bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–11–17
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.
  2. ZIP7 contributes to the pathogenesis of diabetic cardiomyopathy by suppressing mitophagy in mouse hearts.
  3. A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
  4. Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
  5. Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
  6. Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
  7. Role of mitophagy in intervertebral disc degeneration: A narrative review.
  8. The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.
  9. Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.
  10. TRPC6-Calpain-1 Axis Promotes Tubulointerstitial Inflammation by Inhibiting Mitophagy in Diabetic Kidney Disease.
  11. HSP90 Enhances Mitophagy to Improve the Resistance of Car-Diomyocytes to Heat Stress in Wenchang Chickens.
  12. Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy.
  13. Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice.
  14. Klf9 is essential for cardiac mitochondrial homeostasis.
  15. Osteosarcoma stem cells resist chemotherapy by maintaining mitochondrial dynamic stability via DRP1.
  16. Opposing roles for AMPK in regulating distinct mitophagy pathways.
  17. FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.
  18. ATF5-mediated mitochondrial unfolded protein response protects against Pb-induced mitochondria damage in SH-SY5Y cell.
  19. Suppression of PINK1 autophosphorylation attenuates pilocarpine-induced seizures and neuronal injury in rats.
  20. Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
  21. Mitochondrial maintenance as a novel target for treating steroid-induced osteonecrosis of femoral head: a narrative review.
  22. Baicalin attenuates corticosterone-induced hippocampal neuronal injury by activating mitophagy in an AMPK-dependent manner.
  23. Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.
  24. Mitophagy drives maldifferentiation of tissue-resident memory T cells in patients with rheumatoid arthritis.
  25. From bioinformatics to anti-inflammation and immune regulation: ACT001 in lipopolysaccharide-induced lung injury.
  26. Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.
  27. TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.
  28. PI3K p85α/HIF-1α accelerates the development of pulmonary arterial hypertension by regulating fatty acid uptake and mitophagy.
  29. FMRP gains mitochondrial fission control.
  30. Dopamine-D2-agonist targets mitochondrial dysfunction via diminishing Drp1 mediated fission and normalizing PGC1-α/SIRT3 pathways in a rodent model of Subarachnoid haemorrhage.
  31. Targeting NAMPT-OPA1 for treatment of senile osteoporosis.
  32. TFAP2C/FLT3 Axis Reduces Ferroptosis in Breast Cancer Cells by Inhibiting Mitochondrial Autophagy.
  33. Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
  34. Tanshinone IIA alleviates inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction.
  35. Detoxification of Chlorfenapyr by a Parkin-GSTd2 Module in Bactrocera dorsalis (Diptera: Tephritidae).
  36. Resveratrol alleviates Mono-2-ethylhexyl phthalate-induced mitophagy, ferroptosis, and immunological dysfunction in grass carp hepatocytes by regulating the Nrf2 pathway.
  37. PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
  38. HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
  39. Res@ZIF-90 suppress gastric cancer progression by disturbing mitochondrial homeostasis.
  40. Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2.
  41. Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.
  42. Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis.
  43. Benzophenone-3 exposure induced apoptosis via impairing mitochondrial function in human chondrocytes.
  44. Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment.
  45. Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
  46. Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.
  47. αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury.
  48. Astaxanthin Reduces H2O2- and Doxorubicin-Induced Cardiotoxicity in H9c2 Cardiomyocyte Cells.
  49. Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.
  50. Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.
  51. Loss of O6-methylguanine DNA methyltransferase (MGMT) in macrophages alters responses to TLR3 stimulation and enhances DNA double-strand breaks and mitophagy.
  52. 20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway.
  53. Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy.
  54. Kaixinsan regulates neuronal mitochondrial homeostasis to improve the cognitive function of Alzheimer's disease by activating CaMKKβ-AMPK-PGC-1α signaling axis.
  55. AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats.
  56. Oxidative phosphorylation decline and mitochondrial dynamics disequilibrium are involved in chicken large white follicle atresia.
  57. FoxO3a Plays a Role in Wound Healing by Regulating Fibroblast Mitochondrial Dynamics.
  58. Exploring the role of mitophagy-related genes in breast cancer: subtype classification and prognosis prediction.
  59. Resveratrol protects pancreatic beta cell and hippocampal cells from the aggregate-prone capacity of hIAPP.
  60. High intensity interval training as a therapy: Mitophagy restoration in breast cancer.
  61. Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.
  62. Proteomics reveals that nanoplastics with different sizes induce hepatocyte apoptosis in mice through distinct mechanisms involving mitophagy dysregulation and cell cycle arrest.
  63. Buyang Huanwu Decoction restores the balance of mitochondrial dynamics after cerebral ischemia-reperfusion through calcium overload reduction by the PKCε-Nampt-Sirt5 axis.
  64. Pretreatment with growth differentiation factor 15 augments cardioprotection by mesenchymal stem cells in myocardial infarction by improving their survival.
  65. Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.
  66. Mitochondria: great balls of fire.
  67. Mitochondrial E3 ligase TRIM71 affects mitochondrial complex assembly and sensitizes dopaminergic neuronal cells to apoptosis in Parkinson's Disease (PD).
  1. J Mol Neurosci. 2024 Nov 08. 74(4): 107
    Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.
    Mega Obukohwo Oyovwi, Emeka Williams Ugwuishi, Onoriode Andrew Udi, Gregory Joseph Uchechukwu.
      Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.
    Keywords:  Cellular resilience; Mitochondrial dynamics; Mitochondrial health; Mitophagy; Neuroendocrinopathy; Oxidative stress; Therapeutic interventions
    DOI:  https://doi.org/10.1007/s12031-024-02280-w
  2. Cardiovasc Diabetol. 2024 Nov 07. 23(1): 399
    ZIP7 contributes to the pathogenesis of diabetic cardiomyopathy by suppressing mitophagy in mouse hearts.
    Ningzhi Yang, Rui Zhang, Hualu Zhang, Yonghao Yu, Zhelong Xu.
       BACKGROUND: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM.
    METHODS: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB.
    RESULTS: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM.
    CONCLUSIONS: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy.
    Keywords:  Cardiomyopathy; Mitophagy; PINK1/Parkin pathway; T2DM; ZIP7
    DOI:  https://doi.org/10.1186/s12933-024-02499-2
  3. Autophagy. 2024 Nov 09.
    A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
    Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su.
      PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of Rnf7 in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.
    Keywords:  Heart failure; RBX2/SAG; mitophagy; parkin; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2423329
  4. Mol Biol Cell. 2024 Nov 13. mbcE24070306
    Significantly reduced, but balanced, rates of mitochondrial fission and fusion are sufficient to maintain the integrity of yeast mitochondrial DNA.
    Brett T Wisniewski, Jason C Casler, Laura L Lackner.
      Mitochondria exist as dynamic tubular networks and the morphology of these networks impacts organelle function and cell health. Mitochondrial morphology is maintained in part by the opposing activities of mitochondrial fission and fusion. Mitochondrial fission and fusion are also required to maintain mitochondrial DNA (mtDNA) integrity. In Saccharomyces cerevisiae, the simultaneous inhibition of mitochondrial fission and fusion results in increased mtDNA mutation and the consequent loss of respiratory competence. The mechanism by which fission and fusion maintain mtDNA integrity is not fully understood. Previous work demonstrates that mtDNA is spatially linked to mitochondrial fission sites. Here, we extend this finding using live-cell imaging to localize mtDNA to mitochondrial fusion sites. While mtDNA is present at sites of mitochondrial fission and fusion, mitochondrial fission and fusion rates are not altered in cells lacking mtDNA. Using alleles that alter mitochondrial fission and fusion rates, we find that mtDNA integrity can be maintained in cells with significantly reduced, but balanced, rates of fission and fusion. In addition, we find that increasing mtDNA copy number reduces the loss of respiratory competence in double mitochondrial fission-fusion mutants. Our findings add novel insights into the relationship between mitochondrial dynamics and mtDNA integrity.
    DOI:  https://doi.org/10.1091/mbc.E24-07-0306
  5. Metabolism. 2024 Nov 06. pii: S0026-0495(24)00289-0. [Epub ahead of print] 156061
    Wars1 downregulation in hepatocytes induces mitochondrial stress and disrupts metabolic homeostasis.
    Francesca Pontanari, Hadrien Demagny, Adrien Faure, Xiaoxu Li, Giorgia Benegiamo, Antoine Jalil, Alessia Perino, Johan Auwerx, Kristina Schoonjans.
      Several laboratories, including ours, have employed the Slc25a47tm1c(EUCOMM)Hmgu mouse model to investigate the role of SLC25A47, a hepatocyte-specific mitochondrial carrier, in regulating hepatic metabolism and systemic physiology. In this study, we reveal that the hepatic and systemic phenotypes observed following recombination of the Slc25a47-Wars1 locus in hepatocytes are primarily driven by the unexpected downregulation of Wars1, a cytosolic tryptophan aminoacyl-tRNA synthetase located adjacent to Slc25a47. While the downregulation of Wars1 predictably affects cytosolic translation, we also observed a significant impairment in mitochondrial protein synthesis within hepatocytes. This disturbance in mitochondrial function leads to an activation of the mitochondrial unfolded protein response (UPRmt), a critical component of the mitochondrial stress response (MSR). Our findings clarify the distinct roles of Slc25a47 and Wars1 in maintaining both systemic and hepatic metabolic homeostasis. This study sheds new light on the broader implications of aminoacyl-tRNA synthetases in mitochondrial physiology and stress responses.
    Keywords:  Hepatocytes; ISR; MSR; SLC25A47; Translation; UPR(mt); WARS1
    DOI:  https://doi.org/10.1016/j.metabol.2024.156061
  6. Autophagy. 2024 Nov 08.
    Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).
    Moumita Roy, Sumangal Nandy, Elena Marchesan, Chayan Banerjee, Rupsha Mondal, Federico Caicci, Elena Ziviani, Joy Chakraborty.
      Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this phenomenon. Through in vitro biochemical assays and imaging, we have found that VDAC1-PHB2 interaction increases during mitochondrial depolarization. Subsequently, this interaction enhances the efficiency of PHB2 exposure and mitophagy. To investigate the relevance in vivo, we utilized porin (equivalent to VDAC1) knockout Drosophila line. Our findings demonstrate that during mitochondrial stress, porin is essential for Phb2 exposure, Phb2-Atg8 interaction and mitophagy. This study highlights that VDAC1 predominantly synchronizes efficient PHB2 exposure through mitochondrial rupture sites during mitophagy. These findings may provide insights to understand progressive neurodegeneration.
    Keywords:  Neurodegeneration; PHB2-LC3 interaction; PINK1-PRKN; parkinson disease; porin; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1080/15548627.2024.2426116
  7. Osteoarthritis Cartilage. 2024 Nov 12. pii: S1063-4584(24)01446-8. [Epub ahead of print]
    Role of mitophagy in intervertebral disc degeneration: A narrative review.
    Zuo-Long Wu, Yong Liu, Wei Song, Kai-Sheng Zhou, Yan Ling, Hai-Hong Zhang.
       OBJECTIVE: The pivotal role of mitophagy in the initiation and progression of intervertebral disc (IVD) degeneration (IDD) has become increasingly apparent due to a growing body of research on its pathogenesis. This review summarizes the role of mitophagy in IDD and the therapeutic potential of targeting this process.
    DESIGN: This narrative review is divided into three parts: the regulatory mechanisms of mitophagy, the role of mitophagy in IDD, and the applications and prospects of mitophagy for the treatment of IDD.
    RESULTS: Mitophagy protects cells against harmful external stimuli and plays a crucial protective role by promoting extracellular matrix (ECM) production, inhibiting ECM degradation, and reducing apoptosis, senescence, and cartilage endplate calcification. However, excessive mitophagy is often detrimental to cells. Currently, the regulatory mechanisms governing appropriate and excessive mitophagy remain unclear.
    CONCLUSIONS: Proper mitophagy effectively maintains IVD cell homeostasis and slows the progression of IDD. Conversely, excessive mitophagy may accelerate IDD development. Further research is needed to elucidate the regulatory mechanisms underlying appropriate and excessive mitophagy, which could provide new theoretical support for the application of mitophagy targeting to the treatment of IDD.
    Keywords:  Autophagy lysosomes; Intervertebral disc; Intervertebral disc degeneration; Mitophagy; Nucleus pulposus
    DOI:  https://doi.org/10.1016/j.joca.2024.09.013
  8. Front Cell Dev Biol. 2024 ;12 1464773
    The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.
    Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Sara Falvo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.
       Introduction: The contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes.
    Methods: We used CB1-/- and CB1+/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis.
    Results and discussion: In the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1-/- mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPRmt). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPRmt and UPRER pathways.
