bims-mihora 2026-01-18 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–01–18
sixteen papers selected by
Lisa Patel, Istesso

What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
A non-canonical role for UPR ER during heat stress in C. elegans.
A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
Manipulating the Mitochondrial Unfolded Protein Response for Broad-Spectrum Genotoxicity Mitigation and Tumorigenesis Suppression by Ultrasmall Gold Nanoparticles.
Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.
Ocular Risks of Spaceflight and a Path to Prevention: Targeting Mitochondria-ER Stress With Low-Intensity Ultrasound.
Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications.
Naringenin-functionalized polyester nanoparticles improve oral urolithin A delivery and protect against cisplatin-induced kidney injury via heme oxygenase-1 activation and mitochondrial quality control.
Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.
Naphthylimide-based mitochondrial immobilized probes for polarity-specific imaging of mitochondrial autophagy in cells and mouse cardiac tissue.
Sera from patients with dermatomyositis and antisynthetase syndrome mediate muscle weakness, impair mitochondrial respiration and induce local cytokine production in muscle tissue.
Targeting SPHK1 by 8-HETrE attenuates MASH-Driven fibrosis via restoration of hepatic stellate cell mitochondrial dynamics.
Chronic stress disrupts the network among stress granules, P-bodies, and motor proteins.

Neurology. 2026 Feb 10. 106(3): e214618

What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?

Eduardo Benarroch.

Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.

DOI: https://doi.org/10.1212/WNL.0000000000214618
bioRxiv. 2026 Jan 09. pii: 2026.01.08.698479. [Epub ahead of print]

A non-canonical role for UPR ER during heat stress in C. elegans.

Athena Alcala, Toni Castro Torres, Rebecca Aviles Barahona, Phillip A Frankino, Ryo Higuchi-Sanabria, Gilberto Garcia.

Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response (ISR), which reduces global translation under various stress conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteosome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and ER chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPR ER ). Using robust transcriptional reporters in the C. elegans model system, we explore a non-canonical activation of the UPR ER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter tissue communications of stress whereby neuronal or glial activation of the UPR ER can result in heterotypic enhancement of the HSR in peripheral and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole cell and whole organism damage.
Article Summary: A reductionist approach to studying cellular stress responses is critical for dissecting specific molecular and genetic drivers of stress response. However, stress responses are often convergent and overlapping, and these single input and output studies may miss their complex interplay. Many studies have revealed the intricate coordination of stress responses, including the ability of seemingly organelle-specific stress responses, like mitochondrial stress responses, to directly influence cytosolic and ER health. Our study adds to this growing field by describing a unique, bidirectional crosstalk between the cytosolic and ER stress pathways, highlighting systemic coordination of stress resilience.

DOI: https://doi.org/10.64898/2026.01.08.698479
Cell Mol Life Sci. 2026 Jan 12.

A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.

Marlena Helms, Angelika B Harbauer.

  Neurons have adapted the transport and positioning of mitochondria to fit their extended shape and high energy needs. To sustain mitochondrial function, neurons developed systems that allow local biogenesis and adaption to locally regulate mitochondrial form and function. Likewise, fine-tuned degradative systems are required to protect the neurons from mitochondrial dysfunction. Throughout both domains of mitostasis, the local synthesis of the mitochondrial damage-induced kinase PINK1 emerges as a central player. Along with other nuclear encoded mitochondrial proteins, its mRNA associates with mitochondria to sustain mitochondrial function locally. It also regulates mitochondrial degradation, via regulation of proteases, the generation of mitochondria-derived vesicles and mitophagy. In this review, we provide a general overview of the mechanisms governing mitochondrial health in neurons, with a special focus on the role of PINK1 in this endeavor.

Keywords:  Local translation; Mitochondrial proteases; Mitophagy; mRNA transport

DOI:  https://doi.org/10.1007/s00018-025-06054-4
Bioconjug Chem. 2026 Jan 13.

Manipulating the Mitochondrial Unfolded Protein Response for Broad-Spectrum Genotoxicity Mitigation and Tumorigenesis Suppression by Ultrasmall Gold Nanoparticles.

