bims-mihora 2026-02-01 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–02–01
23 papers selected by
Lisa Patel, Istesso

Mito-nuclear communication: From cellular responses to organismal health.
Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.
Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.
4-(1-Methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide (CDN1163) Attenuates Glutamate-Induced Excitotoxicity by Suppressing ER Stress and Restoring Mitochondrial Dynamics in N2a Cells.
Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides.
PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.
Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.
Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.
Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.
SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.
Mitochondria as sources and targets of cellular signaling.
Functionalized hydrogels of CeO2 and Urolithin A synergistically scavenge ROS and activate mitophagy for cartilage repair.
Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.
Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury.
Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.
Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
Viable exogenous mitochondria modulate neurochemical and behavioral features of fibromyalgia in a reserpine-induced fibromyalgia model.
Immune Determinants of MASLD Progression: From Immunometabolic Reprogramming to Fibrotic Transformation.
Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.
In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.

Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00021-3. [Epub ahead of print]

Mito-nuclear communication: From cellular responses to organismal health.

Guanyu Chen, Hangyu Dong, Ye Tian.

  The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPRmt) and the mitochondrial integrated stress response (ISRmt), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcasted through secreted mitokines and neural circuits, and then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.

Keywords:  ISRmt; UPRmt; aging; mito-nuclear communication; mitokine; proteostasis

DOI:  https://doi.org/10.1016/j.molcel.2026.01.001
Acta Pharm Sin B. 2026 Jan;16(1): 1-12

Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.

Joshua Kramer, Eric Rohwer, Palaniappan Sethu, Min Xie, Timmy Lee, Victor Darley-Usmar, Jianhua Zhang.

  Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.

Keywords:  Cardiomyocytes; Exophers; Fibroblasts; Macrophages; Migrasomes; Mitophagy; TNTs; Transmitophagy

DOI:  https://doi.org/10.1016/j.apsb.2025.11.030
Curr Issues Mol Biol. 2025 Dec 14. pii: 1042. [Epub ahead of print]47(12):

Mitochondrial Dysfunction and Metabolic Reprogramming in Chronic Inflammatory Diseases: Molecular Insights and Therapeutic Opportunities.

Mi Eun Kim, Yeeun Lim, Jun Sik Lee.

  Chronic inflammatory diseases are driven by persistent immune activation and metabolic imbalance that disrupt tissue homeostasis. Mitochondrial dysfunction disrupts cellular bioenergetics and immune regulation, driving persistent inflammatory signaling. Mitochondrial dysfunction, characterized by excessive production of ROS, release of mitochondrial DNA, and defective mitophagy, amplifies inflammatory signaling and contributes to disease progression. Meanwhile, metabolic reprogramming in immune and stromal cells establishes distinct bioenergetic profiles. These profiles maintain either pro-inflammatory or anti-inflammatory phenotypes through key signaling regulators such as HIF-1α, AMPK, mTOR, and SIRT3. Crosstalk between mitochondrial and metabolic pathways determines whether inflammation persists or resolves. Recent advances have identified critical molecular regulators, including the NRF2-KEAP1 antioxidant system, the cGAS-STING innate immune pathway, and the PINK1-Parkin mitophagy pathway, as potential therapeutic targets. Pharmacologic modulation of metabolic checkpoints and restoration of mitochondrial homeostasis represent key strategies for re-establishing cellular homeostasis. Developing approaches, including NAD+ supplementation, mitochondrial transplantation, and gene-based interventions, also show significant therapeutic potential. This review provides a mechanistic synthesis of how mitochondrial dysfunction and metabolic reprogramming cooperate to maintain chronic inflammation and highlights molecular pathways that represent promising targets for precision therapeutics in inflammatory diseases.

Keywords:  chronic inflammation; immuno-metabolism; metabolic reprogramming; mitochondrial dysfunction; therapeutic targeting

DOI:  https://doi.org/10.3390/cimb47121042
Int J Mol Sci. 2026 Jan 08. pii: 630. [Epub ahead of print]27(2):

Cystinosis and Cellular Energy Failure: Mitochondria at the Crossroads.

Francesco Bellomo, Domenico De Rasmo.