    Keywords:  cannabinoid receptor 1; homeostasis; mitochondrial quality control; mitochondrial unfolded protein response; oxidative stress; respiratory chain supercomplexes
    DOI:  https://doi.org/10.3389/fcell.2024.1464773
  9. J Gen Physiol. 2024 Dec 02. pii: e202313485. [Epub ahead of print]156(12):
    Exercise training may reduce fragmented mitochondria in the ischemic-reperfused heart through DRP1.
    Mathilde Dubois, Florian Pallot, Maxime Gouin-Gravezat, Doria Boulghobra, Florence Coste, Guillaume Walther, Gregory Meyer, Isabelle Bornard, Cyril Reboul.
      Mitochondrial fission is a key trigger of cardiac ischemia-reperfusion injuries (IR). Exercise training is an efficient cardioprotective strategy, but its impact on mitochondrial fragmentation during IR remains unknown. Using isolated rat hearts, we found that exercise training limited the activation of dynamin-like protein 1 and limited mitochondrial fragmentation during IR. These results support the hypothesis that exercise training contributes to cardioprotection through its capacity to modulate the mitochondrial fragmentation during IR.
    DOI:  https://doi.org/10.1085/jgp.202313485
  10. Kidney Int Rep. 2024 Nov;9(11): 3301-3317
    TRPC6-Calpain-1 Axis Promotes Tubulointerstitial Inflammation by Inhibiting Mitophagy in Diabetic Kidney Disease.
    Cong-Cong Liu, Jia-Ling Ji, Ze Wang, Xing-Jian Zhang, Lin Ding, Yao Zhang, Yan Zhou, Dong-Jie Zhang, Zhen-Lin Tang, Jing-Yuan Cao, Ai-Qing Zhang, Bi-Cheng Liu, Zuo-Lin Li, Rui-Xia Ma.
       Introduction: Renal tubulointerstitial inflammation represents an effective indicator for predicting the progression of diabetic kidney disease (DKD). Mitophagy abnormality is 1 of the most important factors involved in tubule injury. However, the exact molecular mechanism underlying mitophagy abnormality-mediated tubulointerstitial inflammation in DKD remains poorly understood.
    Methods: In this study, a streptozotocin-induced DKD mouse model was established and HK-2 cells treated with high glucose (HG) served as an in vitro model. Tubular mitophagy was regulated through pharmacological urolithin A (UA) administration. The functional effect of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) was explored using genetic interventions in vivo and in vitro.
    Results: We found that renal tubulointerstitial inflammation in DKD was closely associated with mitophagy inhibition, which was mediated by disturbance of PINK1/Parkin pathway. Mitophagy activation significantly attenuated tubular injury and tubulointerstitial inflammation. Further, it was found that TRPC6 was markedly increased in DKD and played an essential role in mitophagy inhibition by activating calpain-1. Knockdown of Trpc6 partially reversed mitophagy abnormality and consequently attenuated tubular injury and tubulointerstitial inflammation in vivo and in vitro. Finally, we found that tubular TRPC6-mediated mitophagy inhibition was blocked with BAPTA (a specific Ca2+ chelator) or calpeptin (a specific calpain-1 inhibitor).
    Conclusion: Our study reveals that TRPC6-calpain-1 axis promotes tubulointerstitial inflammation in DKD by inhibiting mitophagy.
    Keywords:  TRPC6; calpain-1; diabetic kidney disease; mitophagy; tubulointerstitial inflammation
    DOI:  https://doi.org/10.1016/j.ekir.2024.08.019
  11. Int J Mol Sci. 2024 Oct 30. pii: 11695. [Epub ahead of print]25(21):
    HSP90 Enhances Mitophagy to Improve the Resistance of Car-Diomyocytes to Heat Stress in Wenchang Chickens.
    Jiachen Shi, Zeping Ji, Xu Yao, Yujie Yao, Chengyun Li, Qijun Liang, Xiaohui Zhang.
      Heat shock protein 90 (HSP90) is recognized for its protective effects against heat stress damage; however, the specific functions and underlying molecular mechanisms of HSP90 in heat-stressed cardiomyocytes remain largely unexplored, particularly in tropical species. In our study, Wenchang chickens (WCCs) were classified into two groups: the heat stress survival (HSS) group and the heat stress death (HSD) group, based on their survival following exposure to heat stress. Heat stress resulted in significant cardiomyocyte damage, mitochondrial dysfunction, and apoptosis in the HSD group, while the damage was less pronounced in the HSS group. We further validated these findings in primary cardiomyocytes derived from Wenchang chickens (PCWs). Additionally, heat stress was found to upregulate Pink1/Parkin-mediated mitophagy, which was accompanied by an increase in HSP90 expression in both cardiomyocytes and PCWs. Our results demonstrated that HSP90 overexpression enhances PINK1/Parkin-mediated mitophagy, ultimately inhibiting apoptosis and oxidative stress in heat-stressed PCWs. However, the application of Geldanamycin (GA) reversed these effects. Notably, we discovered that HSP90 interacts with Beclin-1 through mitochondrial translocation and directly regulates mitophagy levels in PCWs. In summary, we have elucidated a novel role for HSP90 and mitophagy in regulating heat stress-induced acute cardiomyocyte injury.
    Keywords:  HSP90; Wenchang chicken; cardiomyocytes; heat stress damage; mitophagy
    DOI:  https://doi.org/10.3390/ijms252111695
  12. Eur J Pharmacol. 2024 Nov 12. pii: S0014-2999(24)00790-8. [Epub ahead of print] 177100
    Taxifolin attenuates hepatic ischemia-reperfusion injury by enhancing PINK1/Parkin-mediated mitophagy.
    Ruixin Zhang, Qi Fang, Lei Yao, Xiaolan Yu, Xingyun Liu, Mengting Zhan, Deng Liu, Qi Yan, Jian Du, Lijian Chen.
       BACKGROUND: Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms.
    METHODS: C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 minutes of 70% hepatic ischemia. After 6 hours of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R).
    RESULTS: Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX.
    CONCLUSION: The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R.
    Keywords:  Apoptosis; Hepatic ischemia-reperfusion injury; Mitochondria; PINK1/Parkin; Taxifolin
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177100
  13. ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3462-3475
    Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice.
    Ela Mishra, Mahendra Kumar Thakur.
      Mitophagy, the targeted breakdown of damaged mitochondria, plays a vital role in maintaining cellular homeostasis. As impairment of mitophagy leads to neurodegeneration and memory decline, the current study explores the therapeutic potential of an autophagy inducer Tat-Beclin-1 during scopolamine-induced amnesia. Tat-Beclin-1 improved contextual and recognition memory and also mitochondrial ultrastructure by restoring mitochondrial length and area and reducing the number of fragmented mitochondria. Tat-Beclin-1 upregulated the expression of genes associated with mitophagy (PTEN-induced kinase 1, Parkin, Lamp2, and LC3), mitochondrial fusion (Mfn1, Mfn2, and optic atrophy1), and fission (dynamin-related protein 1 and Fis1) in amnesic mice. Subsequently, these results were supported by a decreased level of p-Drp1 (S616) and Drp 1 ratios and an increased level of Mfn2, LC3BI, and BII in Tat-Beclin-1-treated mice. Moreover, Tat-Beclin-1 maintained mitochondrial membrane potential and complex I/V activity in amnesic mice. Tat-Beclin-1 enhanced myelination and diminished the activity of acetylcholinesterase and caspase-3 activity. Sholl analysis revealed augmented dendritic branching and length, elevated dendritic spine density, and upregulated the expression of synaptophysin and PSD95 proteins, indicating neuronal plasticity enhancement by Tat-Beclin-1. Thus, these findings provide valuable insights into the therapeutic potential of Tat-Beclin-1, addressing mitochondrial dysfunction to mitigate cognitive impairment associated with amnesic conditions.
    DOI:  https://doi.org/10.1021/acsptsci.4c00283
  14. Nat Cardiovasc Res. 2024 Nov;3(11): 1318-1336
    Klf9 is essential for cardiac mitochondrial homeostasis.
    Lei Zhang, Menglin Zhang, Jinlong Huang, Jincan Huang, Yujie Zhang, Yinliang Zhang, Houzao Chen, Cuizhe Wang, Xiangwen Xi, Heng Fan, Jikui Wang, Dingsheng Jiang, Jinwei Tian, Jun Zhang, Yongsheng Chang.
      Mitochondrial dynamics and mitophagy are intimately linked physiological processes that are essential for cardiac homeostasis. Here we show that cardiac Krüppel-like factor 9 (Klf9) is dysregulated in human and rodent cardiomyopathy. Both global and cardiac-specific Klf9-deficient mice displayed hypertrophic cardiomyopathy. Klf9 knockout led to mitochondrial disarray and fragmentation, impairing mitochondrial respiratory function in cardiomyocytes. Furthermore, cardiac Klf9 deficiency inhibited mitophagy, thereby causing accumulation of dysfunctional mitochondria and acceleration of heart failure in response to angiotensin II treatment. In contrast, cardiac-specific Klf9 transgene improved cardiac systolic function. Mechanistically, Klf9 knockout decreased the expression of PGC-1α and its target genes involved in mitochondrial energy metabolism. Moreover, Klf9 controlled the expression of Mfn2, thereby regulating mitochondrial dynamics and mitophagy. Finally, adeno-associated virus-mediated Mfn2 rescue in Klf9-CKO hearts improved cardiac mitochondrial and systolic function. Thus, Klf9 integrates cardiac energy metabolism, mitochondrial dynamics and mitophagy. Modulating Klf9 activity may have therapeutic potential in the treatment of heart failure.
    DOI:  https://doi.org/10.1038/s44161-024-00561-6
  15. Int J Mol Med. 2025 Jan;pii: 10. [Epub ahead of print]55(1):
    Osteosarcoma stem cells resist chemotherapy by maintaining mitochondrial dynamic stability via DRP1.
    Boren Tian, Yaxuan Wu, Xiaoyun Du, Yan Zhang.
      Osteosarcoma malignancy exhibits significant heterogeneity, comprising both osteosarcoma stem cells (OSCs) and non‑OSCs. OSCs demonstrate increased resistance to chemotherapy due to their distinctive cellular and molecular characteristics. Alterations in mitochondrial morphology and homeostasis may enhance chemoresistance by modulating metabolic and regulatory processes. However, the relationship between mitochondrial homeostasis and chemoresistance in OSCs remains to be elucidated. The present study employed high‑resolution microscopy to perform multi‑layered image reconstructions for a quantitative analysis of mitochondrial morphology. The results indicated that OSCs exhibited larger mitochondria in comparison with non‑OSCs. Furthermore, treatment of OSCs with cisplatin (CIS) or doxorubicin (DOX) resulted in preserved mitochondrial morphological stability, which was not observed in non‑OSCs. This finding suggested a potential association between mitochondrial homeostasis and chemoresistance. Further analysis indicated that dynamin‑related protein 1 (DRP1) might play a pivotal role in maintaining the stability of mitochondrial homeostasis in OSCs. Depletion of DRP1 resulted in the disruption of mitochondrial stability when OSCs were treated with CIS or DOX. Additionally, knocking out DRP1 in OSCs led to a reduction in chemoresistance. These findings unveil a novel mechanism underlying chemoresistance in osteosarcoma and suggest that targeting DRP1 could be a promising therapeutic strategy to overcome chemoresistance in OSCs. This provided valuable insights for enhancing treatment outcomes among patients with osteosarcoma.
    Keywords:  cancer stem cells; chemoresistance; mitochondrial dynamics; osteosarcoma
    DOI:  https://doi.org/10.3892/ijmm.2024.5451
  16. Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]
    Opposing roles for AMPK in regulating distinct mitophagy pathways.
    Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.
      Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.
    Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
  17. Nat Cell Biol. 2024 Nov 15.
    FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.
    Adam R Fenton, Ruchao Peng, Charles Bond, Siewert Hugelier, Melike Lakadamyali, Yi-Wei Chang, Erika L F Holzbaur, Thomas A Jongens.
      Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission.
    DOI:  https://doi.org/10.1038/s41556-024-01544-2
  18. Neurotoxicology. 2024 Nov 13. pii: S0161-813X(24)00133-5. [Epub ahead of print]
    ATF5-mediated mitochondrial unfolded protein response protects against Pb-induced mitochondria damage in SH-SY5Y cell.
    Yihan Xu, Min Liu, Sikang Gao, Xiaoyi Li, Jun Chen, Fang Ye.