Wendi Huo, Yaqi Jiang, Wencong Zhao, Liyuan Xue, Panpan Ruan, Kaidi Luo, Xiaofei Huang, Yunhao Ren, Xueyun Gao, Kai Cao.

Mitochondrial dysregulation, represented by both imbalanced mitochondrial dynamics and dysfunction, has been found as a key driver of cell transformation and tumorigenesis due to enhanced apoptotic priming and genotoxic stress. The mitochondrial unfolded protein response (UPRmt) represents a protective mechanism that maintains mitochondrial function under mitochondrial damage, making it an attractive target for restoring mitochondrial homeostasis and preventing tumorigenesis. Here, we report an ultrasmall glutathione (GSH)-protected gold nanoparticle (GGNP) that exhibits mitochondrial presence. When mitochondria are damaged by various genotoxic insults, GGNP dramatically activates UPRmt and improves mitochondrial function without altering mitochondrial dynamics. As a result, GGNP significantly attenuates DNA damage and apoptosis, leading to the prevention of malignant transformation in vitro. More importantly, in a spontaneous lung cancer model, GGNP significantly delays tumorigenesis with reduced DNA damage and cell death within lung tissue without causing systemic toxicity. These findings not only reveal the role of UPRmt in tumorigenesis but also identify GGNP as a biocompatible nanomaterial that effectively modulates UPRmt to alleviate mitochondrial stress responses and thus acts as a broad-spectrum genotoxicity mitigator to offer a promising strategy for cancer prevention.

DOI: https://doi.org/10.1021/acs.bioconjchem.5c00514
Cell Rep. 2026 Jan 13. pii: S2211-1247(25)01581-5. [Epub ahead of print]45(1): 116809

Unveiling the neuroprotective power of mitochondrial transfer in orofacial inflammatory pain through ER membrane remodeling.

Chen Li, Yike Li, Fei Liu, Boyao Lu, Shiyang Ye, Dexin Zhu, Muyun Wang, Junyu Chen, Cheng Zhou, Chunjie Li, Yanyan Zhang, Jiefei Shen.

  Neuro-glial mitochondrial transfer critically sustains neuronal function in disease. While this transfer reshapes inflammatory microenvironments, its pathological mechanisms in peripheral inflammatory pain remain uncharacterized, impeding targeted interventions. Here, employing primary satellite glial cells (SGCs)-trigeminal ganglion neurons (TGNs) co-culture models, we demonstrate that, during acute inflammation, SGCs transfer functional mitochondria to injured TGNs via tunneling nanotubes and free mitochondrial uptake. Inflammatory stress impairs mitophagy, leading to dysfunctional mitochondrial accumulation and heightened neuronal hyperexcitability. Mitochondria from SGCs restore mitophagic flux and enhance mitochondrial-endoplasmic reticulum (ER) contact sites, thereby facilitating calcium exchange and homeostasis while reducing neuronal hyperexcitability. Critically, Atl1 knockout and overexpression mice models reveal that ATL1-driven ER restructuring initiates autophagosome formation during mitophagy and regulates early-stage autophagic progression. Taken together, our findings uncover a neuroprotective axis wherein glial mitochondrial donation safeguards neurons, directly nominating mitochondrial dynamics for therapeutic intervention in orofacial inflammatory pain.

Keywords:  ATL1; CP: cell biology; CP: neuroscience; endoplasmic reticulum; inflammatory pain; mitochondrial transplantation; mitophagy; trigeminal ganglion

DOI:  https://doi.org/10.1016/j.celrep.2025.116809
FASEB J. 2026 Jan 31. 40(2): e71462

Ocular Risks of Spaceflight and a Path to Prevention: Targeting Mitochondria-ER Stress With Low-Intensity Ultrasound.

Jee Hoon Lee, Hankyung Kim, Dae Yu Kim.