  Cystinosis is a rare lysosomal storage disorder characterized by defective cystine transport and progressive multi-organ damage, with the kidney being the primary site of pathology. In addition to the traditional perspective on lysosomal dysfunction, recent studies have demonstrated that cystinosis exerts a substantial impact on cellular energy metabolism, with a particular emphasis on oxidative pathways. Mitochondria, the central hub of ATP production, exhibit structural abnormalities, impaired oxidative phosphorylation, and increased reactive oxygen species. These factors contribute to proximal tubular cell failure and systemic complications. This review highlights the critical role of energy metabolism in cystinosis and supports the emerging idea of organelle communication. A mounting body of evidence points to a robust functional and physical association between lysosomes and mitochondria, facilitated by membrane contact sites, vesicular trafficking, and signaling networks that modulate nutrient sensing, autophagy, and redox balance. Disruption of these interactions in cystinosis leads to defective mitophagy, accumulation of damaged mitochondria, and exacerbation of oxidative stress, creating a vicious cycle of energy failure and cellular injury. A comprehensive understanding of these mechanisms has the potential to reveal novel therapeutic avenues that extend beyond the scope of cysteamine, encompassing strategies that target mitochondrial health, enhance autophagy, and restore lysosome-mitochondria communication.

Keywords:  bioenergetics; cAMP; cysteamine; cystinosis; flavonoids; ketogenic diet; lysosomal storage diseases; mitochondria; mitophagy

DOI:  https://doi.org/10.3390/ijms27020630
ACS Chem Neurosci. 2026 Jan 28.

4-(1-Methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide (CDN1163) Attenuates Glutamate-Induced Excitotoxicity by Suppressing ER Stress and Restoring Mitochondrial Dynamics in N2a Cells.

Vikrant Rahi, Swapnil Sharma, Ravinder K Kaundal.

  Excessive glutamate release during excitotoxic events such as stroke and neurodegeneration leads to elevated mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane depolarization, contributing to dysfunction of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and subsequent endoplasmic reticulum (ER) stress. SERCA is critical for maintaining ER Ca2+ homeostasis, and its impairment exacerbates ER stress and neuronal excitotoxicity. In this study, we investigated the neuroprotective potential of CDN1163 (4-(1-methylethoxy)-N-(2-methyl-8-quinolinyl)-benzamide), a small-molecule SERCA activator, in an in vitro model of glutamate-induced toxicity using N2a cells. Glutamate exposure markedly reduced cell viability and induced apoptosis, as evidenced by increased caspase-3 and Bax expression along with suppression of the antiapoptotic protein Bcl-2. These cytotoxic effects were accompanied by excessive intracellular and mitochondrial ROS generation and dissipation of the mitochondrial membrane potential (ΔΨm), indicating mitochondrial dysfunction. Glutamate further disrupted mitochondrial quality control by impairing mitophagy initiation, reflected by reduced PINK1 and Parkin expression and altered LC3-II and phospho-p62 levels. This mitochondrial impairment coincided with pronounced ER stress, characterized by activation of unfolded protein response signaling pathways, including increased expression of BiP, p-IRE1α, XBP 1s, p-PERK, p-eIF2α, ATF4, CHOP, and ATF6, together with downregulation of SERCA1a and SERCA2b, leading to ER Ca2+ dyshomeostasis. Treatment with CDN1163 significantly reversed glutamate-induced cytotoxicity by restoring cell viability, suppressing apoptosis, reducing mitochondrial and cellular ROS, stabilizing mitochondrial membrane potential, reactivating mitophagy, and alleviating ER stress through restoration of SERCA expression and ER Ca2+ homeostasis. Collectively, these findings demonstrate that CDN1163 confers neuroprotection against glutamate-induced excitotoxic injury by targeting interconnected mitochondrial and ER stress pathways, highlighting its therapeutic potential in excitotoxic neurodegenerative conditions.

Keywords:  endoplasmic reticulum stress; excitotoxicity; mitochondrial dynamics; mitophagy; neuronal apoptosis; sarco-endoplasmic reticulum Ca2+-ATPase

DOI:  https://doi.org/10.1021/acschemneuro.5c00863
Mitochondrion. 2026 Jan 25. pii: S1567-7249(26)00009-7. [Epub ahead of print] 102119

Transcriptional activation by MNRR1 is effected by recruiting p300 and can be induced by minimal peptides.