      Mitochondria is the primary target of lead (Pb) in neural cells, and Pb exposure can cause impairment to mitochondrial function and morphology. Recent studies have reported that a conserved cellular stress response, called mitochondrial unfolded protein response (mtUPR), is activated in response to mitochondrial dysfunction and protein misfolding and play protective roles in aging and neurodegeneration, but it's unknown whether mtUPR could protect against Pb-induced neurotoxicity. In this study, we found that sublethal level exposure of PbAc (2.5μM) could cause mitochondria damage and then activate mtUPR by promoting the expression of mitochondrial proteases (LonP1 and ClpP), molecular chaperone (HSPA1A). ATF5 mediated mtUPR activation as knocking out ATF5 significantly inhibited Pb-induced LonP1 and ClpP expression. Moreover, ATF5 deficiency exacerbated Pb-induced mitochondrial morphological and oxidative phosphorylation (OXPHOS) functional damage, resulting in oxidative stress and ultimately promoting cell death. Conversely, overexpression of ATF5 confers protection against Pb-induced oxidative stress and cell death. Collectively, thess results highlight that mtUPR mediated by ATF5 safeguards against mitochondria damage caused by Pb exposure, providing insights into the development of new strategies for mitigating the Pb neurotoxicity.
    Keywords:  ATF5; Lead; Mitochondrial unfolded protein response; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.neuro.2024.11.001
  19. Brain Res Bull. 2024 Nov 08. pii: S0361-9230(24)00251-X. [Epub ahead of print]219 111117
    Suppression of PINK1 autophosphorylation attenuates pilocarpine-induced seizures and neuronal injury in rats.
    Yujie Zhai, Yi Yuan, Yaru Cui, Xiaoqian Wang, Hua Zhou, Qian Teng, Hongjin Wang, Bohan Sun, Hongliu Sun, Jianhua Tang.
      PTEN-induced kinase 1 (PINK1) autophosphorylation triggers the PINK1/Parkin pathway, which is the main mitophagic pathway in the mammalian nervous system. In the present study, we aimed to mechanistically explore the role of PINK1 in pilocarpine-induced status epilepticus (SE) in Sprague-Dawley rats. Evidence from immunohistochemistry, western blotting, biochemical assays, and behavioral testing showed that pilocarpine-induced SE led to increased levels of PINK1 phosphorylation, mitophagy, mitochondrial oxidative stress, neuronal damage and learning and memory deficits. Using shRNA interference to suppress the expression of translocase outer mitochondrial membrane 7, a positive regulator of PINK1 autophosphorylation, lowered the increased levels of phosphorylated PINK1 following pilocarpine administration. It also reduced the levels of mitophagy, mitochondrial oxidative stress and neuronal damage, and attenuated seizure severity and cognitive deficits. In contrast, suppressing the expression of overlapping with the m-AAA protease 1 homolog, a negative regulator of PINK1 autophosphorylation, led to higher levels of phosphorylated PINK1 following pilocarpine administration. It also led to more serious mitophagy, neuronal damage, as well as worsened seizure severity and cognitive deficits. Our results indicate that PINK1 autophosphorylation plays a vital role in epileptic seizures and neuronal injury by mediating mitophagy. Regulating PINK1 autophosphorylation may change the adverse consequences of epilepsy, and may be an effective neuroprotective strategy.
    Keywords:  Mitochondrial oxidative stress; Mitophagy; Neuronal injury; PTEN-induced kinase 1; Status epilepticus
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.111117
  20. Cell Death Dis. 2024 Nov 08. 15(11): 803
    Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
    Hui-Xiang Su, Luo-Luo Xu, Pang-Bo Li, Hai-Lian Bi, Wen-Xi Jiang, Hui-Hua Li.
      The mitochondrial dynamic imbalance is an important cause of myocardial ischaemia/reperfusion (I/R) injury and dysfunction. Psmb8, as one of the immunoproteasome catalytic subunits, is a key regulator of protein homoeostasis, inflammation and some cardiac diseases. Here, we found that the expression level and activity of Psmb8 were significantly reduced in the heart of I/R mice and in subjects with myocardial infarction (MI). Cardiomyocyte-specific Psmb8 overexpression in mice markedly ameliorated I/R-mediated cardiac injury and dysfunction, which was accompanied by reduced mitochondrial division via the downregulation of dynamin-related protein-1 (Drp1). However, Psmb8 knockout (KO) mice exhibited the opposite changes. The effects of Psmb8 on mitochondrial fission and apoptosis was confirmed in primary cardiomyocytes with overexpression or knockdown of Psmb8 in vitro. Mechanistically, Psmb8 was directly associated with Drp1 and enhanced its degradation, which subsequently suppressed I/R-mediated mitochondrial fission and cardiac injury. Conversely, knockdown of Drp1 in Psmb8-KO mice restored I/R-induced cardiac dysfunction and mitochondrial dynamic imbalance. Our study identified a new cardioprotective role of Psmb8 in cardiac I/R damage through targeting Drp1, and highlight that increasing Psmb8 activity may constitute a promising therapy for ischaemic heart disease.
    DOI:  https://doi.org/10.1038/s41419-024-07189-1
  21. EFORT Open Rev. 2024 Nov 08. 9(11): 1013-1022
    Mitochondrial maintenance as a novel target for treating steroid-induced osteonecrosis of femoral head: a narrative review.
    Yidan Yang, Yi Jian, Youwen Liu, Maoxiao Ma, Jiayi Guo, Bin Xu, Chen Yue.
      The pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) remains unclear; however, emerging evidence suggests that mitochondrial injury plays a significant role. This review aims to elucidate the involvement of mitochondrial dysfunction in SONFH and explore potential therapeutic targets. A comprehensive literature search was conducted in PubMed, Web of Science, and Elsevier ScienceDirect, focusing on mitochondrial homeostasis, including mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and oxidative stress in SONFH. Ultimately, we included and analyzed a total of 16 studies. Glucocorticoids initially promote but later inhibit mitochondrial biogenesis in osteoblasts, leading to excessive ROS production and mitochondrial dysfunction. This dysfunction impairs osteoblast survival and bone formation, contributing to SONFH progression. Key proteins such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) are potential therapeutic targets for promoting mitochondrial biogenesis and reducing ROS-induced damage. Enhancing mitochondrial function and reducing oxidative stress in osteoblasts may prevent or slow the progression of SONFH. Future research should focus on developing these strategies.
    Keywords:  mitochondria dynamics; mitochondrial homeostasis; mitophagy; steroid-induced osteonecrosis of the femoral head
    DOI:  https://doi.org/10.1530/EOR-24-0023
  22. Eur J Pharmacol. 2024 Nov 09. pii: S0014-2999(24)00781-7. [Epub ahead of print] 177091
    Baicalin attenuates corticosterone-induced hippocampal neuronal injury by activating mitophagy in an AMPK-dependent manner.
    Yuan Liu, Xiaohui Jin, Caiyin Li, Jingjing Bu, Baoying Wang, Ming Bai, Pan Su, Erping Xu, Yucheng Li.
      Defective mitophagy is closely related to the neuronal dysfunction and major depressive disorder (MDD). Our previous study found that baicalin could enhance nip-like protein (NIX)-mediated mitophagy and exhibit antidepressant effects, and predicted that AMPK may be the pharmacological target of baicalin. However, validated experiments are lacking. In the present study, we first demonstrated the effect of baicalin on hippocampal NIX-mediated mitophagy in CORT-induced depressive mice. Secondly, we transfected siRNA to knockdown AMPK, PGC-1α, and NIX respectively in HT22 cells, and detected the effects of baicalin on mitochondrial function, AMPK/PGC-1α/NIX pathway protein expression and mitophagy levels. Finally, AAV-shAMPKα was injected into hippocampal CA3 to knockdown AMPK in mice to validate the antidepressant effects of baicalin in vivo. The results showed that CORT induced depressive-like behaviors, accompanied with neuronal damage, mitochondrial injury, and inhibited mitophagy in the hippocampus, which were prevented by baicalin (20 mg/kg) treatment. In HT22 cells, baicalin remarkably ameliorated mitochondrial dysfunction and mitophagy disturbance induced by CORT, and these protective effects of baicalin were blocked by knockdown of AMPK, PGC-1α and NIX. Moreover, the beneficial effects of baicalin on depressive-like behaviors and NIX-mediated mitophagy were suppressed by knockdown of AMPKα in mice. Our present results further demonstrated that baicalin promotes NIX-mediated mitophagy and improves depression in an AMPK-dependent manner.
    Keywords:  AMPK/PGC-1α/NIX; Baicalin; Corticosterone; Depression; Mitophagy
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177091
  23. ACS Nano. 2024 Nov 15.
    Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.
    Yi Wang, Li-Fan Hu, Na-Hui Liu, Jing-Song Yang, Lei Xing, Jee-Heon Jeong, Ling Li, Hu-Lin Jiang.
      Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mitochondria mediated by mitophagy-enhanced nanoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.
    Keywords:  alveolar epithelial cells; mitophagy; nanoengineered mitochondria; nanoparticle; pulmonary fibrosis
    DOI:  https://doi.org/10.1021/acsnano.4c10328
  24. Scand J Rheumatol. 2024 Nov 15. 1-10
    Mitophagy drives maldifferentiation of tissue-resident memory T cells in patients with rheumatoid arthritis.
    T Liu, M Wang, L Li, T Wu, H Ji, M Zheng, L Tang, W Gan, Z Wen, F Yuan.
       OBJECTIVE: To investigate the function of mitophagy in instructing T-cell differentiation of patients with rheumatoid arthritis (RA).
    METHOD: The mRNA and protein levels of optic atrophy protein-1 were detected in T cells from 94 RA patients and 37 age- and sex-matched healthy individuals by quantitative polymerase chain reaction and Western blotting. The impact of mitophagy on the differentiation of T cells was determined by flow cytometry. The therapeutic effect of targeting mitophagy was explored in humanized RA chimeras.
    RESULTS: Our study showed that T cells exerted high levels of mitophagy in RA patients. Since multiple T-cell subtypes play crucial roles in RA, we determined that mitophagy had a significant impact on the differentiation of tissue-resident memory T (Trm) cells, but not Th1 or Th17 cells. Importantly, we demonstrated that inhibiting mitophagy significantly reduced the number of Trm cells and downregulated inflammatory responses, as evidenced by diminished levels of T cell receptor β, interferon-γ, and interleukin-17A, in the humanized RA chimeras.
    CONCLUSIONS: Mitophagy is elevated in RA T cells, leading to maldifferentiation of Trm cells in RA patients. Since these findings were obtained from clinical patients, mitophagy may be a potential therapeutic target for RA treatment.
    DOI:  https://doi.org/10.1080/03009742.2024.2420432
  25. Allergol Immunopathol (Madr). 2024 ;52(6): 151-161
    From bioinformatics to anti-inflammation and immune regulation: ACT001 in lipopolysaccharide-induced lung injury.
    Yan Fan, Yuanlin Wang, Weiwei Zhang, Keliang Xie.
       BACKGROUND: ACT001 is a potent anti-inflammatory small-molecule drug. However, the single cell and spatial molecular basis of pyroptosis and whether ACT001 exerts a therapeutic effect by preventing pyroptosis on acute lung injury (ALI) remains unclear.
    METHODS: The bioinformatics approach was employed to identify single cell and spatial landscape of nucleotide-binding domains and leucine-rich repeat protein 3 (NLRP3)-dependent pyroptosis in lipopolysaccharide (LPS) and influenza virus-induced ALI. Molecular docking was performed to elucidate the relationship between ACT001 and NLRP3. LPS-induced ALI mice model was established. Histopathological analysis and bronchoalveolar lavage fluid collection were conducted to investigate the anti-inflammatory and protective effects. In vitro experiments were also performed on bone marrow-derived macrophages to explore the effect of ACT001 on the balance of mitochondrial fusion and fission protein.
    RESULTS: Single cell transcriptomic and spatial transcriptomic analysis predicted that NLRP3-dependent pyroptosis significantly correlated with the development of ALI both in single cell and spatial distribution. Molecular docking provided a stable and reliable docking between ACT001 and NLRP3. ACT001 improved the 7-day survival of mice by approximately 50% over the loading dose of LPS-induced ALI. ACT001 (5 uM) attenuated the disruption of mitochondrial integrity and reactive oxygen species. Further, ACT001 reduced the overexpression of the mitochondrial fission protein DRP1 without affecting fusion protein Mitofusin2 levels. Moreover, ACT001 exerted a similar protective effect of suppressing pyroptosis as the DRP1-inhibitor Mdivi-1.
    CONCLUSIONS: Our study revealed that pyroptosis genes were highly expressed in single-cell and spatial mapping along the first week of ALI occurrence. ACT001 attenuates ALI by reducing the NLRP3-dependent pyroptosis and balancing mitochondrial fission and fusion.
