bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–02–09
sixty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Phytochemicals Targeting Mitophagy to Treat Heart Diseases: Retrospective Insights and Prospective Directions.
  2. Hypothermia regulates mitophagy and apoptosis via PINK1/Parkin-VDAC 3 signaling pathway during oxygen-glucose deprivation/recovery injury.
  3. Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function.
  4. The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.
  5. Chikusetsu saponin IVa attenuates aging by improving autophagy and mitophagy.
  6. Proteomic analysis reveals QiShenYiQi Pills ameliorates ischemia-induced heart failure through inhibition of mitochondrial fission.
  7. Inhibition of Mitochondrial Fission Reverses Simulated Microgravity-Induced Osteoblast Dysfunction by Enhancing Mechanotransduction and Epigenetic Modification.
  8. Therapeutic modulation of mitochondrial dynamics by agmatine in neurodegenerative disorders.
  9. Twist2 knockdown alleviates renal ischemia-reperfusion injury by maintaining mitochondrial function and enhancing mitophagy through Bnip3.
  10. Harmine promotes axon regeneration through enhancing glucose metabolism.
  11. Electroacupuncture alleviates damage to myopic RGCs probably through lncRNA-XR_002789763.1-mediated mitophagy.
  12. Development and validation of a sensitive sandwich ELISA against human PINK1.
  13. Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII.
  14. Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
  15. HACE1 protects against myocardial ischemia-reperfusion injury via inhibition of mitochondrial fission in mice.
  16. Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.
  17. Hsp90 and HIF-1α regulate mitophagy by promoting BNIP3 expression in renal ischemia-reperfusion injury.
  18. Retraction: Nanocurcumin Prevents Hypoxia Induced Stress in Primary Human Ventricular Cardiomyocytes by Maintaining Mitochondrial Homeostasis.
  19. Lycium barbarum polysaccharide mitigates high-fat-diet-induced skeletal muscle atrophy by promoting AMPK/PINK1/Parkin-mediated mitophagy.
  20. VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
  21. Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival.
  22. Mitophagy is induced in human engineered heart tissue after simulated ischemia and reperfusion.
  23. The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.
  24. Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.
  25. Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
  26. CircSPG21 ameliorates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells and mitigates intervertebral disc degeneration through the miR-217/SIRT1 axis and mitophagy.
  27. Dahuang chuanxiong decoction against contrast-induced nephropathy: Multi-omics, crosstalk between BNIP3-mediated mitophagy and IL-17 pathway.
  28. Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.
  29. Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
  30. Neuroprotective Role of Da Qin Jiu Decoction in Ischemic Stroke: Mitochondrial Rescue through PI3K/Akt-Mediated UPRmt Activation.
  31. Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
  32. Physiological and pathological roles of PGAM5: An update and future trend.
  33. Xin-Ji-Er-Kang balances mitochondrial fusion and fission to protect cardiomyocytes in mice with heart failure by regulating the ERα/SIRT3 pathway.
  34. Nutrient status alters developmental fates via a switch in mitochondrial homeodynamics.
  35. CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.
  36. Skeletal Muscle Mitochondrial and Autophagic Dysregulation Are Modifiable in Spinal Muscular Atrophy.
  37. Role of calcium overload-mediated disruption of mitochondrial dynamics in offspring neurotoxicity due to methylmercury exposure during pregnancy and lactation.
  38. mTOR-related linc-PMB promotes mitochondrial biogenesis via stabilizing SIRT1 mRNA through binding to the HuR protein.
  39. Harnessing an MMP-Independent NIR Probe Unveiling the Different Mitochondrial Cristae Changes during Mitophagy and Ferroptosis under STED Microscopy.
  40. Cardioprotective Effects of Adiponectin-Stimulated Autophagy.
  41. Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.
  42. Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to High-risk Behavior, in Multiple Myeloma.
  43. Resveratrol enhances post-injury muscle regeneration by regulating antioxidant and mitochondrial biogenesis.
  44. Pubescenoside D Ameliorates Myocardial Ischemia-Reperfusion Injury via Preventing the Dissociation of HK2 and Promoting Mitophagy by Targeting GSK-3β.
  45. A novel PDE4 inhibitor ZX21011 alleviates neuronal apoptosis by decreasing GSK3β-mediated Drp1 Ser616 phosphorylation in cerebral ischemia reperfusion.
  46. An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
  47. Protocol for assessing the clogging of the mitochondrial translocase of the outer membrane by precursor proteins in human cells.
  48. Identification of mitophagy-related biomarkers and immune infiltration in polycystic ovarian syndrome by bioinformatic study.
  49. Dnajc5b contributes to male fertility by maintaining the mitochondrial functions and autophagic homeostasis during spermiogenesis.
  50. The role of Mitofusin-1 and Mitofusin-2 in periodontal disease: a comprehensive review.
  51. Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
  52. The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
  53. Aggregation-induced emission-twisted intramolecular charge transfer-activated fluorescent probe for analyzing mitochondrial viscosity in cells and zebrafish.
  54. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  55. Creating Optimal Western Blot Conditions for OPA1 Isoforms in Skeletal Muscle Cells and Tissue.
  56. Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
  57. Electroacupuncture promotes neural function recovery by alleviating mitochondria damage in cerebral ischemia mice.
  58. Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans.
  59. HINT1 Suppression Protects Against Age-Related Cardiac Dysfunction by Enhancing Mitochondrial Biogenesis.
  60. Mitochondrial Calcium Uniporter knockdown improves the viability of HT22 hippocampal neurons in Alzheimer's disease.
  61. Mothers with obesity and gestational diabetes did not induce brain pathologies or premature brain aging in their adolescent and early adult offspring in rats.
  1. Phytother Res. 2025 Feb 06.
    Phytochemicals Targeting Mitophagy to Treat Heart Diseases: Retrospective Insights and Prospective Directions.
    Qin Dong, Yichan Zhu, Xinghai Zhang, Lu Li, Yi Yang, Chuan Liu, Jianxia Wen.
      Mitophagy is a process by which cells selectively eliminate damaged or dysfunctional mitochondria through the autophagy-lysosome pathway, thereby maintaining mitochondrial quality and cellular homeostasis. This process is closely linked to the onset and progression of various heart diseases. Modern pharmacological research has demonstrated that phytochemicals can regulate mitochondrial homeostasis in cardiomyocytes through multiple mechanisms, influencing mitophagy and protecting cardiomyocytes, which in turn exerts anti-cardiovascular effects. However, the underlying mechanisms of these effects are not yet fully understood. This study summarizes the pharmacological effects and molecular mechanisms of mitophagy in heart diseases, aiming to provide reference for the research and treatment of phytochemicals targeting mitophagy against heart diseases. The results indicated that phytochemicals (such as Berberine, Ginsenoside Rg1, Quercetin, Resveratrol, Baicalein, and so on) can exert preventive and therapeutic effects on heart diseases (such as cardiac toxicity or damage, myocardial ischemia/reperfusion injury, heart failure, heart aging, cardiac hypertrophy, cardiomyopathy, and so on.) via regulating the PINK1/Parkin and FUNDC1-dependent mitophagy pathway. These compounds mainly exert their effects by regulating mitochondrial homeostasis, mitochondrial dynamics, mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial energy metabolism. This study provides a reference that phytochemicals have effect on anti-cardiovascular effects by regulating mitophagy. However, further in-depth mechanistic and clinical research are needed in the future.
    Keywords:  PINK1/Parkin; energy metabolism; heart diseases; mitophagy; phytochemicals
    DOI:  https://doi.org/10.1002/ptr.8448
  2. Sci Rep. 2025 Feb 07. 15(1): 4607
    Hypothermia regulates mitophagy and apoptosis via PINK1/Parkin-VDAC 3 signaling pathway during oxygen-glucose deprivation/recovery injury.
    Luying Zhang, Song Yang, Hao Cui, Chenchen Hang, Xingsheng Wang, Le An, Zhenyu Shan, Zhen Liang, Rui Shao, Ziren Tang.
      Post-cardiac arrest brain injury (PCABI), as the main cause of high mortality and long-term disability in patients, induces mitochondrial damage and cell apoptosis. Hypothermia is well-known as an effective neuroprotective therapy, but its underlying mechanisms deserve further exploration. Previous study has demonstrated that hypothermia provides neuroprotection via increasing PINK1/Parkin-mediated mitophagy. However, whether hypothermia can regulate both apoptosis and mitophagy through the PINK1/Parkin-VDAC3 signaling pathway or not. In this study, BV2 mouse microglial cells were cultured under oxygen-glucose deprivation for 6 h following reperfusion with or without hypothermia for 2-4 h. Cell viability was examined by trypan blue stain. Mitophagy was observed by transmission electron microscope. Mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening were determined respectively by JC-1 staining and BBcellProbe M61 staining using a flow cytometer. Expression of mitophagy-related proteins (Cleaved PINK1, Parkin, SQSTM1/p62, Beclin-1, LC3B II/LC3B I), apoptosis-related proteins (Bcl-2, Cytochrome C, caspase-3, cleaved caspase3) and VDAC3 were assessed using western blot analysis and quantitative real-time PCR. The interaction between Parkin and VDAC3 was confirmed by immunofluorescence colocalization. The results showed that hypothermia alleviated MMP damage, inhibited mPTP opening, then decreased cell apoptosis and activated mitophagy at 2 h after temperature intervention, which might be mediated by the PINK1/Parkin-VDAC3 signaling pathway. Moreover, the effects of hypothermia were reduced or reversed at 4 h after temperature intervention. In conclusion, the potential mechanisms of hypothermia during oxygen-glucose deprivation/recovery could be summarized as follows:1) At 2 h after temperature intervention, hypothermia provided neuroprotective effects via promoting mitophagy and reducing apoptosis through activating the PINK1/Parkin-VDAC3 signaling pathway. 2) The curative effect of hypothermia was timeliness. At 4 h after temperature intervention, hypothermia aggravated apoptosis through inhibiting Parkin recruitment to mitochondria and aggravating the release of Cyt C through open mPTP.
    Keywords:  Apoptosis; Hypothermia; Mitophagy; Oxygen-glucose deprivation/Recovery; Post-cardiac arrest brain injury
    DOI:  https://doi.org/10.1038/s41598-025-89176-w
  3. J Am Heart Assoc. 2025 Feb 04. 14(3): e037640
    Vascular Contractility Relies on Integrity of Progranulin Pathway: Insights Into Mitochondrial Function.
    Shubhnita Singh, Ariane Bruder, Rafael M Costa, Juliano V Alves, Sivakama Bharathi, Eric S Goetzman, Thiago Bruder-Nascimento.
       BACKGROUND: The complex interplay between vascular contractility and mitochondrial function is central to cardiovascular disease. The progranulin gene (GRN) encodes glycoprotein PGRN (progranulin), a ubiquitous molecule with known anti-inflammatory property. However, the role of PGRN in cardiovascular disease remains undefined. In this study, we sought to dissect the significance of PGRN in the regulation vascular contractility and investigate the interface between PGRN and mitochondrial quality.
    METHODS AND RESULTS: We used aortae from male and female C57BL6/J wild-type (PGRN+/+) and B6(Cg)-Grntm1.1Aidi/J (PGRN-/-) mice. Our results showed suppression of contractile activity in PGRN-/-, followed by reduced α-smooth muscle actin expression. Mechanistically, PGRN deficiency suppressed mitochondrial respiration, induced mitochondrial fission, and disturbed autophagy process and redox signaling, while restoration of PGRN levels in aortae from PGRN-/- mice via lentivirus delivery ameliorated contractility and boosted mitochondria activity. In addition, in vivo treatment with mitochondrial fission inhibitor restored mitochondrial quality and vascular contractility, while vascular smooth muscle cells overexpressing PGRN displayed higher lysosome biogenesis, accelerated mitophagy flux, and mitochondrial respiration accompanied by vascular hypercontractility. Finally, angiotensin II failed to induce vascular contractility in PGRN-/-, suggesting a key role of PGRN to maintain the vascular tone.
    CONCLUSIONS: Our findings suggest that PGRN preserves the vascular contractility via regulating mitophagy flux, mitochondrial activity and dynamics, and redox signaling. Therefore, loss of PGRN function appears as a pivotal risk factor in cardiovascular disease.
    Keywords:  progranulin; vascular contractility; vasculature
    DOI:  https://doi.org/10.1161/JAHA.124.037640
  4. Mitochondrion. 2025 Feb 03. pii: S1567-7249(25)00005-4. [Epub ahead of print] 102008
    The unusual suspect: A novel role for intermediate filament proteins in mitochondrial morphology.
    Irene M G M Hemel, Carlijn Steen, Simon L I J Denil, Gökhan Ertaylan, Martina Kutmon, Michiel Adriaens, Mike Gerards.
      Mitochondrial dynamics is crucial for cellular homeostasis. However, not all proteins involved are known. Using a protein-protein interaction (PPI) approach, we identified ITPRIPL2 for involvement in mitochondrial dynamics. ITPRIPL2 co-localizes with intermediate filament protein vimentin, supported by protein simulations. ITPRIPL2 knockdown reveals mitochondrial elongation, disrupts vimentin processing, intermediate filament formation, and alters vimentin-related pathways. Interestingly, vimentin knockdown also leads to mitochondrial elongation. These findings highlight ITPRIPL2 as vimentin-associated protein essential for intermediate filament structure and suggest a role for intermediate filaments in mitochondrial morphology. Our study demonstrates that PPI analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.
    Keywords:  Intermediate filaments; Mitochondria; Mitochondrial dynamics; Network analysis; Protein-protein interactions
    DOI:  https://doi.org/10.1016/j.mito.2025.102008
  5. Free Radic Biol Med. 2025 Jan 31. pii: S0891-5849(25)00074-7. [Epub ahead of print]230 17-32
    Chikusetsu saponin IVa attenuates aging by improving autophagy and mitophagy.
    Jing-Zhi Wan, Cheng-Quan Li, Ying-Na Li, Ao-Zhong Li, Qi-Long Yang, Meng Kang, Jia-Hao Cao, Hui-Jie Ran, Qi-Ling Liu, Yi Wan, Song Zhai, Miao-Miao Xi, Hai-Feng Tang, Xu-Jun Qin, Ka Bian.