Neeraja Purandare, Vignesh Pasupathi, Deepesh Padhan, Sagarika Rai, Lawrence I Grossman, Siddhesh Aras.

Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1; also, CHCHD2, PARK22, AAG10), which functions in both the mitochondria and the nucleus, modulates mitochondrial function as well as cellular stress response. We have previously shown that stress response is predominantly mediated by its nuclear function as a transcriptional regulator at an 8-bp DNA element. This 8-bp element is the consensus DNA binding site for the transcription factor Recombination Signal Binding Protein For Immunoglobulin Kappa J Region (RBPJk). Here we have refined the mechanism by which MNRR1 regulates transcription at the ORE. We show that MNRR1 interacts with RBPJk and recruits the transcriptional co-activator p300 to facilitate transcription. We also show that a minimal domain of MNRR1 is sufficient to activate its nuclear function. Peptides based on this minimal domain can activate transcription by MNRR1 by enhancing p300 and RBPJk interaction. MNRR1 peptides activate downstream pathways such as mitochondrial biogenesis and the unfolded protein response (UPRmt) in an in vitro model for MELAS.

DOI: https://doi.org/10.1016/j.mito.2026.102119
iScience. 2026 Feb 20. 29(2): 114365

PHB2 mitigates intervertebral disc degeneration by modulating mitophagy to inhibit necroptosis in nucleus pulposus cells.

Zhenyu Zhu, Yongcheng Liang, Xiaowen Liu, Fanqi Kong, Kaiqiang Sun, Ximing Xu, Jiangang Shi.

  Intervertebral disc degeneration involves loss of nucleus pulposus (NP) cells driven by inflammatory and mitochondrial stress-related death pathways. Because mitophagy maintains mitochondrial quality, its disruption may influence cell fate during degeneration. Using human tissues, a mouse lumbar instability model, a rat disc puncture model, and human NP cells stimulated with TNF-α, SM-164, and Z-VAD-FMK (TSZ), we examined how mitochondrial quality control shapes necroptotic signaling. Necroptotic cells displayed mitochondrial damage and reduced mitophagy, while mitophagy activation limited necroptosis and preserved extracellular matrix components. We identified the mitochondrial protein PHB2 as a key regulator linking mitophagy to suppression of necroptosis. PHB2 loss impaired mitophagy, disrupted mitochondrial function, and intensified necroptotic death, whereas PHB2 overexpression restored mitophagy, maintained mitochondrial membrane potential, and reduced degeneration. In vivo PHB2 delivery mitigated necroptosis and protected disc structure. These findings highlight a mitochondria-centered mechanism that shapes cell survival during disc degeneration.

Keywords:  Biological sciences; Cell biology; Health sciences; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.114365
J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.

Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.

Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.

DOI: https://doi.org/10.1083/jcb.202501023
Redox Biol. 2026 Jan 16. pii: S2213-2317(26)00036-4. [Epub ahead of print]90 104038

Context-specific Angiogenin-mediated tRNA fragments (tDRs) biogenesis shapes the mitochondrial stress response.

Shadi Al-Mesitef, Daisuke Ando, Tomoya Saigasaki, Yuki Sakaguchi, Shunya Akagi, Abdulrahman Mousa, Sherif Rashad, Kuniyasu Niizuma.