    Keywords:  ACT001; NLRP3; acute lung injury; pyroptosis; single and spatial transcriptomics
    DOI:  https://doi.org/10.15586/aei.v52i6.1146
  26. J Colloid Interface Sci. 2024 Oct 30. pii: S0021-9797(24)02535-9. [Epub ahead of print]680(Pt A): 429-440
    Mitochondrial dynamics and energy metabolism interference therapy for promoting photothermal sensitization.
    Cuimei Liu, Sihang Cheng, Xue Zhou, Lu Li, Chungang Wang, Lingyu Zhang.
      Photothermal therapy (PTT) is minimally invasive, precisely controlled, and therapeutically effective treatment method. However, its efficacy is limited by the overexpression of heat shock proteins (HSP), which leads to cellular thermal blockade. Targeting mitochondria with PTT can enhance anticancer efficacy, as mitochondria encode genes related to HSP and provide energy for their production. Nevertheless, mitochondrial dynamics confer resistance to damage from external stimuli. Therefore, disrupting the balance of mitochondrial dynamics is essential to impede HSP production. Herein, we synthesized degradable Cu3BiS3 (CBS) nanosheets (NSs) with one face modified by carboxylated triphenylphosphonium (TPP) to target mitochondria. This modification increases the production of exogenous reactive oxygen species (ROS) and induces the overexpression of dynamin-related protein 1 (Drp1), disrupting mitochondrial dynamic homeostasis. The other face was modified with carboxylated β-cyclodextrin (CD) to load the glycolysis inhibitor (2-deoxyglucose, 2DG), thereby reducing adenosine triphosphate (ATP) production in the extra-mitochondrial space, as glycolysis also occurs in the cytoplasm. The resulting TPP-CBS-2DG Janus NSs (JNSs) not only disrupt mitochondrial energy production, leading to cell starvation, but also inhibit HSP production. Consequently, TPP-CBS-2DG JNSs can enhance tumor thermal sensitivity in PTT, improving its efficacy. This work holds great promise for overcoming tumor heat resistance in PTT and provides a feasible method for fabricating selectively modified multifunctional NSs.
    Keywords:  Degradation; Energy metabolism; Janus nanosheets; Mitochondrial dynamics; Sensitized photothermal therapy; Targeting mitochondria
    DOI:  https://doi.org/10.1016/j.jcis.2024.10.180
  27. Cell Death Dis. 2024 Nov 08. 15(11): 807
    TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.
    Niall A Buckley, Andrew Craxton, Xiao-Ming Sun, Emanuele Panatta, Lucia Giraldez Pinon, Sina Beier, Lajos Kalmar, Jaime Llodrá, Nobuhiro Morone, Ivano Amelio, Gerry Melino, L Miguel Martins, Marion MacFarlane.
      Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic Atrophy 1 (OPA1), a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We additionally show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 knock-out) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 gene expression is decreased in chronic obstructive pulmonary disease (COPD) patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. Our findings also add to the growing body of evidence for growth-promoting roles of TAp73 isoforms.
    DOI:  https://doi.org/10.1038/s41419-024-07130-6
  28. Mol Med. 2024 Nov 11. 30(1): 208
    PI3K p85α/HIF-1α accelerates the development of pulmonary arterial hypertension by regulating fatty acid uptake and mitophagy.
    Chenyang Chen, Sirun Qin, Xiaohua Song, Juan Wen, Wei Huang, Zhe Sheng, Xiaogang Li, Yu Cao.
       BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by lipid accumulation and mitochondrial dysfunction. This study was designed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on fatty acid uptake and mitophagy in PAH.
    METHODS: Peripheral blood samples were obtained from PAH patients. Human pulmonary arterial smooth muscle cells and rat cardiac myoblasts H9c2 were subjected to hypoxia treatment. Male Sprague-Dawley rats were treated with monocrotaline (MCT). Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary artery remodeling, and lipid accumulation were measured. Cell proliferation and ROS accumulation were assessed. Mitochondrial damage and autophagosome formation were observed. Co-immunoprecipitation was performed to verify the interaction between HIF-1α and CD36/PI3K p85α.
    RESULTS: HIF-1α, CD36, Parkin, and PINK1 were upregulated in PAH samples. HIF-1α knockdown or PI3K p85α knockdown restricted the expression of HIF-1α, PI3K p85α, Parkin, PINK1, and CD36, inhibited hPASMC proliferation, promoted H9c2 cell proliferation, reduced ROS accumulation, and suppressed mitophagy. CD36 knockdown showed opposite effects to HIF-1α knockdown, which were reversed by palmitic acid. The HIF-1α activator dimethyloxalylglycine reversed the inhibitory effect of Parkin knockdown on mitophagy. In MCT-induced rats, the HIF-1α antagonist 2-methoxyestradiol (2ME) reduced RVSP, RVHI, pulmonary artery remodeling, lipid accumulation, and mitophagy. Recombinant CD36 abolished the therapeutic effect of 2ME but inhibited mitophagy. Activation of Parkin/PINK1 by salidroside (Sal) promoted mitophagy to ameliorate the pathological features of PAH-like rats, and 2ME further enhanced the therapeutic outcome of Sal.
    CONCLUSION: PI3K p85α/HIF-1α induced CD36-mediated fatty acid uptake and Parkin/PINK1-dependent mitophagy to accelerate the progression of experimental PAH.
    Keywords:  CD36; Fatty acid intake; HIF-1α; Mitophagy; Pulmonary arterial hypertension
    DOI:  https://doi.org/10.1186/s10020-024-00975-9
  29. Nat Cell Biol. 2024 Nov 15.
    FMRP gains mitochondrial fission control.
    Carissa L Sirois, Soraya O Sandoval, Xinyu Zhao.
      
    DOI:  https://doi.org/10.1038/s41556-024-01567-9
  30. Neuroscience. 2024 Nov 12. pii: S0306-4522(24)00609-2. [Epub ahead of print]
    Dopamine-D2-agonist targets mitochondrial dysfunction via diminishing Drp1 mediated fission and normalizing PGC1-α/SIRT3 pathways in a rodent model of Subarachnoid haemorrhage.
    Ahmed Shaney Rehman, Pravir Kumar, Suhel Parvez.
      The adverse impact of disturbmitochondrialbiogenesis onearly brain injury (EBI) following Subarachnoid Haemorrhage (SAH) has been broadly recognized and is closely associated with oxidative stress and neuronal apoptosis. Previous studies have indicated the therapeutic potential of Ropinirole in Ischemic Stroke. However, there is a lack of evidence regarding the ability of Ropinirole to enhance mitochondrial biogenesis and quality control after Subarachnoid Haemorrhage. The objective of this study is to investigate the effects of Ropinirole specific doses (10 & 20 mg/kg b. wt.) on mitochondria dysfunction in endovascular perforation SAH model in male Wistar rat. An endovascular perforation model was established using male Wistar rats that had sustained SAH injury. After the SAH injury, SAH grading on blood clot, Nissl staining, and neurobehavioral assessment were used to determine the severity. ROS and MMP, which are indicators of oxidative stress, were examined using flow cytometry. The findings demonstrated that the use of Ropinirole improved neurobehavioral outcomes, decreased brain edema, and reduced oxidative stress and mitochondrial based apoptosis. Further research showed that, Ropinirole therapy inhibit Drp1-mediated fission by accelerating the activity of fusion protein Mfn2/OPA1 along with regulating the translocation of PGC1-α and SIRT3 through restricting cytochrome C inside mitochondria to maintain mitochondrial metabolism. Ropinirole exerted neuroprotective effects by improving mitochondrial activity in a PGC1-α/SIRT3-dependent way via regulating Drp1 mediated fission. The effective treatment for SAH-induced EBI may involve increasing biogenesis and inhibiting excessive mitochondrial fission with Ropinirole.
    Keywords:  Apoptosis; Drp1; Mitochondrial Biogenesis; Neuroinflammation; Ropinirole; Subarachnoid Haemorrhage
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.11.028
  31. Aging Cell. 2024 Nov 14. e14400
    Targeting NAMPT-OPA1 for treatment of senile osteoporosis.
    Chao-Wen Bai, Bo Tian, Ming-Chao Zhang, Qin Qin, Xin Shi, Xi Yang, Xiang Gao, Xiao-Zhong Zhou, Hua-Jian Shan, Jin-Yu Bai.
      Senescence of bone marrow mesenchymal stem cells (BMSCs) impairs their stemness and osteogenic differentiation, which is the principal cause of senile osteoporosis (SOP). Imbalances in nicotinamide phosphoribosyltransferase (NAMPT) homeostasis have been linked to aging and various diseases. Herein, reduction of NAMPT and impaired osteogenesis were observed in BMSCs from aged human and mouse. Knockdown of Nampt in BMSCs promotes lipogenic differentiation and increases age-related bone loss. Overexpression of Nampt ameliorates the senescence-associated (SA) phenotypes in BMSCs derived from aged mice, as well as promoting osteogenic potential. Mechanistically, NAMPT inhibits BMSCs senescence by facilitating OPA1 expression, which is essential for mitochondrial dynamics. The defect of NAMPT reduced mitochondrial membrane potential, interfered with mitochondrial fusion，and increased SA protein and phenotypes. More importantly, we have confirmed that P7C3, the NAMPT activator, is a novel strategy for reducing SOP bone loss. P7C3 treatment significantly prevents BMSCs senescence by improving mitochondrial function through the NAMPT-OPA1 signaling axis. Taken together, these results reveal that NAMPT is a regulator of BMSCs senescence and osteogenic differentiation. P7C3 is a novel molecule drug to prevent the pathological progression of SOP.
    Keywords:  NAMPT; Optic atrophy protein 1; cellular senescence; mesenchymal stem cell; mitochondrial function
    DOI:  https://doi.org/10.1111/acel.14400
  32. Int J Biochem Cell Biol. 2024 Nov 11. pii: S1357-2725(24)00184-5. [Epub ahead of print] 106691
    TFAP2C/FLT3 Axis Reduces Ferroptosis in Breast Cancer Cells by Inhibiting Mitochondrial Autophagy.
    Jiayue Shen, Yali He, Bingchuan Zhou, Huabo Qin, Shuai Zhang, Zixiang Huang, Xiangcheng Zhang.
       BACKGROUND: FMS-like tyrosine kinase 3 (FLT3), a key target protein for treating acute myeloid leukemia, has recently been found to be closely related to ferroptosis in breast cancer (BC). However, the mechanism by which FLT3 regulates ferroptosis in BC remains unknown. Whether this regulatory relationship can be exploited for BC treatment needs further exploration.
    METHODS: This study combined analysis from The Cancer Genome Atlas database with immunohistochemistry/quantitative reverse transcription-PCR/Western blot experiments to verify the expression of FLT3 in BC. FLT3 knockdown/overexpression plasmids were used in conjunction with mitochondrial autophagy inducers to treat BC cells, analyzing the effects of FLT3 on autophagy and ferroptosis. Key transcription factors for FLT3 were determined through predictions from the KnockTF database and dual luciferase/chromatin immunoprecipitation experiments, further analyzing the impact of this regulatory axis on autophagy and ferroptosis in BC cells.
    RESULTS: FLT3 was significantly overexpressed in BC tissues and cells. Overexpression of FLT3 could inhibit autophagy and ferroptosis in BC cells, a regulation that was restored upon the addition of mitochondrial autophagy inducers. Additionally, transcription factor AP-2 gamma (TFAP2C) could mediate the transcriptional activation of FLT3, further inhibiting ferroptosis induced by mitochondrial autophagy.
    CONCLUSION: The TFAP2C/FLT3 axis reduced ferroptosis in BC cells by inhibiting mitochondrial autophagy. These research findings elucidated the mechanism by which FLT3 regulated ferroptosis in BC and provided potential targets for BC treatment.
    Keywords:  FLT3; TFAP2C; breast cancer; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1016/j.biocel.2024.106691
  33. Methods Mol Biol. 2025 ;2878 211-221
    Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
    Pedro A Dionísio, Vilma A Sardão, Nuno Raimundo.
      Live cell imaging is a robust method to visualize dynamic cellular structures, especially organelles with network-like structures such as mitochondria. In this regard, mitochondrial dynamics, namely mitochondrial fission and fusion, are highly dynamic processes that regulate mitochondrial size and morphology depending on a plethora of cellular cues. Likewise, lysosome size and distribution may hint at their function and state.Here, we describe how to perform live cell confocal imaging using commercially available organelle dyes (MitoTracker, LysoTracker), followed by either 2D or 3D analyses of mitochondrial morphology/network connectivity and lysosomal morphology using the freely available Mitochondria Analyzer plugin for ImageJ/Fiji.