      Chikusetsu saponin IVa (CHS) is an essential active triterpenoid saponin found in various medicinal herbs, such as Aralia taibaiensis, Panax japonicus, and Aralia elata. While multiple health benefits have been documented, the effect of CHS on aging remains unclear. By employing the D-galactose-induced aging mice and the replicative senescence of primary mouse embryonic fibroblasts (MEFs) as the aging models, we found that CHS significantly attenuated aging both in vitro and in vivo. RNA sequencing analysis revealed that CHS greatly improved autophagy and mitophagy. Corresponding to the improved mitophagy, CHS remarkably reduced mitochondrial ROS and enhanced mitochondrial respiratory function. Mitophagy inhibition and Atg 7 genetic knockout (KO) almost abolished the anti-aging effect of CHS. AMPK pathway was activated during the attenuation of aging by CHS treatment, and a specific AMPK inhibitor reversed the induction of mitophagy and autophagy, as well as the attenuation of aging by CHS. Molecular docking data indicated AMPK as the direct binding target of CHS. In conclusion, our study initially demonstrates that CHS exhibits a potent anti-aging effect both in vitro and in vivo. CHS may directly bind to AMPK and activate the AMPK-dependent pathway to enhance autophagy and mitophagy, thereby reducing mitochondrial ROS and improving mitochondrial respiratory function, contributing to the anti-aging effect. These findings offer a new clue for the promising application of CHS in the improvement of aging and aging-related diseases in the future.
    Keywords:  Anti-aging; Chikusetsu saponin IVa (CHS); Mitophagy; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.055
  6. Phytomedicine. 2025 Jan 28. pii: S0944-7113(25)00076-5. [Epub ahead of print]138 156435
    Proteomic analysis reveals QiShenYiQi Pills ameliorates ischemia-induced heart failure through inhibition of mitochondrial fission.
    Jia Li, Xinyao Zhang, Liuqing Hou, Bo-Yu Liu, Yuan-Ming Fan, Yajun Zhang, Feizuo Wang, Keke Jia, Xiang Li, Zongxiang Tang, Xiaojian Yin.
       BACKGROUND: QiShenYiQi Pills (QSYQ) has widely used in clinical treatment of cardiovascular diseases; however, the exact mechanism behind its effectiveness still requires further investigation.
    PURPOSE: The purpose of the study was to explore the potential mechanism of QSYQ in the treatment of ischemic heart failure from the perspective of proteomics.
    METHODS: In vivo, to observe QSYQ actions on the progression of ischemia-induced heart failure, cardiac function and remodeling was analyzed. The heart tissues of mice were used for Tandem Mass Tag (TMT)-based proteomic analysis. Cardiomyocytes were prepared and subjected to oxygen-glucose deprivation injury. QSYQ effects on differential proteins expressions, mitochondrial fission and mitochondrial function were assayed.
    RESULTS: QSYQ treatment preserved cardiac function, limited cardiac fibrosis and alleviated cardiomyocyte hypertrophy in post-myocardial ischemia mice. Proteomic analysis revealed that QSYQ-responsive proteins were mainly involved in mitochondrial fission, including mitochondrial calcium uniporter (MCU), membrane associated ring-CH-type finger 5 (MARCHF5), and mitochondrial fission process 1 (MTFP1). Protein-protein interaction analysis revealed that MCU, MARCHF5 and MTFP1 commonly interacted with dynamin-related protein 1 (DRP1). Knockdown of MCU, MARCHF5, or MTFP1 attenuated excessive mitochondrial fission in cardiomyocytes through regulating DRP1 phosphorylation and its mitochondrial translocation. QSYQ decreased the phosphorylation of DRP1 at Ser616 and enhanced its inhibitory phosphorylation at Ser637, as well as mitigating the mitochondrial recruitment and oligomerization of DRP1, through downregulation of these three differential proteins. As a result, QSYQ alleviated aberrant mitochondrial fission, ameliorated mitochondrial dysfunction, and protected cardiomyocytes from ischemic injury.
    CONCLUSION: The novelty lies in the proteomics-based investigation of the mechanism of QSYQ, uncovering that QSYQ mitigated ischemia-induced heart failure by suppressing MCU/MARCHF5/MTFP1-DRP1-driven mitochondrial fission.
    Keywords:  Dynamin-related protein 1; Ischemia-induced heart failure; Mitochondrial fission; Proteomic analysis; QiShenYiQi pills
    DOI:  https://doi.org/10.1016/j.phymed.2025.156435
  7. Research (Wash D C). 2025 ;8 0602
    Inhibition of Mitochondrial Fission Reverses Simulated Microgravity-Induced Osteoblast Dysfunction by Enhancing Mechanotransduction and Epigenetic Modification.
    Qiusheng Shi, Yaxin Song, Jingqi Cao, Jing Na, Zhijie Yang, Xinyuan Chen, Ziyi Wang, Yubo Fan, Lisha Zheng.
      Simulated microgravity (SMG) poses substantial challenges to astronaut health, particularly impacting osteoblast function and leading to disuse osteoporosis. This study investigates the adverse effects of SMG on osteoblasts, focusing on changes in mitochondrial dynamics and their consequent effects on cellular energy metabolism and mechanotransduction pathways. We discovered that SMG markedly reduced the expression of osteoblast differentiation markers and promoted mitochondrial fission, as indicated by an increase in punctate mitochondria, a decrease in mitochondrial length, and a reduction in cristae density. These mitochondrial alterations are linked to elevated reactive oxygen species levels, a decrease in ΔΨm, and a metabolic shift from oxidative phosphorylation to glycolysis, resulting in decreased adenosine triphosphate production, which are all indicative of mitochondrial dysfunction. Our results showed that treatment with mitochondrial division inhibitor-1 (mdivi-1), a mitochondrial fission inhibitor, effectively inhibited these SMG-induced effects, thereby maintaining mitochondrial structure and function and promoting osteoblast differentiation. Furthermore, SMG disrupted critical mechanotransduction processes, by affecting paxillin expression, the RhoA-ROCK-Myosin II pathway, and actin dynamics, which subsequently altered nuclear morphology and disrupted Yes-associated protein signaling. Notably, treatment with mdivi-1 prevented these disruptions in mechanotransduction pathways. Moreover, our study showed that SMG-induced chromatin remodeling and histone methylation, which are epigenetic barriers to osteogenic differentiation, can be reversed by targeting mitochondrial fission, further highlighting the significance of mitochondrial dynamics in osteoblast function in an SMG environment. Therefore, targeting mitochondrial fission emerges as a promising therapeutic strategy to alleviate osteoblast dysfunction under SMG conditions, providing novel approaches to maintain bone health during prolonged space missions and safeguard the astronaut well-being.
    DOI:  https://doi.org/10.34133/research.0602
  8. Neuroscience. 2025 Jan 29. pii: S0306-4522(25)00077-6. [Epub ahead of print]569 43-57
    Therapeutic modulation of mitochondrial dynamics by agmatine in neurodegenerative disorders.
    Dhanshree Nibrad, Amit Shiwal, Manasi Tadas, Raj Katariya, Mayur Kale, Nandkishor Kotagale, Milind Umekar, Brijesh Taksande.
      Mitochondrial dysfunction is a pivotal factor in the pathogenesis of neurodegenerative disorders, driving neuronal degeneration through mechanisms involving oxidative stress, impaired energy production, and dysregulated calcium homeostasis. Agmatine, an endogenous polyamine derived from arginine, has garnered attention for its neuroprotective properties, including anti-inflammatory, anti-oxidative, and antiapoptotic effects. Recent studies have highlighted the potential of agmatine in preserving mitochondrial function and mitigating neurodegeneration, making it a promising candidate for therapeutic intervention. One of the key mechanisms by which agmatine exerts its neuroprotective effects is through the maintenance of mitochondrial homeostasis. Agmatine has been shown to modulate mitochondrial dynamics, promoting mitochondrial fusion and fission balance essential for cellular energy metabolism and signaling. Moreover, agmatine acts as a regulator of mitochondrial permeability transition pore (mPTP) opening, preventing excessive calcium influx and subsequent mitochondrial dysfunction. Despite promising findings, challenges such as optimizing agmatine's pharmacokinetics, determining optimal dosing regimens, and elucidating its precise molecular targets within mitochondria remain to be addressed. Future research directions should focus on developing targeted delivery systems for agmatine, investigating its interactions with mitochondrial proteins, and conducting well-designed clinical trials to evaluate its therapeutic efficacy and safety profile in neurodegenerative disorders. Overall, agmatine emerges as a novel therapeutic agent with the potential to modulate mitochondrial homeostasis and alleviate neurodegenerative pathology, offering new avenues for treating these debilitating conditions.
    Keywords:  Agmatine; Calcium Homeostasis; Mitochondrial Dynamics; Mitochondrial Homeostasis; Neurodegenerative Disorders; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.01.061
  9. Hum Cell. 2025 Feb 07. 38(2): 50
    Twist2 knockdown alleviates renal ischemia-reperfusion injury by maintaining mitochondrial function and enhancing mitophagy through Bnip3.
    Lexi Zhang, Jianfeng Ye, Cheng Qiu.
      Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Twist-related protein 2 (Twist2) is a basic helix/loop/helix transcription factor. However, the underlying effects of Twist2 in IRI remain to be elucidated. Herein, we found that the expression of Twist2 was significantly upregulated in renal tissues of mice induced by ischemia/reperfusion (I/R) and in human renal tubular epithelial cell HK-2 exposed to hypoxia-reoxygenation. We silenced Twist2 with RNAi technology. Twist2 knockdown alleviated renal pathological damage in mice. Twist2 depletion ameliorated IRI-induced mitochondrial dysfunction, such as increasing ATP content and mitochondrial DNA copy number and restoring mitochondrial membrane potential in the kidneys of mice, and similar results were observed in in vitro experiments. Twist2 interference increased the expression of LC3B and decreased the expression of p62 and mitochondrial membrane proteins TIMM23 and TOMM20 both in vivo and in vitro. Electron microscope and the co-localization of LC3B and mitotracker DsRed suggested the induction of autophagy and mitophagy after Twist2 knockdown in kidneys or cells. Mechanism studies revealed that Twist2 exerted a direct inhibitory effect on BCL2 interacting protein 3 (Bnip3) transcriptional activity by targeting the Bnip3 promoter. In hypoxia/reoxygenation-induced renal tubular epithelial cells, the interference of Bnip3 reversed the effect of Twist2 depletion on mitochondrial function and mitophagy. In conclusion, our findings suggest that the depletion of Twist2 exerts renoprotective effect in I/R-induced AKI. Twist2 regulates mitochondrial function and mitophagy in part by targeting and downregulating Bnip3. Our study provides new insights into the pathological mechanisms of I/R-induced AKI.
    Keywords:  Acute kidney injury; Bnip3; Ischemia–reperfusion injury; Mitophagy; Twist2
    DOI:  https://doi.org/10.1007/s13577-025-01177-z
  10. J Biol Chem. 2025 Feb 02. pii: S0021-9258(25)00101-2. [Epub ahead of print] 108254
    Harmine promotes axon regeneration through enhancing glucose metabolism.
    Ruixuan Liu, Bing Zhou.
      Axon regeneration requires a substantial mitochondrial energy supply. However, injured mature neurons often fail to regenerate due to their inability to meet these elevated energy demands. Our findings indicate that harmine compensates for the energy deficit following axonal injury by enhancing the coupling between glucose metabolism and mitochondrial homeostasis, thereby promoting axon regeneration. Notably, harmine facilitates mitochondrial biogenesis and enhances mitophagy, ensuring efficient mitochondrial turnover and energy supply. Thus, harmine plays a crucial role in enhancing glucose metabolism to maintain mitochondrial function, demonstrating significant potential in treating mature neuronal axon injuries and sciatic nerve injuries.
    Keywords:  axon regeneration; energy supply; glucose metabolism; harmine; metabolic coupling; mitochondrial function; neuron
    DOI:  https://doi.org/10.1016/j.jbc.2025.108254
  11. Chin Med. 2025 Feb 02. 20(1): 16
    Electroacupuncture alleviates damage to myopic RGCs probably through lncRNA-XR_002789763.1-mediated mitophagy.
    Xuejun Wang, Qinghong Lin, Li Tian, Xiaoying Li, Teruko Fukuyama, Weijung Ten, Xiehe Kong, Yanting Yang, Xiaopeng Ma, Xingtao Zhou.
       BACKGROUND: Mitophagy is closely related to the regulation of retinal ganglion cell (RGC) structure and function. Our previous study suggested that long noncoding RNAs (lncRNAs) can cause damage to myopic RGCs. However, whether electroacupuncture (EA) treatment can delay myopia progression through lncRNA-mediated mitophagy in RGCs is currently unknown. This study aimed to investigate the effect of EA on lncRNA-mediated mitophagy in myopic RGCs.
    METHODS: Our study investigated the modulatory effect of EA on mitophagy in RGCs of guinea pigs with form-deprived myopia (FDM). RNA sequencing was performed to further analyze the expression profiles of lncRNAs and mRNAs in RGCs of guinea pigs with FDM after EA treatment, and the related competing endogenous RNA (ceRNA) network was constructed. Importantly, PINK1, a mitophagy-related gene, was included in the core ceRNA network to explore the relationship between lncRNAs and mitophagy in myopic RGCs regulated by EA. We also collected eyeballs from myopic and highly myopic adults to further verify the mechanistic results.
    RESULTS: This study demonstrated that EA treatment delayed the reduction in refraction and increase in axial length and alleviated RGC damage in guinea pigs with FDM. We further found that EA could induce mitophagy in guinea pig RGCs with FDM by promoting the mitophagy-related PINK1/Parkin signaling pathway. Moreover, mitophagy is inhibited in the retina of highly myopic adults. RNA sequencing revealed that 599 lncRNAs and 455 mRNAs were differentially expressed in guinea pig RGCs with FDM after EA treatment. A core ceRNA network was constructed by incorporating PINK1 and verified by related molecular experiments, and we found that EA treatment may induce mitophagy and attenuated RGC injury in guinea pigs with FDM by sponging miR-342-5p through lncRNA-XR_002789763.1 to activate the PINK1/Parkin signaling pathway and promote Mfn2 ubiquitination.