  The cornea is highly susceptible to spaceflight-induced stress, compromising visual acuity and mission safety. Here, we identify endoplasmic reticulum (ER) and mitochondrial dysfunction as key mediators of corneal degeneration under simulated microgravity (SMG). SMG exposure led to corneal epithelial thinning, reduced nerve fiber density, and delayed wound healing. Multi-omics profiling and cellular assays revealed aberrant ER-mitochondrial crosstalk, characterized by excessive formation of mitochondria-associated membranes (MAMs) and activation of stress signaling pathways. Notably, treatment with low-intensity ultrasound (LIUS) restored corneal epithelial integrity by modulating MAM dynamics, alleviating organelle stress, and normalizing cellular homeostasis. These findings identify a novel molecular axis in microgravity-induced ocular degeneration and propose LIUS as a deployable, non-invasive countermeasure for preserving corneal health during deep spaceflight.

Keywords:  corneal degeneration; endoplasmic reticulum (ER) stress; inter‐organelle communication; low‐intensity ultrasound (LIUS); microgravity; mitochondrial dysfunction; mitochondria‐associated membranes (MAMs); spaceflight

DOI:  https://doi.org/10.1096/fj.202502831RR
Cell Mol Biol Lett. 2026 Jan 11.

Mitochondria-endoplasmic reticulum contact sites in hepatocytic senescence.

Pavitra Kumar, Mohsin Hassan, Frank Tacke, Cornelius Engelmann.

  Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria-endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence-such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype-are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.

Keywords:  Calcium; Contact sites; ER; Hepatocyte; MERCs; Mitochondria; Senescence

DOI:  https://doi.org/10.1186/s11658-025-00809-4
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]

MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.002
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00023-7. [Epub ahead of print]

TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.

Yixiao Xu, Yishun Gong, Jiafa Zhong, Binghong Gao.

   OBJECTIVE: Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
METHODS: A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
RESULTS: In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
CONCLUSION: TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.

Keywords:  TRPV1; active heat acclimation; mitochondrial turnover; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.015
FASEB J. 2026 Jan 31. 40(2): e71441

Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications.

Enhui Dai, Dongjie Sun, Yanxiao Zhao, Mengtao Zhang, Yifan Wu, Jiabo Ding.

  The unfolded protein response (UPR) is a cellular stress response mechanism that maintains endoplasmic reticulum (ER) homeostasis through three signaling pathways mediated by IRE1α, PERK, and ATF6 sensors. While UPR's role in viral infections has been well documented, recent studies indicate that intracellular bacterial pathogens have evolved specific mechanisms to hijack UPR signaling for survival and replication. This review examines UPR manipulation strategies employed by major bacterial pathogens, including Brucella, Mycobacterium tuberculosis, Legionella, and Salmonella. These pathogens utilize effector proteins that target specific UPR components: Brucella effectors VceC, BspB, TcpB, and BspL interact with ER chaperones and ERAD machinery; M. tuberculosis proteins Rv0297, ESAT-6, HBHA, and CdhM disrupt calcium homeostasis and alter ER morphology; Legionella Lpg0519 activates atypical ATF6 signaling; and bacterial toxins including cholera toxin bind IRE1α structural motifs for pathway activation. The molecular basis of UPR manipulation includes direct protein-protein interactions, calcium signaling interference, ER morphological disruption, and transcriptional program modulation. Bacterial hijacking of UPR pathways affects ER-phagy processes and host immune responses, facilitating intracellular survival. UPR pathway components serve as potential targets for host-directed therapy against persistent and drug-resistant infections. Small molecule modulators targeting IRE1α kinase activity, PERK inhibitors, and ATF6 pathway regulators may complement conventional antimicrobial approaches. Characterization of these host-pathogen interactions provides insights for developing therapeutic strategies that target bacterial dependencies on cellular stress responses.

Keywords:  bacterial infection; effector proteins; endoplasmic reticulophagy; immune response; therapeutic strategy; unfolded protein response

DOI:  https://doi.org/10.1096/fj.202503547R
J Pharmacol Exp Ther. 2025 Dec 15. pii: S0022-3565(25)40307-3. [Epub ahead of print]393(2): 103794

Naringenin-functionalized polyester nanoparticles improve oral urolithin A delivery and protect against cisplatin-induced kidney injury via heme oxygenase-1 activation and mitochondrial quality control.

Abiodun T Wahab, Raghu Ganugula, David Sheikh-Hamad, Subhashini Bolisetty, Meenakshi Arora, M N V Ravi Kumar.