  Transfer RNA-derived small RNAs (tDRs) are emerging regulators of cellular stress response, yet their biogenesis and activities during mitochondrial dysfunction remain poorly understood. Here we profiled tDRs generated in HEK293T cells exposed to inhibitors of respiratory complexes I-V (rotenone, TTFA, antimycin A, KCN, oligomycin) or to arsenite and assessed the impact of CRISPR-mediated angiogenin (ANG) knockout, ANG over-expression and recombinant ANG supplementation on the stress response and tDRs production. tDR-seq revealed stress-specific, highly ordered tDR repertoires: rotenone and antimycin predominantly induced internal (i-tRF) and 3' tRNA (tRF3) fragments, whereas arsenite induced anticodon-cleaved tRNA halves (tiRNAs). mito-tDRs were mostly internal fragments and antimycin induced the strongest mitochondrial tDRs expression. ANG deletion markedly impaired stress-induced tDR biogenesis and sensitized cells to antimycin and oligomycin stress, whereas its overexpression selectively enhanced tDR biogenesis and conferred protection against these mitochondrial stressor. Synthetic tDR mimics failed to rescue viability, implying that native modification patterns or cooperative tDR pools are required. tDR motif enrichment analysis identified YBX1-binding sites among antimycin-induced tDRs, and genetic perturbation of YBX1 phenocopied aspects of enhanced mitochondrial bioenergetics and stress resistance. Together, these findings demonstrate that context-specific, ANG-directed tDR biogenesis forms a crucial arm of the mitochondrial stress response.

Keywords:  Angiogenin; Mitochondrial stress; RNA binding proteins; YBX1; tRNA; tRNA derived fragments

DOI:  https://doi.org/10.1016/j.redox.2026.104038
Genes (Basel). 2026 Jan 13. pii: 82. [Epub ahead of print]17(1):

Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.

Magan N Pittman, Mary Beth Nelsen, Marlo K Thompson, Aishwarya Prakash.

  Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration.

Keywords:  base excision repair; damage associated molecular patterns; mitochondrial DNA; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3390/genes17010082
FEBS J. 2026 Jan 29.

ER proteostasis meets mitochondrial function: contact sites as hubs of communication and therapeutic targets.

Giorgia Maria Renna, Alessandro Cherubini, Ersilia Varone, Serena Germani, Alice Marrazza, Ester Zito.

  Proteostasis maintains the balance between protein synthesis, folding, and degradation within the endoplasmic reticulum (ER). This quality-control system ensures that proteins undergo proper post-translational modifications-such as PDI-ERO1-mediated oxidative folding and STT3-dependent N-glycosylation-so that only correctly folded proteins proceed through the secretory pathway. Impairment of protein load, folding capacity, or degradation via the ER-associated degradation (ERAD) pathway leads to the accumulation of unfolded proteins, triggering ER stress and activating the unfolded protein response (UPR), which, in the first instance, is an adaptive signaling network designed to restore homeostasis by adjusting protein synthesis, enhancing folding capacity, and promoting the clearance of misfolded proteins. During ER stress, the ER undergoes morphological and functional remodeling to manage the increased folding burden, including an increase of ER-mitochondria contact sites (ERMCs). These nanometric junctions (~10-100 nm) facilitate lipid and metabolite exchange and mediate calcium and reactive oxygen species signaling to support cellular metabolism. However, chronic ER stress can further tighten ERMCs, leading to calcium overload, mitochondrial dysfunction, and apoptosis. This review examines the core mechanisms underlying ER proteostasis in the context of ER stress and explores how ER stress first boosts mitochondrial activity and later impairs it through ERMCs, contributing to cell death and disease. Finally, emerging therapeutic strategies aimed at restoring proteostasis and modulating the dynamics of ERMCs are highlighted as promising interventions for conditions, such as cancer and congenital myopathies, where ER and mitochondrial dysfunction play central roles in pathogenesis.

Keywords:  ERMC; cancer; mitochondria metabolism; neuromuscular diseases; proteostasis

DOI:  https://doi.org/10.1111/febs.70431
Biomedicines. 2026 Jan 08. pii: 126. [Epub ahead of print]14(1):

Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers.

Isabella Ionela Stoian, Daciana Nistor, Mihaela Codrina Levai, Daian Ionel Popa, Roxana Popescu.

  Background and Objectives: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. Methods: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34-PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. Results: Twelve studies met the criteria across tauopathies and Alzheimer's disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington's disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer's hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. Conclusions: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation.

Keywords:  drug effects; drug therapy; endoplasmic reticulum; eukaryotic metabolism; neurodegenerative diseases; protein kinase; protein response physiology

DOI:  https://doi.org/10.3390/biomedicines14010126
Sci Rep. 2026 Jan 27.