    CONCLUSION: EA treatment might regulate lncRNA-XR_002789763.1/miR-342-5p axis and activate the mitophagy-related PINK1/Parkin signaling pathway, and promote Mfn2 ubiquitination, thereby alleviating RGC damage and delaying myopia progression.
    Keywords:  LncRNA; LncRNA-XR_002789763.1/miR-342-5p/PINK1 axis; Mitophagy; Myopia; Retinal ganglion cell
    DOI:  https://doi.org/10.1186/s13020-025-01058-5
  12. Autophagy. 2025 Feb 06. 1-16
    Development and validation of a sensitive sandwich ELISA against human PINK1.
    Zahra Baninameh, Jens O Watzlawik, Bernardo A Bustillos, Gabriella Fiorino, Tingxiang Yan, Szymon L Lewicki, Haonan Zhang, Dennis W Dickson, Joanna Siuda, Zbigniew K Wszolek, Wolfdieter Springer, Fabienne C Fiesel.
      The ubiquitin kinase and ligase PINK1 and PRKN together label damaged mitochondria for their elimination in lysosomes by selective autophagy (mitophagy). This cytoprotective quality control pathway is genetically linked to familial Parkinson disease but is also altered during aging and in other neurodegenerative disorders. However, the molecular mechanisms of these mitophagy changes remain uncertain. In healthy mitochondria, PINK1 protein is continuously imported, cleaved, and degraded, but swiftly accumulates on damaged mitochondria, where it triggers the activation of the mitophagy pathway by phosphorylating its substrates ubiquitin and PRKN. Levels of PINK1 protein can therefore be used as a proxy for mitochondrial damage and mitophagy initiation. However, validated methodologies to sensitively detect and quantify PINK1 protein are currently not available. Here, we describe the development and thorough validation of a novel immunoassay to measure human PINK1 on the Meso Scale Discovery platform. The final assay showed excellent linearity, parallelism, and sensitivity. Even in the absence of mitochondrial stress (i.e. at basal conditions), when PINK1 protein is usually not detectable by immunoblotting, significant differences were obtained when comparing samples from patient fibroblasts or differentiated neurons with and without PINK1 expression. Of note, PINK1 protein levels were found increased in human postmortem brain with normal aging, but not in brains with Alzheimer disease, suggesting that indeed different molecular mechanisms are at play. In summary, we have developed a novel sensitive PINK1 immunoassay that will complement other efforts to decipher the roles and biomarker potential of the PINK1-PRKN mitophagy pathway in the physiological and pathological context. Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; iPSC: induced pluripotent stem cell; KO: knockout; LLOQ: lower limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-Ub: serine-65 phosphorylated ubiquitin; Ub: ubiquitin; ULOQ: upper limit of quantification; WT: wild-type.
    Keywords:  Autophagy; P-S65-Ub; PINK1; Parkin; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2025.2457915
  13. Neurobiol Dis. 2025 Feb 03. pii: S0969-9961(25)00041-5. [Epub ahead of print] 106825
    Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII.
    Nishan Mandal, Apurba Das, Rupak Datta.
      Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135-/-) Drosophila model of MPS VII. Taking cues from our initial observation that the adult CG2135-/- flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135-/- fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135-/- fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.
    Keywords:  Apoptosis; Autophagy; MPS VII; Mitophagy; Neurodegeneration; Resveratrol
    DOI:  https://doi.org/10.1016/j.nbd.2025.106825
  14. bioRxiv. 2025 Jan 23. pii: 2025.01.22.634344. [Epub ahead of print]
    Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
    Avijit Mallick, Yunguang Du, Theresa Ramalho, Rui Li, Levi Ali, Sookyung Kim, Lihua Julie Zhu, Cole M Haynes.
      The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.
    DOI:  https://doi.org/10.1101/2025.01.22.634344
  15. BMC Cardiovasc Disord. 2025 Feb 03. 25(1): 77
    HACE1 protects against myocardial ischemia-reperfusion injury via inhibition of mitochondrial fission in mice.
    Bang-Xia Liu, Juan Zheng, Zhan-Wei Tang, Lei Gao, Meng Wang, Ying Sun, Chen Chen, Heng-Chen Yao.
       BACKGROUND: HECT domain and Ankyrin repeat Containing E3 ubiquitin-protein ligase 1 (HACE1) has been found to be associated with mitochondrial protection. Mitochondrial damage is a critical contributor to myocardial ischemia-reperfusion injury (I/RI). However, little is known about the role of HACE1 in the pathogenesis of myocardial I/RI.
    METHODS: Male C57BL6 mice with HACE1 knockout (KO) were subjected to 30 min of ischemia via ligation of the left anterior descending artery, followed by 0, 2, 6, or 24 h of reperfusion. The mice were evaluated for myocardial histopathological injury, serum troponin I (cTnI) levels, oxidative stress injury, apoptosis and cardiac function. Prior to ischemia, Mdivi-1(1.2 mg/kg) or vehicle was administered.
    RESULTS: The study revealed that increased expression of HACE1 was associated with myocardial ischemia/reperfusion injury (I/RI), and that knockout of HACE1 resulted in more severe myocardial damage and cardiac dysfunction during I/R(P < 0.05). The HACE1 knockout group exhibited higher levels of malondialdehyde (MDA), greater mitochondrial fission, and dissipation of mitochondrial membrane potential (MMP), leading to more apoptosis and severe cardiac dysfunction compared to the wild-type I/R group(P < 0.05). On the other hand, HACE1 knockout further reduced superoxide dismutase (SOD) activity in the myocardium(P < 0.05), further supporting the findings. However, the adverse effects were almost completely eliminated by pharmacological blockade of the dynamin-related protein 1 (Drp1) inhibitor, Mdivi-1, which inhibits mitochondrial fission during cardiac I/R(P < 0.05).
    CONCLUSION: Collectively, our data show that myocardial I/RI is associated with HACE1 downregulation and Drp1 activation, causing cardiomyocytes to undergo cell death. Therefore, HACE1 could be a promising therapeutic target for the treatment of myocardial I/RI.
    Keywords:  Apoptosis; Drp1; HACE1; Ischemia/reperfusion; Mitochondrial fission
    DOI:  https://doi.org/10.1186/s12872-024-04445-2
  16. Autophagy. 2025 Feb 04.
    Salmonella Typhimurium persistently infects host via its effector SseJ-induced PHB2-mediated mitophagy.
    Dage Sun, Hongchao Gou, Yu Zhang, Jiayi Li, Changzhi Dai, Haiyan Shen, Kaifeng Chen, Yu Wang, Peng Pan, Ting Zhu, Chenggang Xu, Tongling Shan, Ming Liao, Jianmin Zhang.
      Despite decades of research on effective methods to resist Salmonella enterica serovar Typhimurium (S. Typhimurium) pathogenicity, the mechanisms of S. Typhimurium-host interactions have not been fully determined. S. Typhimurium is characterized as an important zoonosis in public health worldwide because of its endemicity, high morbidity, and difficulty in applying control and prevention measures. Herein, we introduce a novel bacterial factor, secretion system effector J (SseJ), and its interactive host protein, PHB2 (prohibitin 2). We explored whether SseJ affected S. Typhimurium replication and survival in the host. S. Typhimurium infection caused severe mitochondrial damage and mitophagy, which facilitated S. Typhimurium proliferation in cells. S. Typhimurium SseJ activated the PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase)-autophagosome-dependent mitophagy pathway, aided by the mitophagy receptor PHB2, for bacterial survival and persistent infection. Moreover, suppression of mitophagy alleviated the pathogenicity of S. Typhimurium. In conclusion, S. Typhimurium infection could be antagonized by targeting the SseJ-PHB2-mediated host mitochondrial autophagy pathway.
    Keywords:  Mitophagy; PHB2; PINK1; PRKN; SseJ; salmonella typhimurium
    DOI:  https://doi.org/10.1080/15548627.2025.2462511
  17. Transpl Immunol. 2025 Jan 30. pii: S0966-3274(25)00005-X. [Epub ahead of print] 102177
    Hsp90 and HIF-1α regulate mitophagy by promoting BNIP3 expression in renal ischemia-reperfusion injury.
    Qi Dong, Xia Li, Ke Cheng.
       BACKGROUND: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). Studies have shown that mitochondrial damage is involved in the pathogenesis of AKI, and that inhibition of Hsp90 expression can improve IR-induced AKI. However, the mechanisms by which Hsp90 improves IR-induced AKI and whether it is involved in mitochondrial autophagy remain unclear.
    METHODS: An IR-induced AKI mouse model was established, and the degree of renal injury was analyzed using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The expression of Hsp90, HIF-1α, BNIP3, and mitochondrial autophagy proteins was detected by western blotting in vivo and in vitro. HK2 cell viability, apoptosis, mitochondrial autophagy, reactive oxygen species (ROS), and inflammatory cytokines levels were detected using Cell Counting Kit 8 (CCK8) assays, Terminal·deoxynucleotidyl transferase-mediated dUTP nick end·labeling (TUNEL) labeling, immunofluorescence, and enzyme-linked immunosorbent (ELISA).
    RESULTS: A murine IR-induced AKI model was successfully generated, and increased expression levels of Hsp90, HIF-1α, and inflammatory cytokines were observed, accompanied by a worsening of renal injury. After induction of IRI in HK2 cells, downregulation of Hsp90 or HIF-1α expression resulted in decreased downstream BNIP3 expression, an increase in HK2 cell viability, and a decrease in the level of mitochondrial autophagy.
    CONCLUSION: Hsp90 upregulated the expression of HIF-1αand BNIP3, thereby enhancing mitochondrial autophagy in IR-induced AKI.
    Keywords:  BNIP3; HIF-1α; Hsp90; IR-induced AKI; Mitophagy
    DOI:  https://doi.org/10.1016/j.trim.2025.102177
  18. PLoS One. 2025 ;20(2): e0319025
    Retraction: Nanocurcumin Prevents Hypoxia Induced Stress in Primary Human Ventricular Cardiomyocytes by Maintaining Mitochondrial Homeostasis.
    PLOS One Editors
      
    DOI:  https://doi.org/10.1371/journal.pone.0319025
  19. Int J Biol Macromol. 2025 Jan 29. pii: S0141-8130(25)01037-2. [Epub ahead of print]301 140488
    Lycium barbarum polysaccharide mitigates high-fat-diet-induced skeletal muscle atrophy by promoting AMPK/PINK1/Parkin-mediated mitophagy.
    Yanru Ren, Kun Wang, Yuanyuan Wu, Jiarui Li, Jie Ma, Lijuan Wang, Chenglei Zhang, Jianning Li, Yanhong Wei, Yi Yang.
      Sarcopenic obesity (SO) defined as the coexistence of obesity and sarcopenia. While the anti-obesity effects of Lycium barbarum polysaccharide (LBP), the main component of L. barbarum extract, are known, its efficacy against SO remains unexplored. Consequently, we aimed to investigate the therapeutic effects of LBP on SO and the elucidate the underlying mechanisms. Our results revealed that LBP administration decreased obesity-related factors, and increased muscle-related factors in mice fed a high-fat diet (HFD). LBP administration ameliorated PA- and HFD-induced hyperglycaemia by modulating IRS-1 and GLUT-4 levels while also mitigating the ectopic fat deposition. Furthermore, our results demonstrated that LBP can mitigate mitochondrial structural abnormalities and dysfunction-characterized by increased mitochondrial membrane potential and ATP levels, reduced reactive oxygen species levels-through the activation of mitophagy. However, these beneficial effects of LBP on skeletal muscle were negated by AMPK inhibitor and siRNA knockdown of Parkin expression. Taken together, our findings indicate that LBP may effectively modulate glucose and lipid metabolism while ameliorating skeletal muscle atrophy via the activation of the AMPK/PINK1/Parkin-mediated mitophagy pathway, thereby repairing the mitochondrial structure and function. Consequently, LBP emerges as a promising therapeutic candidate for addressing obesity-related impacts on skeletal muscle.
    Keywords:  Lycium barbarum polysaccharide; Mitophagy; Sarcopenic obesity
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140488
  20. bioRxiv. 2025 Jan 25. pii: 2025.01.22.634397. [Epub ahead of print]
    VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
    Xiaomeng Yin, Ruoxi Wang, Andrea Thackeray, Eric H Baehrecke, Mark J Alkema.
      Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13D 's orthologue vps-13D in C. elegans . Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPR mt ). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.
    DOI:  https://doi.org/10.1101/2025.01.22.634397
  21. J Transl Med. 2025 Feb 04. 23(1): 156
    Staphylococcus aureus induces mitophagy via the HDAC11/IL10 pathway to sustain intracellular survival.
    Yaji Yang, Haotian Zhou, Feilong Li, Yanhao Zhang, Jianye Yang, Yidong Shen, Ning Hu, Quanming Zou, Leilei Qin, Hao Zeng, Wei Huang.
       BACKGROUND: The immune evasion and prolonged survival of Staphylococcus aureus (S. aureus) within macrophages are key factors contributing to the difficulty in curing osteomyelitis. Although macrophages play a vital role as innate immune cells, the mechanisms by which S. aureus survives within them and suppresses host immune functions remain incompletely understood.
    METHODS: This study employed confocal microscopy, flow cytometry, ELISA, and siRNA technology to assess the survival capacity of S. aureus within macrophages and the impact of inflammatory cytokines on its persistence. Proteomics was used to investigate the potential mechanisms and differential proteins involved in S. aureus intracellular survival. Additionally, confocal microscopy, flow cytometry, Mdivi-1 intervention, and Western blot were utilized to validate the role of mitophagy in supporting S. aureus survival. The study further explored how the HDAC11/IL10 axis enhances mitophagy to promote intracellular S. aureus survival by using HDAC11 overexpression, siRNA, and rapamycin intervention combined with confocal microscopy and flow cytometry.
    RESULTS: The findings demonstrated that IL10 promotes mitophagy to clear mitochondrial reactive oxygen species (mtROS), thereby enhancing the intracellular survival of S. aureus within macrophages. Additionally, we discovered that the transcriptional repressor of IL10, HDAC11, was significantly downregulated during S. aureus infection. Overexpression of HDAC11 and the use of the autophagy activator rapamycin further validated that the HDAC11/IL10 axis regulates mitophagy via the mTOR pathway, which is essential for supporting S. aureus intracellular survival.