  Cisplatin remains a cornerstone of chemotherapy, but its clinical use is often limited by cisplatin-induced acute kidney injury, a condition driven by oxidative stress, inflammation, and mitochondrial dysfunction. Here, we developed naringenin-functionalized polyester nanoparticles (P2Ns-NAR) to enhance the oral delivery and therapeutic efficacy of urolithin A (UA), a mitochondrial-targeting metabolite with cytoprotective properties. The resulting formulation, P2Ns-NAR-UA, conferred kidney protection in vitro and in vivo, outperforming the nontargeted nanoparticle formulation (P2Ns-UA). Notably, in vivo efficacy was achieved at a 50% lower dose. Molecular docking studies suggest UA exhibits a favorable heme oxygenase-1 binding energy of -7.43 kcal/mol, supporting its potential as a promising drug candidate. Mechanistic studies demonstrated that P2Ns-NAR-UA upregulate heme oxygenase-1 and activate PTEN-induced putative kinase 1/Parkin-mediated mitophagy, promoting mitochondrial quality control and preserving dynamics by increasing mitofusin-1/2 and reducing dynamin-related protein 1 and mitochondrial fission protein 1 expression. Treatment also attenuated inflammatory cytokines (interleukin 6, interleukin 8, and tumor necrosis factor-α), immune activation markers (cluster of differentiation 80 and 45), and kidney injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and osteopontin). Histological analysis confirmed reduced tubular damage and fibrosis. These findings establish P2Ns-NAR-UA as a promising oral therapeutic platform to mitigate cisplatin-induced acute kidney injury through coordinated modulation of inflammation, oxidative stress, and mitochondrial homeostasis. Further investigation in cisplatin-resistant cancer models is warranted to establish this platform's dual therapeutic potential and translational value. SIGNIFICANCE STATEMENT: This study shows that naringenin-functionalized polyester nanoparticles improves intestinal uptake of encapsulated agents through intestinal folate receptors. Naringenin-functionalized polyester nanoparticles loaded with urolithin A (P2Ns-NAR-UA) doubles the efficacy of polyester nanoparticles loaded with urolithin A, achieving comparable results at half the dose. The formulation enhances cell health, reduces inflammation, and restores kidney function, making it a promising adjuvant to cisplatin therapy by improving outcomes while minimizing toxicity.

Keywords:  Cisplatin-induced acute kidney injury; Heme oxygenase-1; Naringenin; Naringenin-functional nanoparticles; Receptor-mediated oral delivery; Urolithin A

DOI:  https://doi.org/10.1016/j.jpet.2025.103794
Sci Rep. 2026 Jan 10.

Disruption of intracellular iron homeostasis through mitochondrial dysfunction associated with suppression of ATP 13A2 expression.

Takanori Murakami, Kazuki Ohuchi, Masanori Kiuchi, Hisaka Kurita, Kanta Kawai, Ryo Kakiuchi, Tasuku Hirayama, Hideko Nagasawa, Zhiliang Wu, Yoichi Maekawa, Isao Hozumi, Masatoshi Inden.

  Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration, yet the underlying mechanism accounting for this iron accumulation is unclear. Although iron is an essential element, excessive amounts produce toxicity. Here, we focused on the role of iron and ATP13A2, the causative gene of PARK9 neurodegeneration with brain iron accumulation, using a cellular model. ATP13A2 deficiency resulted in impaired lysosomal function and iron accumulation in cell organelles. Further, we found dysfunction of mitophagy, which is involved in managing mitochondrial quality, as well as mitochondrial damage. Furthermore, we confirmed a decreased heme synthesis capacity, which is important to maintain intracellular iron homeostasis. Overall, our study indicates that lysosome-derived mitochondrial impairment can disrupt intracellular iron homeostasis in a cell model of PD pathology. This could help better understand the mechanisms underlying PD.

Keywords:  ATP13A2; Heme; IRP2; Intracellular iron homeostasis; Lysosome; Mitochondria; Mitophagy; PARK9; Parkinson’s disease; Transferrin receptor

DOI:  https://doi.org/10.1038/s41598-026-35368-x
J Mater Chem B. 2026 Jan 15.

