bims-tofagi Biomed News
on Mitophagy
Issue of 2026–06–14
fifteen papers selected by
Michele Frison, University of Cambridge
  1. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  2. STING1 senses mitochondrial damage to promote mitophagy.
  3. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  4. Mitophagy-mediated immune evasion: Shared strategies of pathogens.
  5. Mitophagy: an emerging therapeutic target in mitochondrial diseases.
  6. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  7. MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
  8. UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
  9. The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
  10. NOP2-mediated m5C methylation impairs mitophagy and aggravates acute lung injury by targeting PINK1.
  11. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  12. Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.
  13. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  14. Senescent BMSC-Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing PINK1/Parkin-Mediated Mitophagy in Macrophages.
  15. Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
  1. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  2. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  3. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  4. Redox Biol. 2026 Jun 05. pii: S2213-2317(26)00245-4. [Epub ahead of print]95 104247
    Mitophagy-mediated immune evasion: Shared strategies of pathogens.
    Jun Li, Weijian Li, Dan Wang, Yulan Liu.
      Mitophagy selectively eliminates dysfunctional mitochondria, playing a pivotal role in mitochondrial quality control and cellular homeostasis. Emerging evidence reveals that certain pathogens exploit mitophagy to evade host immune defenses. Here, we provide novel insights into the regulatory mechanisms of mitophagy by integrating it with mitochondrial dynamics, and systematically review the mechanisms by which intracellular bacteria, viruses, and parasites utilize mitophagy to subvert host innate immunity. Notably, some pathogens dynamically regulate mitophagy at different infection stages to facilitate their survival, and the mitophagy show a positive correlation with mitochondrial fission/fragmentation. This review further summarizes four therapeutic strategies to counteract pathogen-induced immune evasion via mitophagy: 1) pharmacological modulation of mitophagy pathways; 2) mitochondria-targeted nanomaterials delivery systems; 3) mitochondria transplantation; 4) nanoengineered mitochondria. Moreover, two core mechanistic questions that remain to be addressed: (1) The mechanisms of time-dependent mitophagy-mediated immune evasion during infection, and (2) the mechanistic connection between mitochondrial dynamics and mitophagy. Future studies could employ label-free holographic tomography microscopy combined with artificial intelligence to visualize and quantify pathogen-induced subcellular alterations, enhancing our understanding of how mitophagy is manipulated, particularly through stage-specific regulation. These insights may open new avenues for treating infections resistant to conventional therapies.
    Keywords:  Immune evasion; Mitophagy; Pathogen infection; Therapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104247
  5. Biochem J. 2026 Jul 08. 483(7): 1193-1220
    Mitophagy: an emerging therapeutic target in mitochondrial diseases.
    Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.
    Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20260161
  6. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  7. Autophagy. 2026 Jun 13.
    MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
    Ming-Hua Wu, Xue-Ming Zhu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.
      Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in Magnaporthe oryzae remains poorly understood. In our recent study, we found that upon outer mitochondrial membrane disruption, inner mitochondrial membrane (IMM) protein MoCox6 is rendered available for engagement with cytosolic MoAtg5 and MoAtg14 to drive mitophagy, whereas MoSirt5-mediated desuccinylation of MoCox6 at K144 weakens these interactions and thereby restrains mitophagic flux. Further analyses identified Asp95 at the MoSirt5-MoCox6 interface as a pivotal residue coupling mitochondrial metabolic control to mitophagy. A high-throughput virtual screening targeting an Asp95-centered pocket in MoCox6 identified Pan-RAS-IN-1, a small molecule that effectively suppresses rice blast incidence and exhibits broad-spectrum antifungal activity. Collectively, these findings identify MoCox6 as an IMM regulator of mitophagy whose succinylation state links mitochondrial metabolic cues to mitochondrial turnover, while highlighting mitochondrial quality control as a potential target for fungal disease management.
    Keywords:  Fungicide target; MoCox6; magnaporthe oryzae; mitophagy; succinylation
    DOI:  https://doi.org/10.1080/15548627.2026.2689458
  8. PLoS One. 2026 ;21(6): e0350815
    UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
    Qinhui Lu, Yanli Yang, Biao Ruan.
      Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract, and recent studies suggest that mitochondrial dysfunction may play a role in its pathogenesis. This study aimed to identify key genes related to AR and mitochondrial autophagy through bioinformatics analysis and to verify their functional roles in vitro. Transcriptomic data from the GEO database were analyzed, and ubiquitin C (UBC) and ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) were identified as potential genes associated with AR and mitophagy. In vitro, IL-13-stimulated human nasal epithelial cells (HNEpCs) were used to establish an AR model. RT-qPCR and Western blotting showed that UBC and UBA52 were significantly upregulated, while mitophagy-related genes PINK1 and Parkin were downregulated. Flow cytometry and TMRE staining demonstrated increased ROS levels and reduced mitochondrial membrane potential (MMP), indicating mitochondrial dysfunction. Co-immunoprecipitation confirmed an interaction between UBC and UBA52. Silencing UBC downregulated UBA52 expression, restored PINK1 and Parkin levels, decreased ROS accumulation, and improved MMP, suggesting potential reactivation of the PINK1-Parkin-mediated mitophagy pathway. These findings suggest that UBC and UBA52 may be involved in the regulation of mitophagy and contribute to mitochondrial dysfunction in AR. Targeting the UBC-UBA52 axis may provide a novel therapeutic strategy for restoring mitochondrial homeostasis in allergic inflammation.
    DOI:  https://doi.org/10.1371/journal.pone.0350815
  9. Mol Neurobiol. 2026 Jun 11. pii: 687. [Epub ahead of print]63(1):
    The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
    Liping Xing, Annan Liu, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.
      Mitophagy, the selective clearance of damaged mitochondria, is a critical mechanism for mitochondrial quality control in cerebral ischemia-reperfusion injury (CIRI). The PINK1/Parkin signaling pathway is the primary ubiquitin-dependent pathway mediating mitochondrial autophagy, and its functional status directly influences the pathological progression of CIRI. This review systematically examines the molecular activation mechanisms of PINK1/Parkin-mediated mitophagy in CIRI and analyzes its interactions with core pathological processes, including oxidative stress, calcium homeostasis disruption, ferroptosis, and neuroinflammation. Furthermore, we summarize the latest advances over the past 5 years in modern medical strategies, traditional Chinese medicine interventions, and gene and protein-targeted therapies directed at this pathway. By integrating existing evidence, this review is aimed at deepening our understanding of the molecular mechanisms underlying CIRI and providing a theoretical foundation for developing novel neuroprotective therapies that target this pathway.
    Keywords:  Cerebral ischemia-reperfusion injury; Mitophagy; PINK1/Parkin signaling pathway; Pathological mechanisms; Potential interventions
    DOI:  https://doi.org/10.1007/s12035-026-05997-4
  10. Sci Rep. 2026 Jun 10.
    NOP2-mediated m5C methylation impairs mitophagy and aggravates acute lung injury by targeting PINK1.
    Xiaoyuan Chen, Rui Zhao, Hong Zhu, Yang Lu.
      Sepsis-induced acute lung injury (ALI) involves complex pathological mechanisms. 5-methylcytosine (m5C) RNA modification, catalyzed by methyltransferases like NOP2, plays a crucial role in regulating inflammation and cellular processes. However, the role of NOP2 and its potential regulation of m5C modification in sepsis-induced ALI remains unclear. An in vitro ALI model was established by treating human pulmonary epithelial A549 cells with lipopolysaccharide (LPS). Inflammatory cytokine levels (IL-1β, IL-6, TNF-α) were measured by ELISA. Apoptosis was assessed by flow cytometry. Mitophagy was evaluated via immunofluorescence staining for mitochondrial Parkin and western blot analysis of Parkin, LC3-II, COX IV, and p62. The m5C modification of PINK1 mRNA was analyzed by m5C-RIP-PCR. The specific m5C site was identified using bioinformatics and validated by dual-luciferase reporter assays. LPS treatment significantly upregulated NOP2 expression in A549 cells. Knockdown of NOP2 attenuated LPS-induced inflammation, apoptosis, and promoted mitophagy, as evidenced by increased Parkin translocation, elevated LC3-II levels, and decreased p62 and COX IV levels. Mechanistically, NOP2 knockdown reduced m5C modification on PINK1 mRNA, particularly at site 197, thereby enhancing PINK1 mRNA stability and increasing its expression. Furthermore, knockdown of PINK1 reversed the protective effects of NOP2 knockdown on inflammation, apoptosis, and mitophagy in LPS-treated A549 cells. NOP2 is upregulated in LPS-induced ALI models. Its knockdown alleviates cellular injury by reducing the m5C modification of PINK1 mRNA, which enhances PINK1 expression and promotes mitophagy. The NOP2/m5C/PINK1 axis represents a novel regulatory pathway in sepsis-induced ALI, suggesting potential therapeutic targets for its treatment.