    CONCLUSION: This study reveals that S. aureus enhances IL10 production by inhibiting HDAC11, thereby promoting mitophagy and mtROS clearance, which supports its survival within macrophages. These findings offer new insights into the intracellular survival mechanisms of S. aureus and provide potential therapeutic approaches for the clinical management of osteomyelitis.
    Keywords:  Histone deacetylase 11; Interleukin 10; Intracellular survival; Macrophage; Mitochondrial reactive oxygen species; Mitophagy; Staphylococcus aureus
    DOI:  https://doi.org/10.1186/s12967-025-06161-7
  22. J Cell Sci. 2025 Feb 06. pii: jcs.263408. [Epub ahead of print]
    Mitophagy is induced in human engineered heart tissue after simulated ischemia and reperfusion.
    Mireia Nàger, Kenneth B Larsen, Zambarlal Bhujabal, Trine B Kalstad, Judith Rössinger, Truls Myrmel, Florian Weinberger, Asa B Birgisdottir.
      The paradoxical exacerbation of cellular injury and death during reperfusion remains a problem in treatment of myocardial infarction. Mitochondrial dysfunction plays a key role in the pathogenesis of myocardial ischemia and reperfusion injury. Dysfunctional mitochondria can be removed by mitophagy, culminating in their degradation within acidic lysosomes. Mitophagy is pivotal in maintaining cardiac homeostasis and emerges as a potential therapeutic target. Here we employ beating human engineered heart tissue (EHT) to assess mitochondrial dysfunction and mitophagy during ischemia and reperfusion simulation. Our data indicate adverse ultrastructural changes in mitochondrial morphology and impairment of mitochondrial respiration. Furthermore, our pH-sensitive mitophagy reporter EHTs, generated by CRISPR/Cas9 endogenous knock-in strategy, reveal induced mitophagy flux in EHTs after ischemia and reperfusion simulation. The induced flux requires the activity of the protein kinase ULK1, a member of the core-autophagy machinery. Our results demonstrate the applicability of the reporter EHTs for mitophagy assessment in a clinically relevant setting. Deciphering mitophagy in the human heart will facilitate development of novel therapeutic strategies.
    Keywords:  Engineered heart tissue; HiPSC; Ischemia-reperfusion; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1242/jcs.263408
  23. Microbiol Res. 2025 Jan 31. pii: S0944-5013(25)00036-9. [Epub ahead of print]293 128080
    The 1-acylglycerol-3-phosphate acyltransferase Slc1 is required to regulate mitochondria and lipid droplets.
    Chenhui Zhao, Ke Liu, Yifan Wu, Shuaijie Yan, Jiajia He, Chuanhai Fu.
      Mitochondria are organelles involved in energy metabolism and biosynthesis. As the metabolites released from mitochondria are raw materials used for lipid synthesis, mitochondria also play important roles in lipid metabolism. Here we report that Slc1, a 1-acylglycerol-3-phosphate O-acyltransferase in the fission yeast Schizosaccharomyces pombe, is required to maintain tubular mitochondrial morphology and normal mitochondrial functions. The absence of Slc1 causes mitochondrial fragmentation, increases mitochondrial fission frequency, reduces mitochondrial respiration, and slows down nitrogen starvation-induced mitophagy. In addition, the absence of Slc1 significantly increases the protein level of Ptl2, which is the triacylglycerol lipase localized on lipid droplets. The phenotypes caused by the absence of Slc1 depend on its acyltransferase enzymatic activity. Therefore, our study uncovers new roles of a lipid synthesis enzyme Slc1 in regulating mitochondria and lipid droplets.
    Keywords:  1-acylglycerol-3-phosphate O-acyltransferase; Lipid droplet; Mitochondria; Mitophagy; Schizosaccharomyces pombe
    DOI:  https://doi.org/10.1016/j.micres.2025.128080
  24. J Med Chem. 2025 Feb 05.
    Mitophagy in Neurodegenerative Diseases: Mechanisms of Action and the Advances of Drug Discovery.
    Panpan Yang, Wen Shuai, Xin Wang, Xiuying Hu, Min Zhao, Aoxue Wang, Yongya Wu, Liang Ouyang, Guan Wang.
      Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for other NDDs. Here, we describe the mechanism and key signaling pathway of mitophagy and summarize the roles of defective mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for mitophagy mechanism exploration and drug design.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01779
  25. bioRxiv. 2025 Jan 23. pii: 2025.01.20.633997. [Epub ahead of print]
    Alterations in Lipid Saturation Trigger Remodeling of the Outer Mitochondrial Membrane.
    Sara Wong, Katherine R Bertram, Nidhi Raghuram, Thomas Knight, Adam L Hughes.
      Lipid saturation is a key determinant of membrane function and organelle health, with changes in saturation triggering adaptive quality control mechanisms to maintain membrane integrity. Among cellular membranes, the mitochondrial outer membrane (OMM) is an important interface for many cellular functions, but how lipid saturation impacts OMM function remains unclear. Here, we show that increased intracellular unsaturated fatty acids (UFAs) remodel the OMM by promoting the formation of multilamellar mitochondrial-derived compartments (MDCs), which sequester proteins and lipids from the OMM. These effects depend on the incorporation of UFAs into membrane phospholipids, suggesting that changes in membrane bilayer composition mediate this process. Furthermore, elevated UFAs impair the assembly of the OMM protein translocase (TOM) complex, with unassembled TOM components captured into MDCs. Collectively, these findings suggest that alterations in phospholipid saturation may destabilize OMM protein complexes and trigger an adaptive response to sequester excess membrane proteins through MDC formation.
    Significance Statement: Mitochondrial-derived compartments are multilamellar structures that sequester protein and lipids of the outer mitochondrial membrane in response to metabolic and membrane perturbations, but it is largely unknown how membrane fluidity influences this pathway.Increased levels of unsaturated phospholipids may disrupt the TOM complex, a large multi-subunit complex on the outer mitochondrial membrane, to promote the formation of mitochondrial-derived compartments, while increased levels of saturated phospholipids inhibits formation of mitochondrial-derived compartments.These findings reveal a link between phospholipid composition and protein stress in driving mitochondrial-derived compartment biogenesis, and thus mitochondrial quality control.
    DOI:  https://doi.org/10.1101/2025.01.20.633997
  26. Stem Cell Res Ther. 2025 Feb 07. 16(1): 49
    CircSPG21 ameliorates oxidative stress-induced senescence in nucleus pulposus-derived mesenchymal stem cells and mitigates intervertebral disc degeneration through the miR-217/SIRT1 axis and mitophagy.
    Yongbo Zhang, Sheng Yang, Xuan You, Zhengguang Li, Liuyang Chen, Rui Dai, Hua Sun, Liang Zhang.
       BACKGROUND: The microenvironment of intervertebral disc degeneration (IVDD) is characterized by oxidative stress, leading to the senescence of nucleus pulposus-derived mesenchymal stem cells (NPMSCs). The purpose of this study was to investigate the competitive endogenous RNA mechanism involved in the senescence of NPMSCs induced by tert-butyl hydroperoxide (TBHP).
    METHODS: Bioinformatic analysis identified differentially expressed circRNAs. Interactions among circSPG21, miR-217, and the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) were validated through dual-luciferase assays, RNA fluorescence in situ hybridization and RNA immune precipitation. β-Gal staining, EdU staining, Western blotting, JC-1 assays, cell cycle analysis, and quantitative reverse transcription PCR (RT‒qPCR) were used to examine the functions of these molecules in TBHP-induced senescent NPMSCs. The therapeutic effects of circSPG21 were evaluated in a rat IVDD model.
    RESULTS: CircSPG21 expression was significantly decreased in both human and rat IVDD tissues, whereas miR-217 was upregulated and SIRT1 was downregulated. Overexpression of circSPG21 alleviated NPMSC senescence by reducing P21 and P53 levels and restoring mitophagy through Parkin. The protective effects of circSPG21 were mediated through the miR-217/SIRT1 axis, as SIRT1 knockdown attenuated these benefits. CircSPG21 also ameliorated disc degeneration in the IVDD rat model, highlighting its potential as a therapeutic target.
    CONCLUSION: CircSPG21 reduces oxidative stress-induced NPMSC senescence through the miR-217/SIRT1 axis and mitophagy, providing new insights into IVDD and identifying circSPG21 as a potential therapeutic target for disc degeneration.
    Keywords:  Intervertebral disc degeneration; Mitophagy; Nucleus pulposus-derived mesenchymal stem cell; Senescence; ceRNA
    DOI:  https://doi.org/10.1186/s13287-025-04180-1
  27. Phytomedicine. 2025 Jan 27. pii: S0944-7113(25)00056-X. [Epub ahead of print]138 156416
    Dahuang chuanxiong decoction against contrast-induced nephropathy: Multi-omics, crosstalk between BNIP3-mediated mitophagy and IL-17 pathway.
    Zhiyong Song, Jun Li, Xuezhong Gong.
       BACKGROUND: Contrast-induced nephropathy (CIN), also known as contrast-induced acute kidney injury (CI-AKI), represents a prevalent form of hospital-acquired renal injury. However, the mechanisms underlying its pathogenesis remain unclear. Based on our previous research findings, the Dahuang Chuanxiong decoction (DCH), composed of Radix et Rhizoma Rhei (DH) and Rhizoma Chuanxiong (CX), has demonstrated efficacy for inhibiting CI-AKI by attenuating oxidative stress and apoptosis in renal tubular epithelial cells. Despite these findings, the detailed mechanisms underlying the renoprotective actions have not been thoroughly clarified.
    PURPOSE: The objective of this study was to screen potential targets and signaling pathways involved in inhibition of CI-AKI by DCH using multi-omics analysis and to verify whether the renoprotective mechanism of DCH is related to these identified targets or pathways through in vivo and in vitro experiments.
    METHODS: Initially, we identified the components of DCH using UPLC-Q-TOF-MS. Transcriptomics and proteomics, combined with experimental validation, were used to further elucidate the molecular mechanisms of the herbal pair in CI-AKI treatment. A CI-AKI rat model was established, and the expression levels of proteins related to mitophagy and the IL-17 signaling pathway were detected in renal tissues using immunofluorescence, immunohistochemistry, and western blotting analysis to elucidate the nephroprotective effects of DCH. Additionally, siRNA was used in the HK-2 cell model to investigate the crosstalk between the mitophagy and IL-17 signaling pathways and the impact on apoptosis when these pathways were inhibited.
    RESULTS: Multi-omics results revealed that the crucial signaling pathways involved were mitophagy, the MAPK signaling pathway, and the IL-17 signaling pathway. In vivo experiments indicated that contrast media (CM) led to an increase in AKI biomarkers, with upregulated expression of Parkin, BNIP3, IL-17, and p-NF-κB. Notably, pretreatment with DCH markedly reversed the expression of these proteins. Furthermore, we confirmed the importance of IL-17-mediated inflammation in the pathogenesis of CIN in vitro. We stimulated HK-2 cells with human IL-17 recombinant protein and observed an increase in the expression of p-NF-κB. Conversely, knockdown of IL-17 receptor A (IL-17RA) on the cell membrane reduced the expression of p-NF-κB and BNIP-3 under IL-17 stimulation. Additionally, the results revealed that BNIP3 knockdown reduced p-NF-κB production and alleviated the inflammation triggered by CM. The crosstalk between the two signaling pathways was initially explored.
    CONCLUSION: In conclusion, these findings suggested that DCH may exert ameliorative effects on CI-AKI through a multifaceted approach, including inhibition of BNIP3-mediated mitophagy and IL-17-mediated inflammation. This study elucidated the renoprotective mechanism of DCH through transcriptomics, proteomics, and experimental validation, providing evidence for the therapeutic potential of this agent in the clinical treatment of CI-AKI.
    Keywords:  Contras-induced acute kidney injury; Experimental validation; Proteomics; Radix et Rhizoma Rhei; Rhizoma Chuanxiong; Transcriptomics
    DOI:  https://doi.org/10.1016/j.phymed.2025.156416
  28. NPJ Metab Health Dis. 2025 ;3(1): 4
    Calcium-mediated regulation of mitophagy: implications in neurodegenerative diseases.
    Fivos Borbolis, Christina Ploumi, Konstantinos Palikaras.
      Calcium signaling plays a pivotal role in diverse cellular processes through precise spatiotemporal regulation and interaction with effector proteins across distinct subcellular compartments. Mitochondria, in particular, act as central hubs for calcium buffering, orchestrating energy production, redox balance and apoptotic signaling, among others. While controlled mitochondrial calcium uptake supports ATP synthesis and metabolic regulation, excessive accumulation can trigger oxidative stress, mitochondrial membrane permeabilization, and cell death. Emerging findings underscore the intricate interplay between calcium homeostasis and mitophagy, a selective type of autophagy for mitochondria elimination. Although the literature is still emerging, this review delves into the bidirectional relationship between calcium signaling and mitophagy pathways, providing compelling mechanistic insights. Furthermore, we discuss how disruptions in calcium homeostasis impair mitophagy, contributing to mitochondrial dysfunction and the pathogenesis of common neurodegenerative diseases.
    Keywords:  Metabolic disorders; Mitochondria
    DOI:  https://doi.org/10.1038/s44324-025-00049-2
  29. Front Oncol. 2024 ;14 1532857
    Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
    Elissa Tjahjono, Megan R Daneman, Bernadetta Meika, Alexey V Revtovich, Natalia V Kirienko.
      Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.
    Keywords:  acute myeloid leukemia; glutaminolysis; leukemic stem cells; mitochondria; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fonc.2024.1532857
  30. J Ethnopharmacol. 2025 Jan 31. pii: S0378-8741(25)00116-3. [Epub ahead of print] 119433
    Neuroprotective Role of Da Qin Jiu Decoction in Ischemic Stroke: Mitochondrial Rescue through PI3K/Akt-Mediated UPRmt Activation.
    Jing Luo, Yaling Zheng, Jialei Chen, Xin Xiong, Jiashu Shen, Dou Hong, Ning Jiang, Wenlu Li, Jing Zhao, Jingxian Wu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke (IS) is a highly debilitating neurological condition with limited treatment options and suboptimal outcomes. The traditional Chinese medicine formula Da Qin Jiu Decoction (DQJD) has been widely used for its neuroprotective effects. However, its potential mechanisms of action in IS remain unclear.