    Keywords:  Cell imaging; Fluorescent probes; LysoTracker; Lysosomes; Microscopy; MitoTracker; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/978-1-0716-4264-1_11
  34. Arch Biochem Biophys. 2024 Nov 13. pii: S0003-9861(24)00337-0. [Epub ahead of print] 110215
    Tanshinone IIA alleviates inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction.
    Dong Han, Yun-Biao Chen, Kai Zhao, Hong-Zhou Li, Xing-Yu Chen, Guo-Zheng Zhu, Chen Tu, Jia-Wen Gao, Jing-Shen Zhuang, Zhi-Yong Wu, Zhao-Ming Zhong.
      Skeletal muscle atrophy, characterized by loss of muscle mass and function, is often linked to systemic inflammation. Tanshinone IIA (Tan IIA), a major active constituent of Salvia miltiorrhiza, has anti-inflammatory and antioxidant properties. However, the effect of Tan IIA on inflammation-induced skeletal muscle atrophy remains unclear. Here, a mice model of the inflammatory muscle atrophy was established using lipopolysaccharide (LPS). Tan IIA intervention significantly increased muscle mass and strength, improved muscle fiber size, and maintained the integrity of skeletal muscle mitochondrial morphology in LPS-treated mice. Myotubes derived from myosatellite cells (MUSCs) were exposed to LPS in vitro. Tan IIA treatment inhibited LPS-induced muscle protein degradation and increased myotube diameter. Notably, Tan IIA attenuated LPS-induced inflammatory response and hyperactive mitophagy both in vivo and in vitro. In addition, Tan IIA treatment effectively diminished oxidative stress, inhibited the accumulation of mitochondrial reactive oxygen species (mtROS), and attenuated mitochondrial fission in LPS-treated myotubes. Reducing mtROS production helped to inhibit LPS-induced excessive mitophagy and myotubes atrophy. Together, our results reveal that Tan IIA can protect against inflammation-induced skeletal muscle atrophy by regulating mitochondrial dysfunction, presenting innovative potential therapeutics for skeletal muscle atrophy.
    Keywords:  Inflammation; MUSCs; Mitophagy; Skeletal muscle atrophy; Tanshinone IIA; mtROS
    DOI:  https://doi.org/10.1016/j.abb.2024.110215
  35. J Agric Food Chem. 2024 Nov 07.
    Detoxification of Chlorfenapyr by a Parkin-GSTd2 Module in Bactrocera dorsalis (Diptera: Tephritidae).
    Chao Xie, Biao Zeng, Xiangge Du, Shuo Yan, Jie Shen, Junzheng Zhang.
      The oriental fruit fly, Bactrocera dorsalis (Hendel), is a highly invasive and destructive pest. Chlorfenapyr is a widely used insecticide that disrupts mitochondrial activity. The Parkin protein plays conserved roles in maintaining mitochondrial homeostasis, but the role of Parkin in response to chlorfenapyr remains largely unknown. Here, we report that BdParkin is required for chlorfenapyr detoxification, and dsRNA targeting BdParkin improves the insecticidal efficacy of chlorfenapyr. Among the genes whose expression levels are affected by BdParkin RNAi, knock-down of the glutathione S-transferase gene BdGSTd2 increases the insecticidal efficacy of chlorfenapyr. Molecular docking reveals potential interactions between BdGSTd2 and tralopyril, an insecticidal metabolite of chlorfenapyr. These results suggest that BdParkin could impact the response of B. dorsalis to chlorfenapyr through metabolic processes regulated by BdGSTd2. Our findings could offer new insights into how insects detoxify chlorfenapyr and provide molecular targets for developing a sustainable management strategy for B. dorsalis.
    Keywords:  Bactrocera dorsalis; GSTd2; Parkin; chlorfenapyr
    DOI:  https://doi.org/10.1021/acs.jafc.4c06416
  36. J Environ Manage. 2024 Nov 06. pii: S0301-4797(24)03221-3. [Epub ahead of print]371 123235
    Resveratrol alleviates Mono-2-ethylhexyl phthalate-induced mitophagy, ferroptosis, and immunological dysfunction in grass carp hepatocytes by regulating the Nrf2 pathway.
    Xiaodan Wang, Meichen Gao, Xiunan Lu, Yutian Lei, Jiatong Sun, Mengyao Ren, Tong Xu, Hongjin Lin.
      Mono-2-ethylhexyl phthalate (MEHP) is the major biologically active metabolite of Di(2-ethylhexyl) phthalate (DEHP). This MEHP mono-ester metabolite can be transported through the bloodstream into tissues such as the liver, kidneys, fat, and testes and cause corresponding damage. Resveratrol (RSV) has anti-inflammatory, antioxidant, and detoxification characteristics. Our research examined whether RSV alleviates MEHP-induced grass carp hepatocyte (L8824 cell) injury and its relationship with the Nrf2 pathway, mitophagy, ferroptosis, and immune function. Therefore, we treated L8824 cells with 85 μM MEHP and/or 2 μM RSV. The findings indicated that exposing MEHP resulted in increased reactive oxygen species (ROS) content and decreased mitochondrial membrane potential in L8824 cells, which induced an up-regulation of the expression of mitophagy-related indicators (PINK1, Parkin, Beclin1, LC3B, and ATG5) and a down-regulation of P62. An up-regulation of the expression of the ferroptosis-related indicators TFR1 and COX-2, and GPX4 and FTH expression was down-regulated. In addition, there was a decrease in the expression of IL-2 and IFN-γ and an increase in the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 after exposure to MEHP. RSV activates the Nrf2 pathway and effectively alleviates MEHP-induced mitophagy, ferroptosis, and immunologic dysfunction of L8824 cells.
    Keywords:  Ferroptosis; Immune dysfunction; L8824 cells; MEHP; Mitophagy; Nrf2; Resveratrol
    DOI:  https://doi.org/10.1016/j.jenvman.2024.123235
  37. Autophagy. 2024 Nov 08.
    PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.
    Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue.
      Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from pink1 knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth in vitro and in vivo. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.
    Keywords:  Colorectal cancer; deferiprone; iron chelation; minocycline; mitochondrial iron; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2425594
  38. Nat Commun. 2024 Nov 12. 15(1): 9797
    HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling.
    Annmary Paul Erinjeri, Xunyan Wang, Rhianna Williams, Riccardo Zenezini Chiozzi, Konstantinos Thalassinos, Johnathan Labbadia.
      Increased activity of the heat shock factor, HSF-1, suppresses proteotoxicity and enhances longevity. However, the precise mechanisms by which HSF-1 promotes lifespan are unclear. Using an RNAi screen, we identify ubiquilin-1 (ubql-1) as an essential mediator of lifespan extension in worms overexpressing hsf-1. We find that hsf-1 overexpression leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan. Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.
    DOI:  https://doi.org/10.1038/s41467-024-54136-x
  39. Transl Oncol. 2024 Nov 06. pii: S1936-5233(24)00305-X. [Epub ahead of print]51 102179
    Res@ZIF-90 suppress gastric cancer progression by disturbing mitochondrial homeostasis.
    Guanglin Qiu, Lindi Cai, Gan Li, Yiwei Ren, Enmeng Li, Kai Deng, Mengke Zhu, Shangning Han, Xiangming Che, Xuqi Li, Lin Fan.
       BACKGROUND: Gastric cancer (GC) is still a serious threat to human health worldwide. As a natural compound, resveratrol has been proven to have anti-tumor activity, and the nano-delivery carrier has shown its excellent ability to retain and control drug release.
    METHODS: Res@ZIF-90 underwent synthesis via a one-pot method and subsequent characterization encompassing Dynamic Light Scattering, Scanning Electron Microscope, Transmission Electron Microscope, and UV-vis absorption spectroscope. The release of resveratrol from Res@ZIF-90 across varied pH environments were delineated employing High Performance Liquid Chromatography. The mitochondrial targeting of Res@ZIF-90 was scrutinized utilizing Fluorescent Inverted Microscopy. The cytotoxic impact of Res@ZIF-90 on HGC-27 cells was evaluated through CCK-8 assay, Live/Dead staining, scratch test, and JC-1 assay. Furthermore, the HGC-27 tumor-bearing mice model was established to explore the anti-tumor effect of Res@ZIF-90.
    RESULTS: ZIF-90 can effectively release resveratrol under acidic (pH = 5.5) conditions. In addition, Res@ZIF-90 could be taken up by cells and localized into mitochondria. ZIF-90 has no obvious cytotoxicity at the experimental concentration, while Res@ZIF-90 was more cytotoxic to HGC-27 cells than free resveratrol at the same concentration. Res@ZIF-90 significantly reduced the expressions of PGCS 1α, TFAM, PINK1, and COX IV, which together induced mitochondrial homeostasis disorders and inhibited the tumor growth of HGC-27 tumor-bearing mice in vivo.
    CONCLUSIONS: Res@ZIF-90 can inhibit the progression of gastric cancer by targeting the mitochondria of gastric cancer cells and disrupting mitochondrial homeostasis to produce cytotoxic effects. Res@ZIF-90 may be a promising antitumor drug with potential application value.
    Keywords:  Gastric cancer; Mitochondria; Mitophagy; Res@ZIF-90; Resveratrol
    DOI:  https://doi.org/10.1016/j.tranon.2024.102179
  40. Cell Biosci. 2024 Nov 14. 14(1): 138
    Ancestral retrovirus envelope protein ERVWE1 upregulates circ_0001810, a potential biomarker for schizophrenia, and induces neuronal mitochondrial dysfunction via activating AK2.
    Wenshi Li, Xing Xue, Xuhang Li, Xiulin Wu, Ping Zhou, Yaru Xia, Jiahang Zhang, Mengqi Zhang, Fan Zhu.
       BACKGROUND: Increasingly studies highlight the crucial role of the ancestral retrovirus envelope protein ERVWE1 in the pathogenic mechanisms of schizophrenia, a severe psychiatric disorder affecting approximately 1% of the global population. Recent studies also underscore the significance of circular RNAs (circRNAs), crucial for neurogenesis and synaptogenesis, in maintaining neuronal functions. However, the precise relationship between ERVWE1 and circRNAs in the etiology of schizophrenia remains elusive.
    RESULTS: This study observed elevated levels of hsa_circ_0001810 (circ_0001810) in the blood samples of schizophrenia patients, displaying a significant positive correlation with ERVWE1 expression. Interestingly, in vivo studies demonstrated that ERVWE1 upregulated circ_0001810 in neuronal cells. Circ_0001810, acting as a competing endogenous RNA (ceRNA), bound to miR-1197 and facilitated the release of adenylate kinase 2 (AK2). The bioinformatics analysis of the schizophrenia datasets revealed increased levels of AK2 and enrichment of mitochondrial dynamics. Notably, miR-1197 was reduced in schizophrenia patients, while AK2 levels were increased. Additionally, AK2 showed positive correlations with ERVWE1 and circ_0001810. Further studies demonstrated that AK2 led to mitochondrial dysfunction, characterized by loss of intracellular ATP, mitochondrial depolarization, and disruption of mitochondrial dynamics. Our comprehensive investigation suggested that ERVWE1 influenced ATP levels, promoted mitochondrial depolarization, and disrupted mitochondrial dynamics through the circ_0001810/AK2 pathway.
    CONCLUSIONS: Circ_0001810 and AK2 were increased in schizophrenia and positively correlated with ERVWE1. Importantly, ERVWE1 triggered mitochondrial dysfunction through circ_0001810/miR-1197/AK2 pathway. Recent focus on the impact of mitochondrial dynamics on schizophrenia development had led to our discovery of a novel mechanism by which ERVWE1 contributed to the etiology of schizophrenia, particularly through mitochondrial dynamics. Moreover, these findings collectively proposed that circ_0001810 might serve as a potential blood-based biomarker for schizophrenia. Consistent with our previous theories, ERVWE1 is increasingly recognized as a promising therapeutic target for schizophrenia.
    Keywords:  AK2; Circular RNAs; ERVWE1; Mitochondrial depolarization; Mitochondrial dynamics; Schizophrenia
    DOI:  https://doi.org/10.1186/s13578-024-01318-1
  41. Adv Sci (Weinh). 2024 Nov 08. e2404109
    Targeting ATAD3A Phosphorylation Mediated by TBK1 Ameliorates Senescence-Associated Pathologies.
    Yujiao He, Yanchen Liu, Mingyue Zheng, Yuxiu Zou, Mujie Huang, Linsheng Wang, Ge Gao, Zhongjun Zhou, Guoxiang Jin.