Naphthylimide-based mitochondrial immobilized probes for polarity-specific imaging of mitochondrial autophagy in cells and mouse cardiac tissue.

Yukun Zhang, Lie Li, Ruiyuan Liu, Jinqing Qu.

Mitochondrial autophagy is closely related to various diseases such as neurodegenerative diseases and cancer, and changes in mitochondrial polarity are key markers of these diseases. Traditional fluorescent probes rely on membrane potential and often lose signal during key stages of autophagy. This work develops a mitochondria-immobilized fluorescent probe, Mito-NT, which uses naphthylimide as the fluorescent moiety, triphenylamine as the electron donor, pyridine salt as the electron acceptor, and a mitochondrial-targeting group. The probe achieves polarity-dependent fluorescence response through the activation of an intramolecular charge transfer (ICT) mechanism. The active chlorine unit in its structure ensures that the probe remains stable in the mitochondria and is not affected by changes in the membrane potential. Mito-NT exhibits high polarity sensitivity, pH stability, strong interference resistance, and low cytotoxicity, enabling dynamic monitoring of the mitochondrial autophagy process, tracking the fusion of mitochondria and lysosomes, and distinguishing mouse hunger-induced cardiac mitochondrial autophagy (manifested as enhanced fluorescence). This probe provides a powerful tool for mitochondrial autophagy research and related disease diagnosis.

DOI: https://doi.org/10.1039/d5tb02337h
J Autoimmun. 2026 Jan 09. pii: S0896-8411(25)00167-2. [Epub ahead of print]158 103522

Sera from patients with dermatomyositis and antisynthetase syndrome mediate muscle weakness, impair mitochondrial respiration and induce local cytokine production in muscle tissue.

Cecilia Leijding, Stefano Gastaldello, Tomas Schiffer, Suchada Kaewin, Kristofer M Andreasson, Yi Zhong, Begum Horuluoglu, Maryam Dastmalchi, Antonella Notarnicola, Angeles S Galindo-Feria, Volker M Lauschke, Mattias Carlström, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson.

   OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are systemic autoimmune disorders characterized by skeletal muscle weakness and inflammatory cell infiltrates in muscle tissue. Although circulating systemic factors have been implicated in IIM, it is unclear to what extent such factors shape the muscle disease phenotype. Using a model that can isolate the effect of serum from other systemic influences, we aimed to investigate how serum from IIM affects skeletal muscle contractility, mitochondrial function and inflammatory signalling.
METHODS: Isolated skeletal muscles (m. flexor digitorum brevis) from C57BL/6JRj mice were exposed for 24 h to sera from patients with IIM (n = 11) or healthy control sera. Muscle force was measured before and after serum exposure to assess weakness. Gene and protein expression was analysed to assess mitochondrial biogenesis and inflammatory cytokines. Mitochondrial respiration was assessed by high-resolution respirometry. Muscle transcriptomics was performed to identify signalling pathways perturbed by the IIM sera.
RESULTS: Muscles exposed to sera from patients with IIM displayed significant contractile weakness and impaired mitochondrial respiratory capacity compared to muscles exposed to control sera (complex I; p = 0.0004, complex II; p = 0.0254, maximal electron transport chain activity; p = 0.0012). IIM sera induced upregulation of TNF-α (p = <0.0001) and IL1β (p = 0.0002) in the isolated muscles. Transcriptomics revealed significant enrichment in pathways linked to inflammation, mitochondrial metabolism and cytokine activity.
CONCLUSIONS: Serum from patients with IIM induced disease relevant phenotypes like those observed in muscle of patients, including weakness, local cytokine expression and mitochondrial dysfunction. These findings support the relevance of our model in recapitulating key features of IIM and further the mechanistic insights.

Keywords:  ASyS; DM; IIM; Idiopathic inflammatory myopathies; Mitochondrial dysfunction; Serum; Skeletal muscle

DOI:  https://doi.org/10.1016/j.jaut.2025.103522
Cell Biol Toxicol. 2026 Jan 17.

