes (L-Lipo@H-151). This system releases L-Lipo@H-151 in response to ROS within the inflammatory environment, targeting it to TDSCs to inhibit the cGAS-STING pathway. The simultaneously released HPSe effectively reduces mtDNA leakage and cGAMP production, thereby strengthening the blockade of the cGAS-STING pathway. This process maintains mitochondrial-nuclear communication, which in turn preserves the stemness of young TDSCs by preventing their senescence. Mechanistic studies indicate that HPSe boosts self-renewal and tendinogenic differentiation in young TDSCs by inhibiting the Hippo signaling pathway. In summary, this study develops a novel therapeutic paradigm that targets the mitochondrial-nuclear communication to combat age-related tendinopathy.

Keywords:  age‐related tendinopathy; hydrogel therapy; mitochondria–nucleus communication; reactive oxygen species (ROS); tendon‐derived stem cells (TDSCs)

DOI:  https://doi.org/10.1002/advs.202520941