      Targeting cellular senescence, one of the hallmarks of aging and aging-related pathologies emerges as an effective strategy for anti-aging and cancer chemotherapy. Here, a switch from TBK1-OPTN axis to TBK1-ATAD3A axis to promote cellular senescence is shown. Mechanically, TBK1 protein is abnormally activated and localized to the mitochondria during senescence, which directly phosphorylates ATAD3A at Ser321. Phosphorylated ATAD3A is significantly elevated in cellular senescence as well as in physiological and pathological aging and is essential for suppressing Pink1-mediated mitophagy by facilitating Pink1 mitochondrial import. Inhibition of ATAD3A phosphorylation at Ser321 by either TBK1 deficiency or by a Ser321A mutation rescues the cellular senescence. A blocking peptide, TAT-PEP, specifically abrogating ATAD3A phosphorylation, results in elevated cell death by preventing doxorubicin-induced senescence, thus leading to enhanced tumor sensitivity to chemotherapy. TAT-PEP treatment also ameliorates various phenotypes associated with physiological aging. Collectively, these results reveal the TBK1-ATAD3A-Pink1 axis as a driving force in cellular senescence and suggest a potential mitochondrial target for anti-aging therapy.
    Keywords:  TBK1‐ATAD3A axis; anti‐aging therapy; cellular senescence; chemotherapy; mitophagy
    DOI:  https://doi.org/10.1002/advs.202404109
  42. Heliyon. 2024 Nov 15. 10(21): e39890
    Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis.
    Yi Lei, Xiao-Li Ma, Tong Liu, Meng-Jiao Wang, Jin-Sen Kang, Jian Yang, Na Mi.
      Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells.
    Keywords:  HepG2 cells; Lactucin; Mitochondrial biosynthesis; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e39890
  43. Ecotoxicol Environ Saf. 2024 Nov 08. pii: S0147-6513(24)01362-9. [Epub ahead of print]287 117286
    Benzophenone-3 exposure induced apoptosis via impairing mitochondrial function in human chondrocytes.
    Ye Yang, Rui Gao, Zhenyu Zhu, Wenfeng Xiao, Jing Wang, Wenxia Zhao, Yingjun Li.
      Osteoarthritis (OA) is a chronic joint disease affecting millions of adults worldwide, characterized by degeneration of articular cartilage. Many environmental risk factors contribute to OA development. Benzophenone-3 (BP-3), a commonly used ultraviolet filter in personal care products, has been positively associated with OA risk. However, it remains unclear whether and how BP-3 induces toxic effects on articular chondrocytes and promote OA development. This study aims to investigate the damage of BP-3 at environmentally relevant concentrations to human chondrocytes, as well as potential mechanisms linking BP-3 with injury of chondrocytes. Notably, BP-3 significantly inhibited cell viability, induced apoptosis, and up-regulated matrix metalloproteinase (MMP) 1 and 13 which mediated cartilage degradation in C28/I2 human normal chondrocytes. Moreover, the function of mitochondria was impaired and oxidative stress occurred in BP-3 exposure groups, evidenced by elevation of reactive oxygen species (ROS) generation, reduction of mitochondrial membrane potential, decrease of ATP production and inhibition of mitochondrial respiratory chain complex I, II, III and IV. Meanwhile, BP-3 caused mitochondrial cristae vague and formation of autophagosomes. PTEN induced putative kinase 1/E3 ubiquitin protein ligase (PINK1/Parkin) pathway was also activated by BP-3. Addition of autophagy inhibitor, 3-Methyladenine (3-MA), suppressed PINK1/Parkin-mediated mitophagy, but increased BP-3-induced expression of MMP1 and 13, as well as exacerbated BP-3-induced apoptosis, suggesting mitophagy may exert a chondroprotective effect and partially alleviate apoptosis induced by this compound. In brief, BP-3 exposure may increase OA risk via inducing apoptosis and increasing breakdown of extracellular matrix in chondrocytes, and mitochondrial dysfunction and mitophagy may play a crucial role in the mechanisms of BP-3-induced toxicity to articular chondrocytes.
    Keywords:  Benzophenones; Chondrocytes; Mitochondrial dysfunction; Mitophagy; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117286
  44. J Biomol Struct Dyn. 2024 Nov 12. 1-14
    Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment.
    Rohith Raali, Neha Sivakumar, Harsh Vardhan J, Suresh P K.
      Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on the mucosal epithelium, is the most common oral malignancy. About 10% of cancer patients within the Indian subcontinent suffer from OSCC, primarily due to chewing of betel plant derivatives. Concomitant administration of the chemotherapeutic agent (Cisplatin/Paclitaxel) is the treatment of choice. Analysis of the oral mycobiome of OSCC patients has projected the role of Candida albicans in potentiating OSCC. Hence, repurposing antifungal drugs emerges as a promising approach, as these drugs could target both the cancer cells and the infection. Cancer cells often have heightened energy requirements, and targeting mitochondrial proteins to disrupt mitochondrial division and induce dysfunction contributing to cell death, offers a method for treating OSCC. We identified 18 mitochondrial targets playing a crucial role in the maintenance of mitochondrial homeostasis. They were docked against 125 antifungal ligand molecules sourced from PUBCHEM. Ligand profiling was performed using Lipinski's rule of 5, SwissADME and ProTox. Also, molecular dynamics and MM-PBSA were performed to validate our results. Among all protein ligand interactions, we observed that targeting DRP1 with itraconazole yielded superior binding and stability. Overall, lower toxicity and thumping ADME properties solidified the choice of ligand. We hope this experimental approach will enable us to provide a basis for selecting a lead molecule for a possible novel nano-formulation and validate our finding through in-vitro cell line-based testing.
    Keywords:  OSCC; antifungal ligands; drug repurposing; mitochondrial targets; molecular docking & molecular dynamic simulation
    DOI:  https://doi.org/10.1080/07391102.2024.2425831
  45. J Transl Med. 2024 Nov 11. 22(1): 1012
    Deletion of MAPL ameliorates septic cardiomyopathy by mitigating mitochondrial dysfunction.
    Yinghua Wang, Xiying Huang, Huanhuan Huo, Zhaohua Cai, Qingqi Ji, Yi Jiang, Fei Zhuang, Yi Li, Linghong Shen, Xia Wang, Ben He.
       AIM: Mitochondrial dysfunction is a critical factor in the pathogenesis of septic cardiomyopathy (SCM). Mitochondrial anchored protein ligase (MAPL), a small ubiquitin-like modifier (SUMO) E3 ligase, plays a significant role in mitochondrial function. However, the role of MAPL in SCM remains unclear.
    METHODS: To investigate the role of MAPL in SCM, cardiomyocyte-specific MAPL knockout mice were generated. A cecal ligation and puncture (CLP) procedure was employed to induce a sepsis-like condition.
    RESULTS: The expression of MAPL in heart tissues and H9C2 cardiomyocytes was elevated following CLP challenge or lipopolysaccharide (LPS) stimulation. MAPL deficiency ameliorated CLP-induced cardiac injury, dysfunction, and inflammation, and also improved the survival rate of mice following CLP operation. Additionally, MAPL deficiency or knockdown inhibited LPS-induced cardiomyocyte apoptosis, improved mitochondrial structural abnormalities, and increased ATP production. Furthermore, MAPL knockdown mitigated LPS-induced reductions in mitochondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) production. Mechanistically, the expression of dynamin-related protein 1 (drp1) in the mitochondria of heart tissues or H9C2 cardiomyocytes was elevated under septic conditions. Accordingly, the SUMOylation of drp1 in heart tissues or H9C2 cardiomyocytes was increased under sepsis conditions, which was reduced by MAPL knockout or knockdown.
    CONCLUSION: Our results reveal that MAPL promotes cardiac injury/dysfunction and inflammation in SCM. Deficiency or knockdown of MAPL alleviates SCM by reducing drp1 SUMOylation as well as drp1-mediated mitochondrial dysfunction. These findings suggest that targeting MAPL may represent a therapeutic strategy for patients with SCM.
    Keywords:  MAPL; Mitochondria; SUMOylation; Septic cardiomyopathy
    DOI:  https://doi.org/10.1186/s12967-024-05836-x
  46. Hum Mol Genet. 2024 Nov 13. pii: ddae152. [Epub ahead of print]
    Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.
    Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon.
      Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.
    Keywords:  Barth syndrome; TAFAZZIN; cardiomyopathy; mitophagy
    DOI:  https://doi.org/10.1093/hmg/ddae152
  47. Cell Mol Life Sci. 2024 Nov 15. 81(1): 454
    αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury.
    Xuying Zhu, Qisheng Lin, Yuanting Yang, Shu Li, Xinghua Shao, Weiming Zhang, Hong Cai, Jialin Li, Jingkui Wu, Kaiqi Zhang, Chaojun Qi, Minfang Zhang, Xiajing Che, Leyi Gu, Zhaohui Ni.
      Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting autophagy. However, the specific mechanism underlying αKlotho-mediated autophagy remains unclear. The RNA sequencing analysis of renal cortex revealed that the differentially expressed genes related to autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with mitophagy and apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted mitophagy and decreased cell apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated mitophagy and subsequently increased the oxidative injury and cell apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via mitophagy promotion involving the FoxO3-BNIP3 pathway.
    Keywords:  Acute kidney injury; Contrast media; FoxO3; Klotho; Mitophagy
    DOI:  https://doi.org/10.1007/s00018-024-05473-z
  48. Biochemistry (Mosc). 2024 Oct;89(10): 1823-1833
    Astaxanthin Reduces H2O2- and Doxorubicin-Induced Cardiotoxicity in H9c2 Cardiomyocyte Cells.
    Roman R Krestinin, Margarita I Kobyakova, Yuliya L Baburina, Linda D Sotnikova, Olga V Krestinina.
      Cardiovascular diseases are among the most challenging problems in clinical practice. Astaxanthin (AST) is a keto-carotenoid (xanthophyll) mainly of marine origin, which is able to penetrate the cell membrane, localize in mitochondria, and prevent mitochondrial dysfunction. In this study effect of astaxanthin on the death of H9c2 cardiomyocytes caused by the cytotoxic effect of hydrogen peroxide (H2O2) and doxorubicin (DOX) was examined. Using methods of spectrophotometry, spectrofluorimetry, and Western blotting analysis, it was shown that treatment of the cells with AST contributed to the increase in the number of H9c2 cells resistant to H2O2 and doxorubicin, while maintaining the value of their mitochondrial transmembrane potential, reducing intracellular production of reactive oxygen species, and increasing intracellular content of the mitophagy markers PINK1, Parkin, and prohibitin 2. The obtained results suggest that the use of AST could be a highly effective way to prevent and treat cardiovascular diseases.
    Keywords:  astaxanthin; cardiomyocytes; cytotoxicity; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1134/S0006297924100122
  49. PLoS One. 2024 ;19(11): e0313507
    Palmitoyl-L-carnitine induces tau phosphorylation and mitochondrial dysfunction in neuronal cells.
    Gwangho Yoon, Min Kyoung Kam, Young Ho Koh, Chulman Jo.
      Alzheimer's disease (AD) is characterized by cognitive decline and memory loss, involving mechanisms such as tau hyperphosphorylation and mitochondrial dysfunction. Increasing evidence suggests that age-related alterations in metabolite levels are crucial for the pathogenesis of AD. Here, we analyzed serum metabolites from mice of various ages (2, 4, 14, and 21 months old) using mass spectrometry. We identified palmitoyl-L-carnitine as a key metabolite with significantly increased levels in aged mice. In vitro experiments with SH-SY5Y neuronal cells demonstrated that palmitoyl-L-carnitine treatment enhanced tau phosphorylation, increased mitochondrial fission, and elevated intracellular calcium levels. Furthermore, the increased levels of tau phosphorylation were significantly reduced by the inhibition of GSK-3β, CDK5, and calpain, indicating that tau kinases activated by calcium overload are directly involved in the increase of tau phosphorylation. Considering that mitochondrial fission is related to mitochondrial dysfunction, we propose that the elevated level of serum palmitoyl-L-carnitine during aging contributes to AD pathology through these pathways. These findings highlight the significant role of lipid metabolism in neurodegeneration and offer potential therapeutic targets for age-related diseases, including AD.
    DOI:  https://doi.org/10.1371/journal.pone.0313507
  50. Cells. 2024 Oct 26. pii: 1773. [Epub ahead of print]13(21):
    Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.
    Olivia Sommers, Rholls A Tomsine, Mireille Khacho.