Targeting SPHK1 by 8-HETrE attenuates MASH-Driven fibrosis via restoration of hepatic stellate cell mitochondrial dynamics.

Shuling Chen, Jiayan Li, Kan Xu, Junyi Wen, Feng Zhang, Yuzheng Zhuge, Lei Wang, Yongxiang Yi, Hao Zhang, Wei Zhang.

  Metabolic dysfunction-associated steatohepatitis (MASH) drives hepatic stellate cell (HSC) activation and extracellular matrix deposition, leading to liver fibrosis, for which effective treatments remain lacking. Here, we report that 8-hydroxyoctacosatrienoic acid (8-HETrE), an arachidonic acid metabolite generated through cytochrome P450 or lipoxygenase pathways, significantly ameliorates MASH-related fibrosis by targeting sphingosine kinase 1 (SPHK1) and restoring mitochondrial function. Clinical observations revealed markedly reduced circulating 8-HETrE levels in patients with MASH fibrosis. In vivo studies demonstrated that 8-HETrE administration improved liver function, enhanced expression of mitochondrial fusion proteins (Mfn1, Mfn2, Opa1), and attenuated fibrosis in Gubra-Amylin-NASH (GAN)-diet-induced MASH models. In TGF-β1-activated human HSCs cell line (LX-2 cells), 8-HETrE treatment suppressed fibrotic markers (α-SMA, COL1A1) and improved mitochondrial dynamics. Mechanistic investigations revealed that 8-HETrE exerted its anti-fibrotic effects primarily through SPHK1 inhibition: SPHK1 knockdown moderately reduced HSC activation, decreased sphingosine-1-phosphate (S1P), lactate, and nitrite levels, enhanced glucose uptake, and promoted mitochondrial fusion, while completely abolishing 8-HETrE's therapeutic effects. Conversely, SPHK1 overexpression exacerbated fibrotic and metabolic abnormalities, which were effectively reversed by 8-HETrE treatment. Critically, HSC-specific Sphk1 knockout independently improved MASH fibrosis, mitochondrial function, and metabolic parameters, while completely blocking 8-HETrE's benefits. Our findings identify 8-HETrE as a novel mediator that targets the SPHK1-mitochondrial dynamics axis in HSCs, providing both mechanistic insights and therapeutic potential for MASH-related fibrosis treatment.

Keywords:  8-HETrE; Hepatic stellate cells; MASH-driven fibrosis; Mitochondrial dynamics; SPHK1

DOI:  https://doi.org/10.1007/s10565-026-10142-x
bioRxiv. 2026 Jan 11. pii: 2026.01.09.698697. [Epub ahead of print]

Chronic stress disrupts the network among stress granules, P-bodies, and motor proteins.

Yuichiro Adachi, Masashi Masuda, Yutaka Taketani, Paul J Anderson, Pavel V Ivanov.

Stress granules (SGs) are dynamic RNA granules that rapidly form in response to various stresses concurrent with mRNA translation shutdown, contributing to cellular adaptation and disease pathogenesis. While SG assembly and disassembly under acute stress have been extensively characterized, how SGs behave under chronic stress remains poorly understood. We previously reported that chronic stress preconditioning inhibits the earliest steps of SG assembly via translation-dependent mechanisms. In contrast, the regulation of SG maturation under chronic stress has not yet been investigated. Here, we show that chronic stress decreases SG size by disrupting the MYH9-dependent myosin crosstalk with core SG nucleator G3BP1. This defect leads to impaired SG and processing body (PB) docking as well, limiting the biogenesis of early SGs. Furthermore, chronic stress reduces expression of the SG nucleator UBAP2L, required for SG-PB docking, thus exacerbating these deficiences. In summary, chronic stress disrupts the myosin-SG-PB network and inhibits SG maturation in a translation-independent manner.
Summary: Chronic stress disrupts the MYH9 network with G3BP1, which inhibits stress granule (SG) assembly. It also decreases UBAP2L levels, which inhibits SG and processing body docking. Disrupted MYH9 network further inhibits this docking, thus blocking maturation of SGs.

DOI: https://doi.org/10.64898/2026.01.09.698697