SIRT1 activation by SRT2104 enhances mitophagy and reduces senescence in auditory cells.

Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.

Age-related hearing loss is characterized by the progressive degeneration of cochlear hair cells and neurons, with mitochondrial dysfunction and impaired mitophagy implicated as molecular mechanisms. Sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, plays a critical role in the regulation of mitochondrial quality control and mitophagy. SRT2104, a synthetic SIRT1 activator with improved bioavailability compared to resveratrol, has shown neuroprotective effects in age-related neurodegeneration. However, the role of SIRT1 in auditory cell senescence remains unclear. In this study, we investigated the effects of SRT2104 on cellular senescence and mitophagy in HEI-OC1 auditory cells and organotypic cochlear explants. Senescence was induced using low-dose H₂O₂, and SRT2104 was used as a pre-treatment. SRT2104 significantly enhanced SIRT1 activity, upregulated mitophagy-related proteins (PINK1, Parkin, BNIP3, and LC3-II), and downregulated senescence markers (p53 and p21) in cellular and explant models. β-galactosidase staining confirmed reduced senescence in SRT2104-treated groups. Pre-treatment with SRT2104 preserved mitochondrial function, as indicated by enhanced mitochondrial membrane potential, improved mitochondrial DNA integrity, and increased ATP production. SIRT1 knockdown abolished these protective effects, confirming that SRT2104 mediated its anti-senescence and pro-mitophagy activities via SIRT1. Our findings demonstrated that SRT2104 alleviates premature senescence and promotes mitophagy in auditory cells via SIRT1 activation. The pharmacological activation of SIRT1 may represent a promising therapeutic strategy to counteract age-related degeneration in the auditory system.

DOI: https://doi.org/10.1038/s41598-026-37606-8
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]

Mitochondria as sources and targets of cellular signaling.

Anna Meichsner, Verian Bader, Konstanze F Winklhofer.

  Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.

Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
Mater Today Bio. 2026 Apr;37 102785

Functionalized hydrogels of CeO2 and Urolithin A synergistically scavenge ROS and activate mitophagy for cartilage repair.

Chunhui Ma, Bingxuan Hua, Houlei Wang, Tianle Ma, Qi Lv, Zuoqin Yan.

  In recent years, CeO2 nanoparticles are promising biomaterials due to their excellent biocompatibility and antioxidant properties. This study utilizes a methacrylated gelatin (GelMA) hydrogel platform to construct a dual-functional composite material, CeUA@GelMA, by co-loading CeO2 nanoparticles with urolithin A (UA). This material possesses both reactive oxygen species (ROS) scavenging and mitophagy activation capabilities, aiming to overcome the bottleneck in cartilage regeneration by regulating mitochondrial homeostasis. In vitro experiments confirmed that this material significantly reduces ROS levels within BMSCs under oxidative stress, maintains mitochondrial membrane potential, and promotes chondrogenic differentiation by upregulating genes such as Sox9, Col II, and ACAN. In vivo studies demonstrated that the CeUA@GelMA group achieved hyaline-like cartilage regeneration 8 weeks post-operation. The surface roughness of the newly formed cartilage was comparable to that of natural cartilage, with collagen and glycosaminoglycan density approaching normal cartilage levels. In summary, this research offers an innovative strategy and hydrogel material for cartilage tissue engineering through the regulation of mitochondrial homeostasis.

Keywords:  Cartilage repair; CeO2; Mitophagy; ROS; Urolithin A

DOI:  https://doi.org/10.1016/j.mtbio.2026.102785
Autophagy. 2026 Jan 28.

Mitophagic activity and protein levels differ across and within muscles: implications for future skeletal muscle mitophagy research.

Fasih A Rahman, Mackenzie Q Graham, Joe Quadrilatero.