    AIM OF THE STUDY: This study aims to investigate the therapeutic effects of DQJD on IS and elucidate its underlying mechanisms of action.
    MATERIALS AND METHODS: The neuroprotective effects of DQJD were evaluated in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R). Neurological recovery was assessed using behavioral tests and tissue analysis, including TTC staining, MRI, and HE & Nissl staining. Mitochondrial function was examined through Western blot, JC-1 assay, ROS staining, and electron microscopy. Additionally, network pharmacology, bioinformatics analyses, and Mendelian randomization were employed to identify key molecular targets and mechanisms. Molecular docking was conducted to explore interactions between active components of DQJD and relevant pathways, focusing on PI3K/Akt signaling.
    RESULTS: Treatment with DQJD significantly reduced infarct volume, alleviated tissue damage and improved neurological outcomes. Molecular analyses revealed the upregulation of ATF5 and mitochondrial unfolded protein response (UPRmt)-related proteins, including HSP60, LONP1, and ClpP, indicating UPRmt activation. Enhanced mitochondrial membrane potential (ΔΨm), reduced ROS levels, and restoration of mitochondrial dynamics further demonstrated the rescue of mitochondrial function. Network pharmacology and molecular docking analyses highlighted the central role of PI3K/Akt signaling in DQJD-mediated neuroprotection.
    CONCLUSIONS: DQJD exerts neuroprotective effects in IS by restoring mitochondrial function through UPRmt activation via the PI3K/Akt pathway. These findings support further exploration of DQJD as a therapeutic option for IS.
    Keywords:  Da Qin Jiu Decoction; Ischemic stroke; Mendelian randomization; Molecular docking; Network pharmacology; UPR(mt)
    DOI:  https://doi.org/10.1016/j.jep.2025.119433
  31. J Biol Chem. 2025 Feb 03. pii: S0021-9258(25)00100-0. [Epub ahead of print] 108253
    Transmembrane Parkinson's Disease mutation of PINK1 leads to altered mitochondrial anchoring.
    Raelynn Brassard, Elena Arutyunova, Emmanuella Takyi, L Michel Espinoza-Fonseca, Howard Young, Nicolas Touret, M Joanne Lemieux.
      Parkinson's disease (PD) is a devastating neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Familial and sporadic forms of the disease have been linked to mitochondrial dysfunction. Pathology has been identified with mutations in the PARK6 gene encoding PTEN-induced kinase 1 (PINK1), a quality control protein in the mitochondria. Disease-associated mutations at the transmembrane region of PINK1 protein were predicted to disrupt the cleavage of the transmembrane region by the PARL protease at the inner mitochondrial membrane. Here, using microscopy, kinetic analysis and molecular dynamic simulations, we analyzed 3 PD associated TM mutations; PINK1-C92F, PINK1-R98W and PINK1-I111S, and found that mitochondrial localization and cleavage by the PARL protease were not significantly impaired. However, clearance of hydrolyzed PINK1-R98W appears to be compromised due to altered positioning of the protein in the outer mitochondrial membrane, preventing association with TOM complexes and slowing cleavage by PARL. This single amino acid change slows degradation of proteolyzed PINK1, increasing its accumulation at the outer mitochondrial membrane and resulting in increased mitophagy and decreased mitochondrial content among these cells.
    Keywords:  MD Simulation; PARL; Parkinson’s Disease; Proteostasis; Rhomboid Protease
    DOI:  https://doi.org/10.1016/j.jbc.2025.108253
  32. iScience. 2025 Feb 21. 28(2): 111539
    Physiological and pathological roles of PGAM5: An update and future trend.
    Weibin He, Wenlong He, Zhongchan Sun, Pengcheng He.
      PGAM5, a phosphatase found in mitochondria, is crucial for mitochondrial quality control (MQC) through its regulation on mitochondrial dynamics, biogenesis, and mitophagy. Previous studies have shown its involvement in multiple regulated cell deaths (RCDs), including apoptosis, necroptosis, and pyroptosis. The objective of this review is to enhance our comprehension of the involvement of PGAM5 in MQC and RCDs. Additionally, we summarize some novel roles of PGAM5 in cellular senescence, lipid metabolism, and immune response modulation in recent studies. Finally, we discuss PGAM5's contribution to the pathological state of cardiovascular, hepatic, neurological, and neoplastic diseases, offering potential perspectives for future research.
    Keywords:  Biological sciences; Molecular physiology; Pathology
    DOI:  https://doi.org/10.1016/j.isci.2024.111539
  33. Phytomedicine. 2025 Jan 23. pii: S0944-7113(25)00060-1. [Epub ahead of print]139 156420
    Xin-Ji-Er-Kang balances mitochondrial fusion and fission to protect cardiomyocytes in mice with heart failure by regulating the ERα/SIRT3 pathway.
    Wei-Wei Cai, Yuan-Yuan Qin, Fei Ge, Qing Zhou, Lei Huang, Pang-Bo Yang, Jie Xia, Ke-Ke Li, Yi-Fan Hou, Jia-Min Wu, Ding-Yan Wang, Ya You, Wen-Jie Lu, Shan Gao.
       BACKGROUND: Mitochondrial dynamics imbalance is an essential pathological mechanism in heart failure (HF). The Chinese herbal formula Xin-Ji-Er-Kang (XJEK) has demonstrated good therapeutic effects in various cardiovascular disease models. However, whether XJEK treats HF by regulating mitochondrial dynamics homeostasis and its specific molecular mechanisms remain elusive.
    PURPOSE: To investigate the effect of XJEK on restoring the disrupted mitochondrial dynamics homeostasis in HF and elucidate the potential regulatory mechanism.
    STUDY-DESIGN/METHODS: A mouse model of myocardial ischemia-reperfusion (MIR)-induced HF was established to assess the cardioprotection of XJEK. Subsequently, network pharmacology was employed to predict the mechanism by which XJEK treated HF. Moreover, gene silencing was employed to explore the potential mechanisms behind the cardioprotective effects of XJEK in AC16 cells subjected to hypoxia/reoxygenation (H/R).
    RESULTS: XJEK treatment significantly attenuated myocardial fibrosis and ameliorated ventricular remodeling in post-MIR-induced HF mice. Network pharmacology analysis identified the estrogen receptor α (ERα) as a key regulator of XJEK-mediated cardioprotection. XJEK disordered mitochondrial dynamics in the hearts of MIR-induced HF mice. In addition, XJEK restored mitochondrial fusion-fission imbalance and facilitated ERα nuclear translocation to up-regulate sirtuin 3 (SIRT3) expression in the hearts of MIR-induced HF mice and H/R-induced AC16 cells. Notably, ERα depletion in cardiomyocytes completely abrogated the cardioprotective effects of XJEK.
    CONCLUSION: XJEK safeguards the hearts in mice with MIR-induced HF by facilitating ERα nuclear translocation to up-regulate SIRT3 expression to rescue the mitochondrial fusion-fission imbalance. This study establishes a new theoretical basis for treating HF with XJEK.
    Keywords:  Estrogen receptor α; Heart failure; Mitochondrial dynamics; Myocardial ischemia-reperfusion; Network pharmacology; Sirtuin 3
    DOI:  https://doi.org/10.1016/j.phymed.2025.156420
  34. Nat Commun. 2025 Feb 01. 16(1): 1258
    Nutrient status alters developmental fates via a switch in mitochondrial homeodynamics.
    Jie Zhang, Suning Liu, Yang Li, Guanfeng Xu, Huimin Deng, Kirst King-Jones, Sheng Li.
      Steroid hormones are powerful endocrine regulators, but little is known about how environmental conditions modulate steroidogenesis to reprogram developmental fates. Here, we use the Drosophila prothoracic gland (PG) to investigate how a nutrient restriction checkpoint (NRC) ensures or blocks developmental progression and sexual maturation via regulating steroidogenesis. Extensive transcriptome analysis of the PG reveals that pre-NRC starvation significantly downregulates mitochondria-associated genes. Pre-NRC starvation reduces prothoracicotropic neuropeptide hormone signaling, insulin signaling, and TORC1 activity in PG cells, which prevent mitochondrial fragmentation and import of Disembodied, a key steroidogenic enzyme. Ultimately, pre-NRC starvation causes severe mitophagy and proteasome dysfunction, blocking steroidogenesis and metamorphosis. By contrast, post-NRC starvation does not impair mitochondrial homeostasis in PG cells but reduces sit expression and induces moderate autophagy to promote steroidogenesis, leading to precocious metamorphosis. This study constitutes a paradigm for exploring how steroid hormone levels are controlled in response to environmental stress during developmental checkpoints.
    DOI:  https://doi.org/10.1038/s41467-025-56528-z
  35. Sci Rep. 2025 Feb 04. 15(1): 4298
    CRIP1 inhibits cutaneous melanoma progression through TFAM-mediated mitochondrial biogenesis.
    Jianqiang Wu, Lixia Chen, Peijun Wen.
      Metastasis is the leading cause of death in patients with cutaneous melanoma. CRIP1 (cysteine-rich protein 1) has been reported to be associated with malignant progression of several cancers. However, the biological function and underlying mechanisms of CRIP1 in melanoma progression are largely unknown. Bioinformatic prediction of CRIP1 expression in melanoma and its association with clinical parameters and prognosis of patients. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blots (WB) were used to detect stable overexpression and knockdown of CRIP1 in melanoma cells. The function of CRIP1 in cutaneous melanoma cells was determined by in vitro functional assays. WB, immunofluorescence, OCR detection, mitochondrial DNA assay, and cytosolic ATP assay were used to determine the relationship between CRIP1 and mitochondrial biogenesis, relationship between TFAM. The expression level of CRIP1 in melanoma tissues is lower than that in normal tissues and suggests a poor prognosis for melanoma patients. Functionally, CRIP1 inhibits the proliferation, migration, and invasion of melanoma cells in vitro. Mechanistic studies revealed that CRIP1 inhibited mitochondrial biogenesis in melanoma cells, which included suppression of relative mitochondrial content, mitochondrial DNA copy number, ATP production, respiratory capacity, and expression levels of oxidative phosphorylation-related proteins. Further studies revealed that CRIP1 inhibits mitochondrial biogenesis and malignant progression in melanoma cells by suppressing the protein levels of TFAM. Our results suggest that CRIP1 inhibits the proliferation and invasive ability of cutaneous melanoma cells by suppressing TFAM-mediated mitochondrial biogenesis. Therefore, CRIP1 may be a potential therapeutic target for melanoma.
    Keywords:  CRIP1; Melanoma; Mitochondrial biogenesis; TFAM
    DOI:  https://doi.org/10.1038/s41598-025-88373-x
  36. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13701
    Skeletal Muscle Mitochondrial and Autophagic Dysregulation Are Modifiable in Spinal Muscular Atrophy.
    Andrew I Mikhail, Sean Y Ng, Donald Xhuti, Magda A Lesinski, Jennifer Chhor, Marc-Olivier Deguise, Yves De Repentigny, Joshua P Nederveen, Rashmi Kothary, Mark A Tarnopolsky, Vladimir Ljubicic.
       BACKGROUND: Spinal muscular atrophy (SMA) is a health- and life-limiting neuromuscular disorder. Although varying degrees of mitochondrial abnormalities have been documented in SMA skeletal muscle, the influence of disease progression on pathways that govern organelle turnover and dynamics are poorly understood. Thus, the purpose of this study was to investigate skeletal muscle mitochondria during SMA disease progression and determine the effects of therapeutic modalities on organelle biology.
    METHODS: Smn2B/+ and Smn2B/- severe SMA-like mice were used to investigate mitochondrial turnover and dynamics signalling. Muscles were analysed at postnatal day 9 (P9), P13 or P21 to address pre-symptomatic, early symptomatic and late symptomatic periods of the disorder. Additionally, we utilized an acute dose of exercise and urolithin A (UA) to stimulate organelle remodelling in skeletal muscle of SMA mice in vivo and in SMA patient-derived myotubes in vitro, respectively.
    RESULTS: Smn2B/+ and Smn2B/- mice demonstrated similar levels of muscle mitochondrial oxidative phosphorylation (OxPhos) proteins throughout disease progression. In contrast, at P21 the mRNA levels of upstream factors important for the transcription of mitochondrial genes encoded by the nuclear and mitochondrial DNA, including nuclear respiratory factor 2, sirtuin 1, mitochondrial transcription factor A and tumour protein 53, were upregulated (+31%-195%, p < 0.05) in Smn2B/- mice relative to Smn2B/+. Early and late symptomatic skeletal muscle from SMA-like mice showed greater autophagosome formation as denoted by more phosphorylated autophagy related 16-like 1 (p-ATG16L1Ser278) puncta (+60%-80%, p < 0.05), along with a build-up of molecules indicative of damaged mitochondria such as BCL2 interacting protein 3, Parkin and PTEN-induced kinase 1 (+100%-195%, p < 0.05). Furthermore, we observed a fragmented mitochondrial phenotype at P21 that was concomitant with abnormal splicing of Optic atrophy 1 transcripts (-53%, p < 0.05). A single dose of exercise augmented the expression of citrate synthase (+43%, p < 0.05) and corrected the over-assembly of autophagosomes (-64%, p < 0.05). In patient muscle cells, UA treatment stimulated autophagic flux, increased the expression of OxPhos proteins (+15%-47%, p < 0.05) and improved maximal oxygen consumption (+84%, p < 0.05).
    CONCLUSIONS: Abnormal skeletal muscle mitochondrial turnover and dynamics are associated with disease progression in Smn2B/- mice despite compensatory elevations in upstream factors important for organelle synthesis and recycling. Exercise and UA enhance mitochondrial health in skeletal muscle, which indicates that lifestyle-based and pharmacological interventions may be effective countermeasures targeting the organelle for therapeutic remodelling in SMA.
    Keywords:  autophagy; biogenesis; dynamics; exercise; mitophagy; urolithin A
    DOI:  https://doi.org/10.1002/jcsm.13701
  37. Ecotoxicol Environ Saf. 2025 Feb 01. pii: S0147-6513(25)00171-X. [Epub ahead of print]291 117835
    Role of calcium overload-mediated disruption of mitochondrial dynamics in offspring neurotoxicity due to methylmercury exposure during pregnancy and lactation.
    Lingxu Kong, Huajie Yang, Jing Yang, Liujiangshan Jiang, Bin Xu, Tianyao Yang, Wei Liu.