    Keywords:  Acute lung injury; NOP2; PINK1; Sepsis
    DOI:  https://doi.org/10.1038/s41598-026-56994-5
  11. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  12. Mitochondrion. 2026 Jun 11. pii: S1567-7249(26)00074-7. [Epub ahead of print] 102184
    Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.
    Sudhir Kshirsagar, Arubala P Reddy, P Hemachandra Reddy.
       OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease.
    METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy.
    RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments.
    CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.
    Keywords:  Alzheimer's disease; Mitochondrial dynamics; Mitochondrial fragmentation; Mitophagy enhancers; Urolithin A
    DOI:  https://doi.org/10.1016/j.mito.2026.102184
  13. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  14. Aging Cell. 2026 Jun;25(6): e70575
    Senescent BMSC-Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing PINK1/Parkin-Mediated Mitophagy in Macrophages.
    Yifeng Xing, Jingjing Su, Yanjun Lin, Nengwen Huang, Sihui Zhang, Yuwei Zhou, Jie Lu, Weiping Chen, Kaixun He, Wenxiu Yuan, Yang Li, Geyuan Zheng, Pengyuan Hu, Dong Wu, Yanjing Ou, Jiang Chen.
      The aging bone marrow microenvironment is characterized by chronic low-grade inflammation ("inflammaging"), which disrupts skeletal homeostasis and impairs bone regeneration. However, the stromal-immune crosstalk mechanisms sustaining this pathological state remain poorly defined. Here, transcriptomic analysis identified thrombospondin-1 (Thbs1) as a key upregulated component of the senescence-associated secretory phenotype (SASP) in aged bone mesenchymal stromal cells (BMSCs). We demonstrate that BMSC-derived Thbs1 drives pro-inflammatory M1 macrophage polarization by suppressing PINK1/Parkin-mediated mitophagy. Mechanistically, Thbs1 binds to the TGF-β type II receptor (Tgfbr2) on macrophages to activate Smad3 signaling, which transcriptionally represses the mitophagy regulator Pink1. This repression leads to mitochondrial superoxide accumulation and redox imbalance, thereby skewing macrophages toward an M1-like phenotype. These Thbs1-activated M1 macrophages, in turn, secrete IL-6, which activates the JAK/STAT3 pathway in BMSCs to inhibit osteogenic differentiation. Crucially, activated Stat3 directly binds the Thbs1 promoter, establishing a self-amplifying loop that perpetuates inflammaging and osteogenic decline. In vivo, AAV9-mediated Thbs1 knockdown in aged rat bone defects restored mitochondrial homeostasis, promoted an M2 macrophage transition, and significantly enhanced bone repair. Our study reveals a vicious cycle involving the Thbs1/TGF-β/Smad3/PINK1-IL-6/JAK/STAT3 axis that sustains inflammaging and osteogenic decline, highlighting Thbs1 as a promising therapeutic target for age-related bone regeneration.
    Keywords:  bone regeneration; cellular senescence; inflammaging; macrophage polarization; mitophagy; thrombospondin‐1
    DOI:  https://doi.org/10.1111/acel.70575
  15. Curr Neuropharmacol. 2026 Jun 08.
    Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
    Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.
    Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.
    DOI:  https://doi.org/10.2174/011570159X473929260605103158
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