  Skeletal muscle is a heterogeneous tissue consisting of fibers with distinct contractile speeds, metabolic profiles, and cellular signaling. This heterogeneity may extend to mitochondrial quality control processes such as mitophagy. Using mt-Keima mice, we found that mitophagic activity was greater in the fast-twitch, glycolytic extensor digitorum longus (EDL) compared to the slow-twitch, oxidative soleus (SOL) muscle. Live imaging of quadriceps (QUAD) muscle revealed two distinct fiber populations: those with high total mt-Keima signal but low mitophagic activity, and others with low signal but higher mitophagic activity. Additionally, we observed skeletal muscle type and regional differences in autophagic and mitophagic protein content. Further, select mitophagic proteins strongly correlated with mitochondrial proteins across different regions of the gastrocnemius, while others did not. These findings highlight the complexity of mitophagy regulation in skeletal muscle and emphasize the importance of considering muscle phenotype, including fiber type, region, and mitochondrial content when studying mitophagy.

Keywords:  Fibers; metabolism; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2026.2623988
Int J Biol Sci. 2026 ;22(3): 1247-1265

Targeting CDC42 Protects Mitochondrial Function through KLF2/HIF-1α/PINK1 Signaling in Acute Kidney Injury.

Xue Zhou, Xian Fu, Yi-Wen Meng, Ping Dai, Qing Jiang, Hou-Hua Yin, Qing-Jin Pan, Ai-Zhi Lin, Kai-Di Ni, Zi-Guo Luo, Ru-Yu Liang, Yi-Yu Chen, Hai-Xin Yuan, Jun-Yan Liu.

  Acute kidney injury (AKI) is a severe clinical syndrome strongly associated with mitochondrial dysfunction and oxidative stress, yet effective therapies remain elusive. Here, we identify cell division cycle 42 (CDC42) as a critical mediator of AKI. Analysis of human single-cell RNA sequencing (scRNA-seq) dataset revealed marked upregulation of CDC42 in renal tubular epithelial cells (RTECs), which was validated in murine models of cisplatin- and ischemia-reperfusion-induced AKI. Pharmacological inhibition, conditional knockdown, or genetic ablation of CDC42 significantly alleviated renal injury, preserved mitochondrial function, and reduced reactive oxygen species (ROS) both in vivo and in vitro. Mechanistically, transcriptomic analysis, bioinformatic analysis, dual-luciferase reporter assays, ChIP assays and cellular functional validation revealed that CDC42 suppression activated a KLF2/HIF-1α/PINK1 transcriptional cascade, thereby promoting mitophagy and restoring mitochondrial homeostasis. Functional assays supported that this pathway plays a pivotal role in protecting RTECs from oxidative damage. Collectively, these findings uncover a previously unrecognized role of CDC42 in AKI pathogenesis and highlight CDC42 inhibition as a promising therapeutic strategy for mitigating mitochondrial damage and improving renal outcomes.

Keywords:  acute kidney injury; cell division cycle 42; hypoxia-inducible factor-1alpha; kruppel-like factor 2; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.7150/ijbs.125930
Biomolecules. 2026 Jan 08. pii: 117. [Epub ahead of print]16(1):

Mitochondrial Dysfunction: The Cellular Bridge from Emotional Stress to Disease Onset: A Narrative Review.

Sakthipriyan Venkatesan, Cristoforo Comi, Fabiola De Marchi, Teresa Esposito, Carla Gramaglia, Carlo Smirne, Mohammad Mostafa Ola Pour, Mario Pirisi, Rosanna Vaschetto, Patrizia Zeppegno, Elena Grossini.

  Severe emotional stress constitutes a significant public-health concern associated with negative health outcomes. Although the clinical effects are well acknowledged, the specific biological mechanisms that translate emotional suffering into systemic disease remain incompletely understood. Psychological stress activates the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, which directly target mitochondria and alter their bioenergetic and redox capacity. For this reason, this narrative review proposes that mitochondria serve as the primary subcellular link in the mind-body connection, as they play a pivotal role in converting neuroendocrine signals into cellular dysfunction. In particular, we focus on the concept of mitochondrial allostatic load (MALT), a framework explaining how the progressive decline in mitochondrial functions, from their initial adaptive roles in energy production, reactive oxygen species signaling, and calcium regulation, to being sources of inflammation and systemic damage, occurs when stress exceeds regulatory limits. We also, discuss how this transition turns mitochondria from adaptive responders into drivers of multi-organ disease. In subsequent sections, we examine diagnostic potentials related to MALT, including the use of biomarkers, such as growth differentiation factor 15, cell-free mitochondrial desoxyribonucleic acid, and functional respirometry. Furthermore, we evaluate mitochondria-targeted therapeutic strategies, encompassing pharmacological compounds, such as mitoquinone mesylate, Skulachev ions, and elamipretide, alongside lifestyle and psychological interventions. Here, we aim to translate MALT biology into clinical applications, positioning mitochondrial health as a target for preventing and treating stress-related disorders. We propose that MALT may serve as a quantifiable bridge between emotional stress and somatic disease, enabling future precision medicine strategies integrating mitochondrial care.