      Methylmercury (MeHg) is a potent neurotoxicant with neurodevelopmental toxicity that is widely ingested into the body through drinking water and food. MeHg crosses the placental barrier and accumulates in the brain of the fetus, affecting the growth and development of the central nervous system. Although it has been demonstrated that MeHg induces neuronal calcium overload in the rat cerebral cortex, the role of calcium overload in MeHg-induced neurodevelopmental toxicity remains unclear. Here, we used ICR-pregnant mice and their resulting offspring and administered the BAPTA-AM calcium antagonist to investigate the molecular mechanisms by which MeHg exposure during gestation and lactation affects neurodevelopment. We found that exposure to MeHg during gestation and lactation resulted in developmental arrest and neurobehavioral dysfunction in the offspring, with calcium overload, disturbed mitochondrial dynamics, and apoptosis. However, the calcium overload inhibitor BAPTA-AM rescued MeHg-induced neurodevelopmental damage, attenuated the onset of calcium overload, reduced mitochondrial kinetic disturbances and apoptosis. Meanwhile, the activation of the CaM/CaMKII/DRP1 signaling pathway induced by calcium overload was inhibited, and the interaction between DRP1 and BAX was attenuated, which alleviated apoptosis to a certain extent. In summary, our study suggests that MeHg-induced calcium overload may induce disturbed mitochondrial dynamics through activation of the CaM/CaMKII/DRP1 signaling pathway, resulting in neuronal apoptosis.
    Keywords:  CaMKⅡ; Calcium overload; Methylmercury; Mitochondrial dynamics; Neurodevelopmental toxicity; Neuronal damage
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117835
  38. Acta Biochim Biophys Sin (Shanghai). 2025 Jan 23.
    mTOR-related linc-PMB promotes mitochondrial biogenesis via stabilizing SIRT1 mRNA through binding to the HuR protein.
    Qian Chen, Huaying Zhang, Daokun Wang, Wenjing Liao, Yazhou Liu, Yurui Cai, Siyou Wang, Mengqian Yu.
      Mitochondrial dysfunction is implicated in numerous disorders, including type 2 diabetes, Alzheimer's disease and cancer. Long non-coding RNAs (lncRNAs) are emerging as pivotal regulators of cellular energy metabolism, yet their roles remain largely unclear. In this study, we identify an lncRNA named linc-PMB, which is associated with mTOR and promotes mitochondrial biogenesis, through microarray analysis. We demonstrate that the knockdown of linc-PMB results in significantly impaired mitochondrial respiration and biogenesis, along with altered expressions of related genes. Conversely, overexpression of linc-PMB markedly increases mitochondrial function. We further reveal that linc-PMB interacts with the RNA-binding protein HuR, promoting the stabilization of SIRT1 mRNA and a substantial increase in SIRT1 expression, which in turn activates the PGC-1α/mtTFA pathway and mitochondrial biogenesis. Collectively, our findings reveal a novel regulatory pathway in which linc-PMB, through its interaction with HuR, modulates the SIRT1/PGC-1α/mtTFA axis to maintain mitochondrial biogenesis and function.
    Keywords:  HuR; SIRT1; long non-coding RNA; mTOR; mitochondrial biogenesis
    DOI:  https://doi.org/10.3724/abbs.2024236
  39. Anal Chem. 2025 Feb 02.
    Harnessing an MMP-Independent NIR Probe Unveiling the Different Mitochondrial Cristae Changes during Mitophagy and Ferroptosis under STED Microscopy.
    Yangang Su, Wendong Jin, Jie Niu, Xingyu Lyu, Qiuhua Hao, Qing Lyu, Nan Sheng, Zhiqiang Liu, Xiaoqiang Yu.
      Mitochondrial cristae remain dynamic structures in order to adapt various physiopathologic processes (e.g., mitophagy and ferroptosis); thus, visualizing and tracking different changes of cristae are crucial for a deeper understanding of these processes. Fluorescent probes that can realize long-term visualization of mitochondrial cristae under stimulated emission depletion (STED) microscopy are powerful tools for their in-depth research. However, there are few reports on such probes, and their constructions remain challenging. Here, we reported a robust squaraine probe (CSN) for visualizing and tracking the changes of mitochondrial cristae in various physiological and pathological processes using STED microscopy. The lipophilic unit of CSN enabled it to firmly immobilize in mitochondria via a hydrophobic interaction, which let the labeling ability of CSN independent of mitochondrial membrane potential (MMP). Using CSN, the mitochondrial cristae were clearly observed at a resolution of 52 nm under STED microscopy. Furthermore, CSN was successfully applied to track the destruction processes of mitochondrial cristae during autophagy and ferroptosis. Interestingly, we found that during mitophagy, mitochondria first underwent swelling and cristae rupture, and then partial vacuolization, and finally complete vacuolization, whereas during ferroptosis, mitochondria first underwent a gradual reduction in the number of cristae, and then partial fracture, and finally vacuolization. This work revealed the difference in mitochondrial cristae changes during mitophagy and ferroptosis, which provided insights into the two physiological and pathological processes. We believed that CSN could serve as a desirable tool to track cristae changes of intracellular activity processes.
    DOI:  https://doi.org/10.1021/acs.analchem.4c05544
  40. J Lipid Atheroscler. 2025 Jan;14(1): 40-53
    Cardioprotective Effects of Adiponectin-Stimulated Autophagy.
    Eddie Tam, Mireille Ouimet, Gary Sweeney.
      Cardiovascular diseases (CVDs), including heart failure, pose a significant economic and health burden worldwide. Current treatment strategies for heart failure are greatly limited, in that they mainly mitigate symptoms or delay further progression. In contrast, therapies aimed at proactively preventing the onset of heart failure could greatly improve outcomes. Adiponectin is an adipocyte-derived hormone that confers an array of cardioprotective effects. It exerts anti-inflammatory effects, improves metabolic function, mitigates endothelial cell dysfunction, and reduce cardiomyocyte cell death. Furthermore, it has gained increasing attention for its ability to activate autophagy, a conserved cellular pathway that facilitates the degradation and recycling of cell components. The disruption of autophagy has been linked to CVDs including heart failure. Additionally, growing evidence also points to specific forms of autophagy, namely mitophagy and lipophagy, as crucial adaptive responses in protection against CVDs. The protective effects of adiponectin, autophagy, mitophagy, and lipophagy against CVDs along with potential therapeutic implications will be discussed.
    Keywords:  Adiponectin; Autophagy; Cardiovascular diseases; Lipophagy; Mitophagy
    DOI:  https://doi.org/10.12997/jla.2025.14.1.40
  41. Brain. 2025 Feb 06. pii: awaf051. [Epub ahead of print]
    Parkinson's disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss.
    Axel Chemla, Giuseppe Arena, Ginevra Sacripanti, Kyriaki Barmpa, Alise Zagare, Pierre Garcia, Vyron Gorgogietas, Paul Antony, Jochen Ohnmacht, Alexandre Baron, Jaqueline Jung, Frida Lind-Holm Mogensen, Alessandro Michelucci, Anne-Marie Marzesco, Manuel Buttini, Thorsten Schmidt, Anne Grünewald, Jens C Schwamborn, Rejko Krüger, Cláudia Saraiva.
      The complex and heterogeneous nature of Parkinson's disease (PD) is still not fully understood, however, increasing evidence supports mitochondrial impairment as a major driver of neurodegeneration. Miro1, a mitochondrial GTPase encoded by the RHOT1 gene, is involved in mitochondrial transport, mitophagy and mitochondrial calcium buffering, and is therefore essential for maintaining mitochondrial homeostasis. Recently, Miro1 has been linked genetically and pathophysiologically to PD, further supported by the identification of heterozygous variants of Miro1 in patients. Herein, we used patient-derived cellular models alongside knock-in mice to investigate Miro1-dependent pathophysiological processes and molecular mechanisms underlying neurodegeneration in PD. Experimental work performed in induced pluripotent stem cells (iPSC)-derived models, including midbrain organoids and dopaminergic neuronal cell cultures from a PD patient carrying the p.R272Q Miro1 mutation as well as healthy and isogenic controls, indicated that the p.R272Q Miro1 mutation leads to increased oxidative stress, disrupted mitochondrial bioenergetics and altered cellular metabolism. This was accompanied by increased α-synuclein levels and a significant reduction of dopaminergic neurons. Moreover, the p.R272Q Miro1 mutation - located in the calcium-binding domain of the GTPase - disrupted calcium homeostasis. This resulted in the calcium-dependent activation of calpain proteases and the subsequent cleavage of α-synuclein. Knock-in mice expressing p.R285Q Miro1 (the orthologue of the human p.R272Q mutation) displayed accumulation of phosphorylated α-synuclein in the striatum and a significant loss of dopaminergic neurons in the substantia nigra, accompanied by behavioral alterations. These findings demonstrate that mutant Miro1 is sufficient to comprehensively model PD-relevant phenotypes in vitro and in vivo, reinforcing its pivotal role in PD pathogenesis.
    Keywords:  calcium homeostasis; knock-in mice; neurodegeneration; p.R272Q Miro1; patient-specific iPSC-derived models; α-synuclein
    DOI:  https://doi.org/10.1093/brain/awaf051
  42. Blood. 2025 Feb 06. pii: blood.2024024781. [Epub ahead of print]
    Targeting Caseinolytic Mitochondrial Matrix Peptidase, a Novel Contributor to High-risk Behavior, in Multiple Myeloma.
    Li Qin, Luz Yurany Moreno Rueda, Upasana Ray, Iqbal Mahmud, Lin Tan, Philip L Lorenzi, Suyu Liu, Heather Yan Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Maria Jose Acevedo Calado, Hua Wang, Elisabet E Manasanch, Hans C Lee, Krina K Patel, Isere Kuiatse, David E Symer, Robert Z Orlowski.
      Plasma cell dyscrasias encompass a spectrum from the precursors monoclonal gammopathy of undetermined significance and smoldering myeloma to symptomatic myeloma, but the genes that enable progression and confer poor prognosis are incompletely understood. Using single cell transcriptomics, we identified the Caseinolytic protease proteolytic subunit (CLPP), a key component of the mitochondrial CLP serine endopeptidase, as being over-expressed in CD138+ neoplastic versus normal, and in symptomatic versus precursor plasma cells. Its high expression was associated with an adverse prognosis across multiple molecularly defined subgroups in the newly diagnosed and relapsed/refractory settings, and with extramedullary disease. Pharmacologic CLPP inhibition and genetic suppression reduced organoid growth, cell viability, and cell cycle progression, while triggering an unfolded protein response and apoptosis. This occurred in association with mitochondrial transmembrane potential loss, and caspase and proteasome activation in a reactive oxygen species-dependent manner. Downstream consequences included autophagy and mitophagy induction, and reductions in oxidative phosphorylation and glycolysis with consequent compromise of mitochondrial and cytoplasmic ATP production. CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes.
    DOI:  https://doi.org/10.1182/blood.2024024781
  43. Curr Res Food Sci. 2025 ;10 100972
    Resveratrol enhances post-injury muscle regeneration by regulating antioxidant and mitochondrial biogenesis.
    Xiaoli Qin, Wenjing Niu, Kai Zhao, Yawen Luo, Wenfang Wang, Yang He, Fuyu Yang, Binghai Cao, Min Du, Huawei Su.
      Resveratrol (RES), a natural polyphenolic compound, has shown promise in enhancing skeletal muscle regeneration and metabolic function. This study aims to explore the impact of RES on muscle regeneration after injury through the regulation of antioxidant capacity and mitochondrial biogenesis. RES treatment significantly increased the ratio of tibialis anterior muscle mass to body weight, alongside reduced fasting glucose levels. Following cardiotoxin-induced injury, RES treatment improved muscle regeneration, characterized by greater formation of new fibers and better structural repair compared to the control. Notably, gene expression analyses demonstrated that RES-treated mice exhibited elevated levels of myogenic markers, such as paired box 7 (Pax7), myogenic factor 5 (Myf5), myoblast determination protein (MyoD), and Myogenin (MyoG). Concurrently, yes-associated protein (YAP) increased, underscoring its role in regulating satellite cell activity. Transcriptomic analysis identified enriched pathways related to muscle regeneration and mitochondrial biogenesis, with increased expression of mitochondrial transcription factors and higher mitochondrial DNA content in RES-treated mice. Furthermore, RES enhanced antioxidant capacity via the Kelch-like ECH-associated protein 1 (KEAP-1)/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway, as indicated by elevated activities of total antioxidant capacity, Glutathione peroxidase (GSH-PX), and superoxidase dismutase (SOD). Collectively, these findings suggest that RES not only promotes muscle regeneration but also supports mitochondrial function and antioxidant defenses, positioning it as a food-derived pharmaceutical for targeting muscle repair after injury.
    Keywords:  Antioxidant; Mitochondrial biogenesis; Muscle regeneration; Myogenesis; Resveratrol
    DOI:  https://doi.org/10.1016/j.crfs.2025.100972
  44. Phytother Res. 2025 Feb 06.
    Pubescenoside D Ameliorates Myocardial Ischemia-Reperfusion Injury via Preventing the Dissociation of HK2 and Promoting Mitophagy by Targeting GSK-3β.
    Juanlan Xiao, Peng Wu, Lili Wang, Jianmin Luo, Ying Wang, Yuanyuan Cheng, Rong Zhang, Zhongqiu Liu.
      Myocardial ischemia-reperfusion injury (MI/RI) is a critical challenge for acute myocardial infarction therapy, as there is currently no ideal drug available. Glycogen synthase kinase 3 beta (GSK-3β) serves as an promising therapeutic target for treating MI/RI. Our previous studies have demonstrated that Ilex pubescens ameliorates MI/RI. The purpose of this study is to evaluate the therapeutic efficacy and potential mechanism of the screened GSK-3β inhibitor from Ilex pubescens against MI/RI. Three-dimensional-quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, the oxygen and glucose deprivation/reperfusion (OGD/R) and left anterior descending (LAD) artery ligation-induced MI/RI mice model, and western blotting analysis were used to screen and investigate the myocardial protective efficacy and mechanism. Here, we screened Pubescenoside D (PBD) as a GSK-3β inhibitor with an IC50 value of 0.3769 μM from Ilex pubescens, using 3D-QSAR modeling, molecular docking, and kinase assay verification. Ile217, Leu88, Phe93, and Phe67 are the key binding sites for PBD and GSK-3β. PBD protects cardiomyocytes against MI/RI in vitro and in vivo. Further mechanism studies show that PBD inhibits mitochondrial permeability transition pore (mPTP) opening by preventing GSK-3β-mediated the dissociation of hexokinase2 (HK2) from the outer membrane of the mitochondria and enhances mitophagy by suppressing GSK-3β activity, subsequently reducing cardiomyocyte apoptosis. Our findings shed light on the efficacy of PBD as a promising therapeutic agent in the treatment of MI/RI targeting GSK-3β.