      From quiescence to activation and myogenic differentiation, muscle stem cells (MuSCs) experience drastic alterations in their signaling activity and metabolism. Through balanced cycles of fission and fusion, mitochondria alter their morphology and metabolism, allowing them to affect their decisive role in modulating MuSC activity and fate decisions. This tightly regulated process contributes to MuSC regulation by mediating changes in redox signaling pathways, cell cycle progression, and cell fate decisions. In this review, we discuss the role of mitochondrial dynamics as an integral modulator of MuSC activity, fate, and maintenance. Understanding the influence of mitochondrial dynamics in MuSCs in health and disease will further the development of therapeutics that support MuSC integrity and thus may aid in restoring the regenerative capacity of skeletal muscle.
    Keywords:  DRP1; OPA1; differentiation; glutathione; metabolism; mitochondria; mitochondrial dynamics; muscle stem cells; myogenesis; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/cells13211773
  51. Sci Rep. 2024 11 11. 14(1): 27492
    Loss of O6-methylguanine DNA methyltransferase (MGMT) in macrophages alters responses to TLR3 stimulation and enhances DNA double-strand breaks and mitophagy.
    Md Fazlul Haque, Salisa Benjaskulluecha, Atsadang Boonmee, Pornrat Kongkavitoon, Benjawan Wongprom, Thitiporn Pattarakankul, Rahat Ongratanaphol, Kittitach Sri-Ngern-Ngam, Chitsuda Pongma, Benjawan Saechue, Patipark Kueanjinda, Takashi Kobayashi, Asada Leelahavanichkul, Tanapat Palaga.
      O6-methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme. The roles of this enzyme in immune cells remain unclear. In this study, we explored the roles of MGMT in bone marrow-derived murine macrophages (BMMs) via the use of MGMT knockout (KO) mice. Loss of MGMT altered the response to TLR3 agonists (poly (I:C)), such as dampening the production of TNFα and IL-6. Increased DNA double-strand breaks (DSBs) were observed in MGMT-KO macrophages but did not result in increased cell death. MGMT localized to both nuclei and mitochondria at increasing levels during poly (I:C) stimulation. MGMT deficiency increased the production of mitochondrial reactive oxygen species (mtROS), which was correlated with increased mitophagy. The underlying mechanism involves mediation through activation of the AMPKα pathway. Taken together, our findings reveal the roles of MGMT in macrophages in regulating the response to TLR3, which links DSBs to mtROS and mitophagy via the AMPKα pathway. These roles may have consequences for the inflammatory response and chronic inflammation.
    Keywords:  Autophagy; MGMT; Macrophages; Mitochondria; TLR3
    DOI:  https://doi.org/10.1038/s41598-024-78885-3
  52. Molecules. 2024 Oct 28. pii: 5085. [Epub ahead of print]29(21):
    20 (S)-Protopanaxadiol Alleviates DRP1-Mediated Mitochondrial Dysfunction in a Depressive Model In Vitro and In Vivo via the SIRT1/PGC-1α Signaling Pathway.
    Pengli Guo, Zixian Wang, Li Sun, Zhongmei He, Jianming Li, Jianan Geng, Ying Zong, Weijia Chen, Rui Du.
      Depression is a complex and common mental illness affecting physical and psychological health. Panax ginseng C. A. Mey is a traditional Chinese medicine with abundant pharmacological activity and applications in regulating mood disorders. 20 (S)-Protopanaxadiol is the major intestinal metabolite of ginsenoside and one of the active components in ginseng. In this study, we aimed to investigate the therapeutic effects of 20 (S)-Protopanaxadiol on neuronal damage and depression, which may involve mitochondrial dynamics. However, the mechanism underlying the antidepressant effects of 20 (S)-Protopanaxadiol is unelucidated. In the present study, we investigated the potential mechanisms underlying the antidepressant activity of 20 (S)-Protopanaxadiol by employing a corticosterone-induced HT22 cellular model and a chronic unpredicted mild stress (CUMS)-induced animal model in combination with a network pharmacology approach. In vitro, the results showed that 20 (S)-Protopanaxadiol ameliorated the corticosterone (CORT)-induced decrease in HT22 cell viability, decrease in 5-hydroxytryptamine (5-HT) levels, and increase in nitric oxide (NO) and malondialdehyde (MDA) levels. Furthermore, 20 (S)-Protopanaxadiol exerted improvement effects on the CORT-induced increase in HT22 cell mitochondrial reactive oxygen species, loss of mitochondrial membrane potential, and apoptosis. In vivo, the results showed that 20 (S)-Protopanaxadiol ameliorated depressive symptoms and hippocampal neuronal damage in CUMS mice, and sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-1-Alpha (PGC-1α) activity were activated in the hippocampus of mice, thereby alleviating mitochondrial dysfunction and promoting the clearance of damaged mitochondria. In both in vivo and in vitro models, after inhibiting SIRT1 expression, the protective effect of 20 (S)-Protopanaxadiol on mitochondria was significantly weakened, and dynamin-related protein 1 (DRP1)-mediated mitochondrial division was significantly reduced. These findings suggest that 20 (S)-Protopanaxadiol may exert neuroprotective and antidepressant effects by attenuating DRP1-mediated mitochondrial dysfunction and apoptosis by modulating the SIRT1/PGC-1α signaling pathway.
    Keywords:  20 (S)-Protopanaxadiol; depression; dynamics-related protein 1; mitochondrial dysfunction; sirtuin1
    DOI:  https://doi.org/10.3390/molecules29215085
  53. Free Radic Biol Med. 2024 Nov 05. pii: S0891-5849(24)01028-1. [Epub ahead of print]225 856-870
    Targeting DUSP26 to drive cardiac mitochondrial dynamics via FAK-ERK signaling in diabetic cardiomyopathy.
    Chong Liu, Xiangli Xu, Guiming Sun, Chengchao Song, Shuangquan Jiang, Ping Sun, Jiawei Tian.
      Diabetic cardiomyopathy (DCM) is a severe cardiac complication of diabetes mellitus, characterized by structural and functional myocardial abnormalities. The molecular mechanisms underlying DCM, particularly the role of dual-specificity phosphatase 26 (DUSP26), remain insufficiently understood. Our study reveals that DUSP26 expression is markedly downregulated in the cardiomyocytes of diabetic db/db mice and under glucolipotoxic stress. Overexpression of DUSP26 in db/db mice significantly improved cardiac function, as demonstrated by enhanced left ventricular ejection fraction and fractional shortening, alongside reduced myocardial fibrosis and hypertrophy. Mitochondrial analysis indicated that DUSP26 overexpression led to increased ATP production, enhanced mitochondrial fusion, and improved structural integrity. In addition, lipid accumulation was reduced, reflecting enhanced metabolic function. We also discovered that DUSP26 is necessary for regulating the focal adhesion kinase (FAK)-extracellular signal-regulated kinase (ERK) pathway, with pharmacological activation of FAK partially offsetting the benefits of DUSP26 overexpression in rescue experiments. These findings underscore the pivotal role of DUSP26 as a potential therapeutic target, highlighting the importance of developing targeted molecular interventions to address diabetic cardiac complications.
    Keywords:  Cardiac function; DUSP26; Diabetic cardiomyopathy; FAK-ERK signaling; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.006
  54. Phytomedicine. 2024 Oct 28. pii: S0944-7113(24)00827-4. [Epub ahead of print]135 156170
    Kaixinsan regulates neuronal mitochondrial homeostasis to improve the cognitive function of Alzheimer's disease by activating CaMKKβ-AMPK-PGC-1α signaling axis.
    Jiale Ren, Beibei Xiang, Lili Song, Dehou Jésuton René, Yifang Luo, Guiying Wen, Hao Gu, Zhen Yang, Yanjun Zhang.
       BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease primarily characterized by cognitive impairments. With the intensification of population aging, AD has become a major health concern affecting the elderly. Kaixinsan, a classical traditional Chinese formula, consists of Ginseng Panax et Rhizoma, Polygalae Radix, Poria and Acori Tatarinowii Rhizoma, and is commonly used in clinical for treating memory decline. However, its mechanism remains unclear, which hinders its popularization and application.
    METHOD: Morris water maze (MWM) was performed to evaluate the effect of Kaixinsan on improving learning and memory ability in SAMP8 (senescence-accelerated mouse prone 8, an AD model mice) mice. Nissl staining, TdT-mediated dUTP Nick End Labeling (TUNEL) and western blotting (Bax and Bcl-2) were used to confirm the effect of Kaixinsan on the neuronal structure and apoptosis of SAMP8 mice. Ultra performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was performed to identify the distribution components in brain tissue after administration of Kaixinsan extraction. Based on the identified brain distribution components, the mechanism of Kaixinsan improving the cognitive function was predicted by network pharmacology. Then, using HSP60 as a mitochondrial marker and RBFOX3 as a neuronal marker, immunofluorescence co-localization was used to confirm the effect of Kaixinsan on neuronal mitochondria quantity in SAMP8 mice. Western blotting was employed to access the expression of predicted proteins (AMPK, CaMKKβ, PGC-1α and HSP90) implicated in mitochondrial homeostasis. To further confirm the mechanism of Kaixinsan, SH-SY5Y cell injury model induced by amyloid β - protein fragment 25-35 (Aβ25-35) was replicated and the effect of Kaixinsan - containing serum on apoptosis in injured SH-SY5Y cells was investigated by flow cytometer. The expression level of apoptosis-associated proteins (Bax and Bcl-2) and mitochondrial homeostasis related proteins (AMPK, CaMKKβ, PGC-1α and HSP90) in the presence or absence of CaMKKβ inhibitor (STO-609) were compared.
    RESULTS: The results indicate that Kaixinsan can improve the cognitive function of SAMP8 mice, alleviate the hippocampal tissue lesions and inhibit neuron apoptosis. Seventeen brain distribution components of Kaixinsan were identified. Based on the brain distribution components of Kaixinsan, the results of network pharmacology suggest that Kaixinsan may regulate mitochondrial homeostasis through the CaMKKβ-AMPK-PGC-1α signaling axis. In vivo experiments indicated that Kaixinsan could reverse neuronal mitochondrial loss in SAMP8 mice by upregulating CaMKKβ, AMPK, HSP90 and PGC-1α to promote mitochondrial biogenesis and increase the number of neuronal mitochondria. Additionally, the in vitro experiments demonstrated that Kaixinsan can inhibit apoptosis of Aβ25-35 injured SH-SY5Y cells and upregulate mitochondrial homeostasis-related proteins CaMKKβ, AMPK and PGC-1α. However, in addition to CaMKKβ inhibitors, the neuroprotective effect disappeared.
    CONCLUSION: The results indicate that Kaixinsan can improve the cognitive function of SAMP8 mice by regulating CaMKKβ-AMPK-PGC-1α signaling axis to maintain mitochondrial homeostasis and inhibit neuronal apoptosis.
    Keywords:  Alzheimer's disease; CaMKKβ-AMPK-PGC-1α signaling axis; Kaixinsan; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.phymed.2024.156170
  55. Eur J Pharmacol. 2024 Nov 06. pii: S0014-2999(24)00801-X. [Epub ahead of print]985 177111
    AdipoRon improves mitochondrial homeostasis and protects dopaminergic neurons through activation of the AMPK signaling pathway in the 6-OHDA-lesioned rats.
    Seyed Zanyar Athari, Rana Keyhanmanesh, Fereshteh Farajdokht, Mohammad Karimipour, Negin Azizifar, Soraya Alimohammadi, Gisou Mohaddes.
      The progressive decline of dopaminergic neurons in Parkinson's disease (PD) has been linked to an imbalance in energy and the failure of mitochondrial function. AMP-activated protein kinase (AMPK), the major intracellular energy sensor, regulates energy balance, and damage to nigral dopaminergic neurons induced by 6-hydroxydopamine (6-OHDA) is exacerbated in the absence of AMPK activity. This study aimed to examine the potential therapeutic advantages of AdipoRon, an AMPK activator, on motor function and mitochondrial homeostasis in a 6-OHDA-induced PD model. Male Wistar rats were subjected to unilateral injection of 6-OHDA (10 μg) into the left medial forebrain bundle at two points, and after 7 days, they were treated with intranasal AdipoRon (0.1, 1, and 10 μg) or Levodopa (10 mg/kg, p. o.) for 21 successive days. Following the last treatment day, motor behavior was evaluated through the Murprogo's test, bar test, beam walking test, and apomorphine-induced rotation test. After euthanasia, the left substantia nigra (SN) was separated for evaluation of ATP, mitochondrial membrane potential (MMP), and protein expressions of AMPK, p-AMPK, and mitochondrial dynamics markers (Mfn-2 and Drp-1). Moreover, the number of tyrosine hydroxylase-positive (TH+) cells was quantified in the left substantia nigra. Intranasal AdipoRon effectively reversed muscle rigidity, akinesia, bradykinesia, and rotation caused by 6-OHDA. Moreover, AdipoRon increased the phospho-AMPK/AMPK ratio, mitigated mitochondrial dysfunction, and improved mitochondrial dynamics in the SN. Furthermore, AdipoRon increased the number of TH+ cells in the SN of PD animals. These findings suggest that AdipoRon could protect dopaminergic neurons by activating the AMPK pathway and improving mitochondrial dysfunction.