Keywords:  allostatic load; mitochondrial dysfunction; psychosocial stress; reactive oxygen species; relationship trauma; systemic nervous system

DOI:  https://doi.org/10.3390/biom16010117
Biomolecules. 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):

Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.

Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli, Elisa Greotti.

  Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria-glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer's disease.

Keywords:  Alzheimer’s disease; astrocyte–neuron communication; excitotoxicity; glutamate homeostasis; glutamatergic synapse; metabolic coupling; mitochondrial Ca2+ signaling; mitochondrial signaling; neuronal hyperexcitability; synaptic vulnerability

DOI:  https://doi.org/10.3390/biom16010171
Life Sci. 2025 Dec 01. pii: S0024-3205(25)00684-8. [Epub ahead of print]382 124048

Viable exogenous mitochondria modulate neurochemical and behavioral features of fibromyalgia in a reserpine-induced fibromyalgia model.

Nourhan S Elkholy, Haitham S Mohammed, Ayman Saber Mohamed, Abdou Kamal Allayeh, Ahmed M Al-Abd.

  Fibromyalgia Syndrome (FMS) is a chronic disorder marked by widespread pain, fatigue, and cognitive dysfunction, often associated with mitochondrial dysfunction and oxidative stress. Despite existing treatments, none address the underlying mitochondrial defects. This study investigates the potential of viable exogenous mitochondria, isolated from H9C2 (2-1) myocardial cells, as a preclinical therapeutic and regenerative intervention for FMS in a reserpine-induced fibromyalgia rat model. Three doses (0.15, 0.5, and 1.5 mg/kg) of mitochondria were prepared and characterized using electron microscopy, dynamic light scattering, and flow cytometry for their integrity and viability. The different doses were intravenously administered in reserpine-induced FM female rats to determine the optimal therapeutic dosage. Key findings demonstrated dose-dependent effects on FM-related markers such as nociceptive response latency, blood serum assays, oxidative stress biomarkers, and neurotransmitter levels. A biodistribution study revealed preferential accumulation of mitochondria in affected tissues, such as the brain and soleus muscle, suggesting targeted delivery and potential regenerative effects. These findings provide preliminary preclinical evidence supporting mitochondrial transplantation as a novel and effective regenerative therapy for addressing mitochondrial dysfunction in fibromyalgia, suggesting a promising direction for future research on interventions targeting chronic pain and metabolic dysfunction.

Keywords:  Biodistribution; Exogenous mitochondria; Fibromyalgia; Mitochondrial dysfunction; Neurotransmitters; Oxidative stress; Reserpine model

DOI:  https://doi.org/10.1016/j.lfs.2025.124048
Biology (Basel). 2026 Jan 14. pii: 148. [Epub ahead of print]15(2):

Immune Determinants of MASLD Progression: From Immunometabolic Reprogramming to Fibrotic Transformation.

Senping Xu, Zhaoshan Zhang, Zhongquan Zhou, Jiawei Guo.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a progressive spectrum of metabolic liver injury in which immune activation, metabolic stress, and stromal remodeling evolve in a tightly interdependent manner. Although early disease stages are dominated by metabolic overload, accumulating evidence indicates that immunometabolic rewiring and fibro-inflammatory amplification critically shape the transition toward metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis. This review synthesizes emerging insights into how hepatocyte stress responses, innate and adaptive immune circuits, and extracellular matrix-producing stromal populations interact to form a dynamic, feed-forward network driving disease progression. Particular emphasis is placed on the deterministic role of immune-fibrotic coupling in shaping clinical phenotypes, disease trajectory, and therapeutic responsiveness. Rather than focusing on individual molecular layers, we highlight how integrated clinical, imaging, and biomarker-informed frameworks can capture immune-fibrotic signatures relevant to risk stratification and precision intervention. Building on this systems-level perspective, we outline next-generation therapeutic strategies targeting immunometabolic circuits, cross-organ communication, and multi-system dysfunction. Finally, we discuss how future precision medicine-supported by integrative biomarker profiling and dynamic physiological assessment-may reshape MASLD management and improve long-term hepatic and cardiometabolic outcomes.