    Keywords:  GSK‐3β; Pubescenoside D; mPTP opening; mitophagy; myocardial ischemia–reperfusion injury
    DOI:  https://doi.org/10.1002/ptr.8434
  45. Chem Biol Interact. 2025 Jan 29. pii: S0009-2797(25)00035-3. [Epub ahead of print]408 111405
    A novel PDE4 inhibitor ZX21011 alleviates neuronal apoptosis by decreasing GSK3β-mediated Drp1 Ser616 phosphorylation in cerebral ischemia reperfusion.
    Huizhen Wen, Xingxing Tu, Fulan Luo, Chunyuan Zeng, Chuang Xia, Qian Zhao, Zihong Xian, Zhongzhen Zhou, Jiangping Xu, Haitao Wang.
      Dynamin-related protein 1 (Drp1) regulates mitochondrial fission and participates in neuronal apoptosis during the pathology of cerebral ischemia. We have previously shown that inhibition of phosphodiesterase-4 (PDE4) protects against neuronal apoptosis in models of ischemic stroke. However, it remains unclear whether PDE4 inhibition affects Drp1-mediated mitochondrial dysfunction and apoptosis under cerebral ischemia conditions. This study aimed to determine whether ZX21011, a novel PDE4 inhibitor synthesized in our laboratory, can act on Drp1 to counteract ischemic brain injury and to elucidate its mechanism of action. We demonstrated that ZX21011 effectively reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells and ameliorated neurological deficits caused by middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. ZX21011 enhanced glycogen synthase kinase-3β (GSK3β) phosphorylation (Ser9), GSK3β(S9A) mutation blocked the protective effects of ZX21011. Simultaneously, ZX21011 reduced the levels of reactive oxygen species (ROS), restored the morphology of mitochondria, and inhibited the phosphorylation of Drp1(Ser616). The Drp1(S616E) mutation blocked the protective effects of ZX21011 on ROS production and mitochondrial morphology function after cerebral ischemia. What's more, co-immunoprecipitation analysis revealed that ZX21011 decreased the binding of GSK3β to Drp1, and GSK3β(S9A) mutation reversed the effects of ZX21011 on Drp1 phosphorylation and cell viability. Moreover, ZX21011 decreased Drp1(Ser616) phosphorylation within the ischemic penumbra of rats following cerebral ischemia/reperfusion. In summary, ZX21011 counteracts ischemic stroke-induced oxidative stress and neuronal death, and its action is related to decreased Drp1 phosphorylation at Ser616. Thus, ZX21011 is a potential compound for the intervention of stroke.
    Keywords:  Cerebral ischemia; Drp1; Mitochondria; Neuronal apoptosis; PDE4; ZX21011
    DOI:  https://doi.org/10.1016/j.cbi.2025.111405
  46. Nat Cell Biol. 2025 Jan 31.
    An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
    Michaela Oborská-Oplová, Alexander Gregor Geiger, Erich Michel, Purnima Klingauf-Nerurkar, Sven Dennerlein, Yury S Bykov, Simona Amodeo, André Schneider, Maya Schuldiner, Peter Rehling, Vikram Govind Panse.
      The correct sorting of nascent ribosomal proteins from the cytoplasm to the nucleus or to mitochondria for ribosome production poses a logistical challenge for cellular targeting pathways. Here we report the discovery of a conserved mitochondrial avoidance segment (MAS) within the cytosolic ribosomal protein uS5 that resolves an evolutionary lethal conflict between the nuclear and mitochondrial targeting machinery. MAS removal mistargets uS5 to the mitochondrial matrix and disrupts the assembly of the cytosolic ribosome. The resulting lethality can be rescued by impairing mitochondrial import. We show that MAS triages nuclear targeting by disabling a cryptic mitochondrial targeting activity within uS5 and thereby prevents fatal capture by mitochondria. Our findings identify MAS as an essential acquisition by the primordial eukaryote that reinforced organelle targeting fidelity while developing an endosymbiotic relationship with its mitochondrial progenitor.
    DOI:  https://doi.org/10.1038/s41556-024-01588-4
  47. STAR Protoc. 2025 Jan 31. pii: S2666-1667(25)00023-1. [Epub ahead of print]6(1): 103617
    Protocol for assessing the clogging of the mitochondrial translocase of the outer membrane by precursor proteins in human cells.
    John Kim, Hilla Weidberg.
      Protein import into the mitochondria is required for organellar function. Inefficient import can result in the stalling of mitochondrial precursors inside the translocase of the outer membrane (TOM) and blockage of the mitochondrial entry gate. Here, we present a protocol to assess the clogging of TOM by mitochondrial precursors in human cell lines. We describe how the localization of mitochondrial precursors can be determined by cellular fractionation. We then show how co-immunoprecipitation can be used to test the stalling of precursors inside TOM. For complete details on the use and execution of this protocol, please refer to Kim et al.1.
    Keywords:  cell biology; cell culture; cell separation/fractionation; molecular biology; protein biochemistry; protein expression and purification
    DOI:  https://doi.org/10.1016/j.xpro.2025.103617
  48. Heliyon. 2025 Feb 15. 11(3): e42202
    Identification of mitophagy-related biomarkers and immune infiltration in polycystic ovarian syndrome by bioinformatic study.
    Hongjuan Ye, Xicheng Wang, Zhiying He.
       Background: Polycystic ovarian syndrome (PCOS) is a common endocrine and metabolic disorder in women of reproductive age. In this study, we aimed to investigate the potential prognostic value of mitophagy-related genes in PCOS patients and to analyze their role in immune infiltration during PCOS pathogenesis and progression.
    Methods: Training datasets were used for differential expression genes. Gene ontology annotations and Kyoto encyclopedia of genes and genomes signaling pathway enrichment analysis were performed. The potential biomarkers of mitophagy-related and immune infiltration in PCOS were screened by protein-protein interaction network using different algorithms, and the area under the curve was calculated to analyze their diagnostic value. The test datasets were used to validate the expression of hub genes, and receiver operating characteristic curves were used to evaluate the predictive effect of hub genes.
    Results: Five hub genes: CTSD, IGF2R, ATP13A2, NAPA and GRN were identified as the potential diagnostic biomarkers of immune-mitophagy-related PCOS through five algorithms. GRN and NAPA were validated to be significantly different in oocytes and granulosa cells between primary and secondary follicles, respectively. Based on the single sample Gene Set Enrichment Analysis score, the infiltration of 4 immune cell types in PCOS was associated with PCOS and mitophagy. Specifically, the hub gene GRN showed a positive correlation with monocytes and plasmacytoid dendritic cells, while hub gene NAPA was negatively correlated with gamma delta T cell.
    Conclusions: The current study identified immune-mitophagy-related hub genes for prognostic biomarkers of PCOS, which provided an innovative insight for the prevention and treatment of PCOS.
    Keywords:  Biomarkers; Immune infiltration; Mitophagy; Polycystic ovarian syndrome
    DOI:  https://doi.org/10.1016/j.heliyon.2025.e42202
  49. Cell Mol Life Sci. 2025 Feb 03. 82(1): 69
    Dnajc5b contributes to male fertility by maintaining the mitochondrial functions and autophagic homeostasis during spermiogenesis.
    Dake Chen, Shiqin Zhou, Jinhua Tang, Hao Xiong, Jialian Li, Fenge Li.
      DnaJ heat shock protein family member C5 beta (DNAJC5B), also known as cysteine-string protein beta, exhibits a prominent expression in testicular tissue and plays an important role in acrosomal exocytosis in vitro. Nevertheless, the precise role and underlying mechanism of DNAJC5B in spermatogenesis and male fertility remain poorly understood. The meta-analysis of RNA-sequencing datasets from porcine and murine testes reveals that Dnajc5b could be a pivotal factor in spermatogenesis. This study illustrates that male fertility declines with an increased ratio of abnormal spermatozoa in germ-cell knockout Dnajc5b mice. DNAJC5B has been identified as a mitochondrial protein with high expression in spermatids. The absence of DNAJC5B induces a cascade of mitochondrial damages, including oxidative stress, mitochondrial stress in the testes, and lower mitochondrial membrane potential of spermatozoa. In vivo and in vitro evidence demonstrates that DNAJC5B mitigates excessive cellular autophagy and mitophagy via DNAJ domain under environmental stress conditions, such as starvation or exposure to mitochondrial uncouplers FCCP and CCCP. This study highlights the important role of DNAJC5B in safeguarding male fertility by preserving mitochondrial function and regulating autophagy during spermiogenesis.
    Keywords:   Dnajc5b ; Autophagy; Meta-analysis; Mitochondria; Spermiogenesis
    DOI:  https://doi.org/10.1007/s00018-024-05552-1
  50. Front Oral Health. 2025 ;6 1540178
    The role of Mitofusin-1 and Mitofusin-2 in periodontal disease: a comprehensive review.
    Sudhir R Varma, Omar H A A Ani, Jayaraj K Narayanan, Asok Mathew.
      Periodontal disease is a widespread chronic inflammatory state influencing the supporting anatomy of the teeth, distinguished by oxidative stress, progressive bone loss, and tissue damage. Recent articles have highlighted the significance of mitochondrial dynamics, mainly Mitofusin-1 (MFN1) along with Mitofusin-2 (MFN2), inflammation regulation, tissue homeostasis, and in cellular function. The aim of the current study is to comprehensively review including evaluate the roles of MFN2 and MFN1 in the pathogenesis as well as the progression of periodontal disease, foregrounding their effect on mitochondrial integrity, inflammatory pathways, and oxidative stress. Studies were selected depending on inclusion criteria based on the roles of MFN2 and MFN1 in periodontal disease and health. Data from chosen in vivo, clinical studies, and in vitro were synthesized. Outcomes indicate that MFN2 and MFN1 are important for preserving cellular function, mitigating oxidative damage, and mitochondrial fusion. Decreased levels of these proteins were related to elevated oxidative stress, inflammation, and increased mitochondrial dysfunction in periodontal tissues. The current comprehensive review shows the important roles of MFN1 along with MFN2 in inflammation regulation, cell survival, and mitochondrial dynamics within periodontal disease. The prospective for targeting MFN1 along with MFN2 in therapeutic policy is promising, presenting avenues for upgraded periodontal management and regeneration.
    Keywords:  Mitofusin-1; Mitofusin-2; mitochondrial dynamics; oxidative stress; periodontal disease
    DOI:  https://doi.org/10.3389/froh.2025.1540178
  51. Nat Commun. 2025 Feb 04. 16(1): 1358
    Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
    Xiaofan Sun, Yue Li, Juan Du, Fangshu Liu, Caiping Wu, Weihao Xiao, Guopan Yu, Xiaowei Chen, Robert Peter Gale, Hui Zeng.
      Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.
    DOI:  https://doi.org/10.1038/s41467-025-56520-7
  52. Mol Cell. 2025 Feb 06. pii: S1097-2765(25)00036-X. [Epub ahead of print]85(3): 638-651.e9
    The mitochondrial DNAJC co-chaperone TCAIM reduces α-ketoglutarate dehydrogenase protein levels to regulate metabolism.
    Wang Jiahui, Yu Xiang, Zhong Youhuan, Ma Xiaomin, Gao Yuanzhu, Zhou Dejian, Wang Jie, Fu Yinkun, Fan Shi, Su Juncheng, Huang Masha, Haigis Marcia, Wang Peiyi, Xu Yingjie, Yang Wen.
      Mitochondrial heat shock proteins and co-chaperones play crucial roles in maintaining proteostasis by regulating unfolded proteins, usually without specific target preferences. In this study, we identify a DNAJC-type co-chaperone: T cell activation inhibitor, mitochondria (TCAIM), and demonstrate its specific binding to α-ketoglutarate dehydrogenase (OGDH), a key rate-limiting enzyme in mitochondrial metabolism. This interaction suppresses OGDH function and subsequently reduces carbohydrate catabolism in both cultured cells and murine models. Using cryoelectron microscopy (cryo-EM), we resolve the human OGDH-TCAIM complex and reveal that TCAIM binds to OGDH without altering its apo structure. Most importantly, we discover that TCAIM facilitates the reduction of functional OGDH through its interaction, which depends on HSPA9 and LONP1. Our findings unveil a role of the mitochondrial proteostasis system in regulating a critical metabolic enzyme and introduce a previously unrecognized post-translational regulatory mechanism.
    Keywords:  DNAJC; OGDH; TCAIM; charperon; metabolism; mitochondria; protein degradation; protein interaction; single-particle cryo-EM; α-ketoglutarate dehydrogenase
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.006
  53. Spectrochim Acta A Mol Biomol Spectrosc. 2025 Jan 31. pii: S1386-1425(25)00137-4. [Epub ahead of print]332 125831
    Aggregation-induced emission-twisted intramolecular charge transfer-activated fluorescent probe for analyzing mitochondrial viscosity in cells and zebrafish.
    Shu-Long He, Guo-Bin Wang, Xue-Li Cheng, Lin-Lin Han, Wei Pan, Han-Yang Zou, Shi-Li Shen, Xian-Hong Pang, Yan Zhu.