Keywords:  adaptive immunity; fibrotic remodeling; immunometabolic reprogramming; metabolic dysfunction-associated steatotic liver disease

DOI:  https://doi.org/10.3390/biology15020148
J Adv Res. 2026 Jan 26. pii: S2090-1232(26)00090-1. [Epub ahead of print]

Mitocytosis, mitophagy, and apoptosis coordinately drive mitochondrial clearance to regulate myogenic differentiation.

Dandan Wang, Mei Li, Jun Ma, Guocheng Du, Jingwen Zhou, Jian Chen, Xin Guan.

   INTRODUCTION: Skeletal muscle is a high-energy-consuming tissue whose development and function critically depend on mitochondrial homeostasis. Mitochondrial quality control involves multiple clearance mechanisms, including mitocytosis, mitophagy, and apoptosis. However, how these pathways are coordinated during myogenic differentiation remains systematically unexplained.
OBJECTIVES: This study aimed to investigate the sequential activation and coordination of mitocytosis, mitophagy, and apoptosis inresponse to gradient mitochondrial damage, and to explore their impact on myogenesis.
METHODS: We established a gradient mitochondrial damage model in myoblasts using different concentrations of CCCP. Through fluorescence imaging, western blotting, genetic interventions, and small-molecule inhibitors, we investigated the activation sequence and crosstalk among different clearance pathways, and explored their effects on myotube formation and function.
RESULTS: Escalating mitochondrial damage triggered a sequential activation of clearance mechanisms: KIF5B-mediated mitocytosis was first induced, followed by PINK1-dependent mitophagy, and ultimately Caspase 3-mediated apoptosis. When mitocytosis was inhibited, mitophagy dominated mitochondrial clearance, whereas enhanced mitocytosis suppressed both mitophagy and apoptosis. When mitophagy was impaired, cellular homeostasis could be maintained by upregulating mitocytosis under mild mitochondrial damage, but this led to premature apoptosis under severe mitochondrial damage. Myogenesis was significantly suppressed when either mitocytosis or mitophagy was impaired, whether through small-molecule inhibitors or the genetic knockdown of KIF5B or PINK1. Notably, low-dose CCCP treatment promoted myotube formation and mitochondrial function, and also attenuated the myogenic deficits resulting from KIF5B or PINK1 deficiency. Furthermore, KIF5B overexpression enhanced glycolytic metabolism and accelerated myoblast proliferation, highlighting its role beyond mitochondrial clearance.
CONCLUSION: These findings provide new insights into the coordinated regulatory network among mitochondrial clearance mechanisms and their roles in myogenic differentiation. These insights advance the understanding of muscle biology and offer potential strategies for enhancing muscle regeneration in biomedical and cellular agriculture applications.

Keywords:  Apoptosis; Mitochondrial clearance; Mitocytosis; Mitophagy; Myogenic differentiation

DOI:  https://doi.org/10.1016/j.jare.2026.01.065
Aging Cell. 2026 Feb;25(2): e70390

In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.

Wayne Mitchell, Cecília G de Magalhães, Alexander Tyshkovskiy, Yushi Uchida, Ludger J E Goeminne, Takaharu Ichimura, Emery L Ng, Alibek Moldakozhayev, Joseph V Bonventre, Vadim N Gladyshev.

  Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.

Keywords:  aging; aging biomarkers; chemical reprogramming; lipid droplets; mitochondria; mitochondrial morphology; oxidative phosphorylation; rejuvenation; reprogramming

DOI:  https://doi.org/10.1111/acel.70390