      Mitochondria are crucial energy-supplying organelles that support cellular activities and play vital roles in cell metabolism, aging, autophagy, and apoptosis. Abnormal viscosity can alter the mitochondrial microenvironment, disrupt normal mitochondrial function, and lead to disease. To address this, we designed and developed two aggregation-induced emission-twisted intramolecular charge transfer fluorescent probes, namely, (E)-1,1,3-trimethyl-2-(4-(1,2,2-triphenylvinyl)styryl)-1H-benzo[e]indol-3-ium (HSL-1) and (E)-2-(4-(di-p-tolylamino)styryl)-1,3,3-trimethyl-1H-benzo[e]indol-3-ium (HSL-2). In vitro fluorescence detection revealed that both HSL-1 and HSL-2 were sensitive to viscosity and demonstrated a strong log-linear relationship, with linear coefficients of 0.982 and 0.980, respectively. Notably, the responses of HSL-1 and HSL-2 to viscosity changes were unaffected by pH, polarity, or interfering ions. HSL-1 exhibited stronger resistance to background interference than HSL-2 and significantly enhanced fluorescence intensity; thus, it was selected for cell experiments and animal fluorescence intensity assessments. Furthermore, HSL-1 showed excellent biocompatibility, enabling real-time detection of mitochondrial viscosity changes and identification of viscosity abnormalities triggered by mitophagy in HeLa cells. It could also monitor changes in mitochondrial viscosity in zebrafish. In conclusion, HSL-1 is a valuable tool for studying viscosity and understanding diseases associated with abnormal mitochondrial viscosity.
    Keywords:  Aggregation-induced emission; Mitochondria; Viscosity; Zebrafish
    DOI:  https://doi.org/10.1016/j.saa.2025.125831
  54. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  55. Curr Protoc. 2025 Feb;5(2): e70004
    Creating Optimal Western Blot Conditions for OPA1 Isoforms in Skeletal Muscle Cells and Tissue.
    Margaret Mungai, Amber Crabtree, Han Le, Johnathan Moore, Desiree Nguyen, Benjamin Rodriguez, Chanel Harris, Dominique C Stephens, Heather K Beasley, Edgar Garza-Lopez, Kit Neikirk, Bryanna Shao, Ashton Oliver, Genesis Wilson, Serif Bacevac, Larry Vang, Zer Vue, Neng Vue, Andrea G Marshall, Kyrin Turner, Elma Zaganjor, Jianqiang Shao, Sandra Murray, Jennifer A Gaddy, Celestine Wanjalla, Jamaine Davis, Steven M Damo, Lori D Banks, Antentor Hinton.
      OPA1 is a dynamin-related GTPase that modulates mitochondrial dynamics and cristae integrity. Humans carry eight different isoforms of OPA1 and mice carry five, all of which are expressed as short- or long-form isoforms. These isoforms contribute to OPA1's ability to control mitochondrial energetics and DNA maintenance. However, western blot isolation of all long and short isoforms of OPA1 can be difficult. To address this issue, we developed an optimized western blot protocol based on improving running time to isolate five different isoforms of OPA1 in mouse cells and tissues. This protocol can be applied to study changes in mitochondrial structure and function. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Western Blot Protocol for Isolating OPA1 Isoforms in Mouse Primary Skeletal Muscle Cells.
    Keywords:  isoforms; mitochondria; muscle tissue; optic atrophy‐1 (OPA1); western blot
    DOI:  https://doi.org/10.1002/cpz1.70004
  56. Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00036-1. [Epub ahead of print]44(2): 115265
    Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia.
    Zeng Zhang, Quan Guo, Zhihan Yang, Yukai Sun, Shuaiming Jiang, Yangli He, Jiahe Li, Jiachao Zhang.
      Sarcopenia significantly diminishes quality of life and increases mortality risk in older adults. While the connection between the gut microbiome and muscle health is recognized, the underlying mechanisms are poorly understood. In this study, shotgun metagenomics revealed that Bifidobacterium adolescentis is notably depleted in individuals with sarcopenia, correlating with reduced muscle mass and function. This finding was validated in aged mice. Metabolomics analysis identified nicotinic acid as a key metabolite produced by B. adolescentis, linked to improvements in muscle mass and functionality in individuals with sarcopenia. Mechanistically, nicotinic acid restores nicotinamide adenine dinucleotide (NAD+) levels in muscle, inhibits the FoxO3/Atrogin-1/Murf-1 axis, and promotes satellite cell proliferation, reducing muscle atrophy. Additionally, NAD+ activation enhances the silent-information-regulator 1 (SIRT1)/peroxisome-proliferator-activated-receptor-γ-coactivator 1-alpha (PGC-1α) axis, stimulating mitochondrial biogenesis and promoting oxidative metabolism in slow-twitch fibers, ultimately improving muscle function. Our findings suggest that B. adolescentis-derived nicotinic acid could be a promising therapeutic strategy for individuals with sarcopenia.
    Keywords:  Bifidobacterium adolescentis; CP: Metabolism; CP: Microbiology; NAD+; gut microbiome; mitochondria biogenesis; multi-omics; nicotinic acid; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.115265
  57. Brain Res. 2025 Jan 30. pii: S0006-8993(25)00037-X. [Epub ahead of print] 149479
    Electroacupuncture promotes neural function recovery by alleviating mitochondria damage in cerebral ischemia mice.
    Feng Yashuo, Guan Chong, Yang Zhe, Cao Lu, Xie Hongyu, Wu Yi, Wang Nianhong.
       AIMS: This study aimed to observe the effect of electroacupuncture (EA) at Zusanli point (ST36) on motor function of cerebral ischemia mice, and to observe the effect of EA on mitochondrial morphology of peri-infarct cortex neurons in cerebral ischemia mice.
    METHODS: Middle cerebral artery occlusion (MCAO) was used to develop an ischemic stroke mice model. EA treatment was performed for three consecutive days for 15 min per day after MCAO modeling. We investigated the therapeutic effects of EA on MCAO mice by performing neurobehavioral assessment (modified Neurological Severity Score, Rotarod test, Open-field test and Gait analysis) and TTC staining. The morphology and function of neuronal mitochondria were evaluated by transmission electron microscopy, qRT-PCR, chemiluminescence, and western blot. Nissl staining, TUNEL staining and immunofluorescence staining were used to observe neuronal morphology and apoptosis. Furthermore, ELISA was employed to measure the expression levels of inflammatory factors in mouse serum.
    RESULTS: EA alleviated motor dysfunction and infarct volume in mice with cerebral ischemia. It improved the neuronal mitochondria damage in MCAO mice, and decreased the protein and mRNA expression level of mitochondrial fission related proteins (FIS1 and Drp1). In addition, EA can reduce neuronal damage and apoptosis of nerve cells, and decrease the level of inflammatory factors (IL-1β, TNF-α, IL-6 and IL-8) in cerebral ischemia mice.
    CONCLUSION: EA therapy can improve motor dysfunction and alleviate the damage of neuron mitochondria in cerebral ischemic mice.
    Keywords:  Apoptosis; Electroacupuncture; Ischemic stroke; Mitochondria
    DOI:  https://doi.org/10.1016/j.brainres.2025.149479
  58. PLoS Genet. 2025 Feb 06. 21(2): e1011554
    Shaker/Kv1 potassium channel SHK-1 protects against pathogen infection and oxidative stress in C. elegans.
    Longjun Pu, Jing Wang, Lars Nilsson, Lina Zhao, Chloe Williams, Guanqiao Chi, Jonathan D Gilthorpe, Simon Tuck, Johan Henriksson, Yi-Quan Tang, Sun Nyunt Wai, Changchun Chen.
      The Shaker/Kv1 subfamily of voltage-gated potassium (K+) channels is essential for modulating membrane excitability. Their loss results in prolonged depolarization and excessive calcium influx. These channels have also been implicated in a variety of other cellular processes, but the underlying mechanisms remain poorly understood. Through comprehensive screening of K+ channel mutants in C. elegans, we discovered that shk-1 mutants are highly susceptible to bacterial pathogen infection and oxidative stress. This vulnerability is associated with reduced glycogen levels and substantial mitochondrial dysfunction, including decreased ATP production and dysregulated mitochondrial membrane potential under stress conditions. SHK-1 is predominantly expressed and functions in body wall muscle to maintain glycogen storage and mitochondrial homeostasis. RNA-sequencing data reveal that shk-1 mutants have decreased expression of a set of cation-transporting ATPases (CATP), which are crucial for maintaining electrochemical gradients. Intriguingly, overexpressing catp-3, but not other catp genes, restores the depolarization of mitochondrial membrane potential under stress and enhances stress tolerance in shk-1 mutants. This finding suggests that increased catp-3 levels may help restore electrochemical gradients disrupted by shk-1 deficiency, thereby rescuing the phenotypes observed in shk-1 mutants. Overall, our findings highlight a critical role for SHK-1 in maintaining stress tolerance by regulating glycogen storage, mitochondrial homeostasis, and gene expression. They also provide insights into how Shaker/Kv1 channels participate in a broad range of cellular processes.
    DOI:  https://doi.org/10.1371/journal.pgen.1011554
  59. Mol Metab. 2025 Feb 03. pii: S2212-8778(25)00014-6. [Epub ahead of print] 102107
    HINT1 Suppression Protects Against Age-Related Cardiac Dysfunction by Enhancing Mitochondrial Biogenesis.
    Michio Sato, Tsuyoshi Kadomatsu, Jun Morinaga, Yuya Kinoshita, Daisuke Torigoe, Haruki Horiguchi, Sumio Ohtsuki, Shuji Yamamura, Ryoko Kusaba, Takanori Yamaguchi, Goro Yoshioka, Kimi Araki, Tomohiko Wakayama, Keishi Miyata, Koichi Node, Yuichi Oike.
      Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. Here, we observed inactivation of mitochondrial biogenesis in hearts of aged mice and a reduction in mitochondrial mass. We also showed that activity of the BAF chromatin remodeling complex is repressed by HINT1, whose expression in heart increases with age, leading to decreased transcription of Tfam, which promotes mitochondrial biogenesis. Interestingly, calorie restriction (CR) not only suppressed age-related declines in cardiac function and mitochondrial biogenesis but blocked concomitant increases in cardiac HINT1 protein levels and maintained Tfam transcription. Furthermore, expression of the lncRNA Caren, which inhibits Hint1 mRNA translation, decreased with age in heart, and CR suppressed this effect. Finally, decreased HINT1 expression due to Caren overexpression antagonized age-related declines in mitochondrial biogenesis, ameliorating age-related cardiac dysfunction, exercise intolerance, and exercise-induced cardiac damage and subsequent death of mice. These data suggest overall that the Caren-HINT1-mitochondrial biogenesis axis represents an important mechanism of CR-induced resistance to cardiac aging.
    Keywords:  Calorie restriction; Cardiac aging; Heart failure; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2025.102107
  60. Eur J Pharmacol. 2025 Feb 04. pii: S0014-2999(25)00100-1. [Epub ahead of print] 177347
    Mitochondrial Calcium Uniporter knockdown improves the viability of HT22 hippocampal neurons in Alzheimer's disease.
    Hongyan Cai, Fei Hou, Yu Wang, Linhong Wu, Zhaojun Wang, Meina Wu, Xiao Wang, Christian Hölscher.
      Alzheimer's disease (AD) is a degenerative disorder that poses a serious threat because it has no cure. Recently, mitochondrial dysfunction has been shown to directly promote the development of AD. An imbalance in mitochondrial calcium (mCa2+) homeostasis is an important cause of mitochondrial dysfunction. Abnormal expression of mitochondrial calcium uniporter (MCU), a key channel responsible for mCa2+ uptake, can induce an imbalance in mCa2+ homeostasis, ultimately leading to mitochondrial dysfunction. Importantly, we observed a much higher expression level of MCU in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1)/tau transgenic mice than that in the hippocampus of control mice (C57), suggesting that MCU may be a target for the development of treatments for AD. Our recent study revealed the neuroprotective effect of MCU knockdown on hippocampal neurons in APP/PS1/tau mice. In the present study, we used MCU knockdown to investigate the cellular mechanisms involved in amyloid-β (Aβ)1-42 and okadaic acid (OA) cell models of AD. We found that MCU knockdown could increase the survival and decrease the apoptosis of these two cell models by lowering mCa2+ overload, further increasing the mitochondrial membrane potential (MMP) and ultimately reducing the overproduction of reactive oxygen species (ROS). This study showed that MCU knockdown could increase the proliferation and viability of HT22 hippocampal neurons, which might explain the neuroprotective effect of MCU knockdown on AD, potentially leading to the development of novel and effective therapies for AD.
    Keywords:  Alzheimer’s disease; hippocampal neurons; mitochondrial calcium homeostasis; mitochondrial calcium uniporter; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177347
  61. Neuroscience. 2025 Jan 31. pii: S0306-4522(25)00071-5. [Epub ahead of print]568 454-464
    Mothers with obesity and gestational diabetes did not induce brain pathologies or premature brain aging in their adolescent and early adult offspring in rats.
    Huatuo Huang, Nattayaporn Apaijai, Chanisa Thonusin, Panan Suntornsaratoon, Nipon Chattipakorn, Narattaphol Charoenphandhu, Siriporn C Chattipakorn.
      This study investigated the effect of a medium high-fat diet (HFD)-induced maternal obesity and gestational diabetes mellitus (GDM) on rat offspring to verify the hypothesis that maternal obesity and GDM cause brain pathologies and premature brain aging in the prefrontal cortex and hippocampus of the adolescent and early adult offspring. Maternal obesity and GDM were generated by a medium HFD and HFD combined with streptozotocin, respectively. Metabolic parameters were used to confirm the successful model in mothers. Systemic alterations and brain pathology were investigated in their adolescent and early adult offspring. During pregnancy, HFD-fed rats exhibited obesity, while GDM rats had hyperglycemia with insulin resistance. Offspring from high-fat diet dams (OHFD) had higher body weight when compared with offspring from normal diet dams (OND), while offspring from gestational diabetes mellitus dams (OGDM) had lower body weight than OHFD but comparable with OND. No significant alterations were found in glucose tolerance, systemic oxidative stress, and inflammation in the offspring. Additionally, neither adolescent nor early adult rats OHFD or OGDM developed brain pathologies or premature aging with no difference in oxidative stress, inflammation, mitochondrial dynamics, mitophagy, blood-brain barrier, synaptic plasticity, apoptosis, and aging markers among the offspring groups. Our results indicated that maternal obesity and GDM did not cause brain pathologies or premature brain aging at the adolescent and early adult stages of offspring in rats. Our study highlights the importance of maintaining a healthy diet in the offspring of obese and GDM mothers to keep healthy later in their lives.
    Keywords:  Aging; Brain; Gestational diabetes mellitus; Obesity; Offspring
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.01.056
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