    Keywords:  AMPK; AdipoRon; Mitochondria; Motor performance; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177111
  56. Theriogenology. 2024 Nov 05. pii: S0093-691X(24)00450-3. [Epub ahead of print]232 87-95
    Oxidative phosphorylation decline and mitochondrial dynamics disequilibrium are involved in chicken large white follicle atresia.
    Jianing Hu, Jie Li, Shanyou Zheng, Yan Chen, Yucheng Zhang, Jiguang Deng, Jiasheng Fan, Huiyan Xu, Yangqing Lu, Xingting Liu.
      In domestic hens, the atresia of large white follicles (LWFs) directly affects the number of follicles that enter the hierarchical development and ovulation. Figuring out factors responsible for LWFs atresia is helpful to improve egg production of hens. At the LWF stage, yellow yolk begins to be deposited into the follicles via receptor mediated endocytosis, which requires large amounts of ATP. Mitochondrial oxidative phosphorylation (OXPHOS) is the primary source of ATP for follicular development. However, it is not clear whether the OXPHOS is changed along LWFs atresia. In this study, firstly, differences in morphological appearance, histology, cell proliferation, apoptosis, OXPHOS and mitochondrial dynamics between LWFs and atretic large white follicles (ALWFs) in hens at the peak laying stage (35W) were determined to elucidate whether OXPHOS changes in ALWFs. Then, these differences of LWFs between the peak laying hens (35W-LWFs) and the late laying hens (70W-LWFs) were detected to confirm whether OXPHOS changes during LWFs atresia. The results showed that ALWFs exhibited a wrinkled surface with several hemorrhage spots, and numerous intercellular vacuoles, as well as severe nuclear pyknosis. Compared to LWFs, a higher cell apoptosis rate and a lower proliferation rate were observed in ALWFs. In ALWFs, OXPHOS declined as manifested by reductions in ATP levels, ATP synthetase abundance, NAD+, NADH and NAD+/NADH ratio, and mRNA levels of genes associated with OXPHOS complexes I-V. Meanwhile, mitochondrial dynamics disequilibrium was detected in ALWFs as the expression levels of proteins and genes related to mitochondrial fusion (MFN1, MFN2, and OPA1) decreased, while the expression levels of proteins and genes related to mitochondrial fission (DRP1 and FIS1) increased. Further, compared to 35W-LWFs, 70W-LWFs showed a histology resembling to ALWFs, manifested as a slightly loosen structure of granulosa layers, and a lower cell proliferation rate. Moreover, both lower OXPHOS and impaired mitochondrial dynamics were detected in 70W-LWFs. In conclusion, our results indicated that OXPHOS decline and mitochondrial dynamics disequilibrium are involved in LWFs atresia in laying hens.
    Keywords:  Atresia; Chicken; Large white follicle; Mitochondrial dynamics; Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.theriogenology.2024.11.003
  57. J Invest Dermatol. 2024 Nov 13. pii: S0022-202X(24)02890-2. [Epub ahead of print]
    FoxO3a Plays a Role in Wound Healing by Regulating Fibroblast Mitochondrial Dynamics.
    Mariko Moriyama, Ryoichi Mori, Takao Hayakawa, Hiroyuki Moriyama.
      The skin plays a protective role against harmful environmental stress such as ultraviolet rays. Therefore, the skin is constantly exposed to potential injuries, and wound healing is a vital process for the survival of all higher organisms. Wound healing is dependent on aging and metabolic status at a whole-body level. Because the forkhead box O (FOXO) family plays a role in aging and metabolism, we investigated the molecular functions of FOXO3a in skin wound healing using FoxO3a-/- mice. We observed that FoxO3a-/- mice showed accelerated skin wound healing. During wound healing, more fibroblasts accumulated at the wound edges and migrated into the wound bed in FoxO3a-/- mice. Moreover, cell migration of dermal fibroblasts isolated from FoxO3a-/- mice was significantly induced. During the in vitro cell migration, we observed accelerated mitochondrial fragmentation and decreased oxygen consumption in the mitochondria of FoxO3a-/- fibroblasts. These changes were caused by the upregulation of mitochondrial Rho GTPase 1 (Miro1), which is an essential mediator of microtubule-based mitochondrial motility. Miro1 inhibition significantly attenuated cell migration, mitochondrial fragmentation, and mitochondrial recruitment to the leading edge of the cells. These data indicate that FoxO3a plays a crucial role in wound healing by regulating mitochondrial dynamics.
    Keywords:  FoxO; fibroblasts; migration; mitochondria; wound healing
    DOI:  https://doi.org/10.1016/j.jid.2024.10.600
  58. Int J Med Sci. 2024 ;21(14): 2664-2682
    Exploring the role of mitophagy-related genes in breast cancer: subtype classification and prognosis prediction.
    Lizhao Wang, Nan Mei, Jianpeng Li, Heyan Chen, Jianjun He, Ru Wang.
      Background: Breast cancer (BC) is the most common cancer among women globally and poses the leading health threat to women worldwide, with persistently high incidence rates. Mitophagy is a selective autophagy process that specifically targets mitochondria within the cell, maintaining cellular energy balance and metabolic health by identifying and degrading damaged mitochondria. Although there is an understanding of the relationship between mitophagy and cancer, the specific mechanisms remain unclear due to the complexity and diversity of mitophagy, suggesting that it could be an effective and more targeted therapeutic approach for BC. Methods: In this study, we meticulously examined the BC expression and clinical pathology data from The Cancer Genome Atlas (TCGA) to assess the expression profiles, copy number variations (CNV), and to investigate the correlation, function, and prognostic impact of 34 mitophagy-related genes (MRGs). Differentially expressed genes (DEGs) were identified based on group classification. Lasso and Cox regression were used to determine prognostic genes for constructing a nomogram. Single-cell analysis mapped the distribution of these genes in BC cells. Additionally, the association between gene-derived risk scores and factors such as immune infiltration, tumor mutational burden (TMB), cancer stem cell (CSC) index, and drug responses was studied. In vitro experiments were conducted to confirm the analyses. Results: We included 34 MRGs and subsequently generated a risk score for 7 genes, including RPLP2, PCDHGA2, PRKAA2, CLIC6, FLT3, CHI3L1, and IYD. It was found that the low-risk group had better overall survival (OS) in BC, higher immune scores, but lower tumor mutational burden (TMB) and cancer stem cell (CSC) index, as well as lower IC50 values for commonly used drugs. To enhance clinical applicability, age and staging were incorporated into the risk score, and a more comprehensive nomogram was constructed to predict OS. This nomogram was validated and showed good predictive performance, with area under the curve (AUC) values for 1-year, 3-year, and 5-year OS of 0.895, 0.765, and 0.728, respectively. Conclusion: Our findings underscore the profound impact of prognostic genes on the immune response and prognostic outcomes in BC, indicating that they can provide new avenues for personalized BC treatment and potentially improve clinical outcomes.
    Keywords:  breast cancer; gene signature; immune; mitophagy; prognosis
    DOI:  https://doi.org/10.7150/ijms.100785
  59. Sci Rep. 2024 11 11. 14(1): 27523
    Resveratrol protects pancreatic beta cell and hippocampal cells from the aggregate-prone capacity of hIAPP.
    Carlos González-Blanco, Ángela Cristina Lockwood, Beatriz Jiménez, Sarai Iglesias-Fortes, Patricia Marqués, Gema García, Ana García-Aguilar, Manuel Benito, Carlos Guillén.
      Type 2 diabetes mellitus and Alzheimer's disease, are two closely related pathological situations that are connected at the molecular level. In recent years, amylin, which is co-secreted with insulin, has been proposed for being a main actor in this context due to its capacity to form aggregates in a β-sheet-like structure. In a diabetic milieu, there is an increase in the production and secretion of insulin and amylin. We have analysed the role of resveratrol on aggregate formation and in the production of extracellular vesicles with amylin in its interior and in pancreatic β cells overexpressing human amylin (INS1E-hIAPP). Furthermore, we have explored the consequences of the exposition of the conditioned medium derived from INS1E-hIAPP in the hippocampal cell line HT-22 and the role of resveratrol in this cell line. Hippocampal cells were exposed to conditioned media obtained from rat insulinoma 1E overexpressing human amylin in the presence or in the absence of resveratrol. When we exposed HT-22 cells to the conditioned media of INS1E-hIAPP we observed amylin-aggregates inside HT-22 cells. Resveratrol was able to alleviate this effect not only in HT-22 but also in pancreatic β cells. Furthermore, resveratrol decreased the average exosome size produced by the INS1E-hIAPP stimulated with high glucose, diminishing the toxic effect of these exosomes in HT-22 cells. We have uncovered that resveratrol inhibits the aggregation capacity of amylin and it can diminish the deleterious spreading of the toxic protein, to other cell types such as the hippocampal neuron cells, HT-22.
    Keywords:  Amylin; Beta cell; Beta-sheet-like aggregates; HT-22; Mitochondrial dynamics; Resveratrol
    DOI:  https://doi.org/10.1038/s41598-024-78967-2
  60. Arch Biochem Biophys. 2024 Nov 07. pii: S0003-9861(24)00335-7. [Epub ahead of print]762 110213
    High intensity interval training as a therapy: Mitophagy restoration in breast cancer.
    Kayvan Khoramipour, Afsaneh Soltany, Pouria Khosravi, Maryam Hossein Rezaei, Elham Madadizadeh, Celia García-Chico, Sergio Maroto-Izquierdo, Karen Khoramipour.
      Recent studies have highlighted the role of mitophagy in tumorigenesis. This study aimed to investigate the effects of high-intensity interval training (HIIT) on mitophagy in tumor tissues of mice with breast cancer. Twenty-eight female BALB/c mice were randomly assigned to four groups: Healthy Control (CO), Cancer (CA), Exercise (EX), and Cancer + Exercise (CA + EX). Mammary tumors were induced in the CA and CA + EX groups via 4T1 cell injections. Upon confirmation of tumor formation, the EX and CA + EX groups underwent 8 weeks (40 sessions) of HIIT, comprising 4-10 intervals of running at 80-100 % of maximum speed. The expression levels of mitophagy-related proteins, including parkin, PTEN-induced putative kinase 1 (PINK1), NIP3-like protein X (NIX), BCL2 interacting protein-3 (BINP3), microtubule-associated protein light chain 3-I (LC3-I), microtubule-associated protein light chain 3-II (LC3-II), AMP-activated protein kinase (AMPK), Unc-51 like autophagy activating kinase-1 (ULK1), and sirtuin-1 (SIRT1), were measured in breast and tumor tissues. Tumor volume relative to body weight was assessed weekly during the eight-week HIIT intervention. Protein expression of parkin, PINK1, NIX, BINP3, LC3-II, LC3-I, AMPK, ULK1, and SIRT1 was reduced in the breast tissue of the CA group, while HIIT restored expression levels across all measured variables (P < 0.01). Additionally, tumor volume relative to body weight was significantly lower in the CA + EX group compared to the CA group from weeks 3-8 (P < 0.01). These findings suggest that breast cancer suppresses mitophagy, yet HIIT effectively reverses this suppression, potentially reducing tumor burden. HIIT may thus represent a promising therapeutic strategy for managing breast cancer.
    Keywords:  Breast cancer; Exercise; Mitophagy; Tumor volume
    DOI:  https://doi.org/10.1016/j.abb.2024.110213
  61. Ageing Res Rev. 2024 Nov 10. pii: S1568-1637(24)00395-7. [Epub ahead of print]102 102577
    Mitochondrial dysfunction as a therapeutic strategy for neurodegenerative diseases: Current insights and future directions.
    Ying-Ying Gu, Xin-Ru Zhao, Nan Zhang, Yuan Yang, Ying Yi, Qian-Hang Shao, Ming-Xuan Liu, Xiao-Ling Zhang.
      Neurodegenerative diseases, as common diseases in the elderly, tend to become younger due to environmental changes, social development and other factors. They are mainly characterized by progressive loss or dysfunction of neurons in the central or peripheral nervous system, and common diseases include Parkinson's disease, Alzheimer's disease, Huntington's disease and so on. Mitochondria are important organelles for adenosine triphosphate (ATP) production in the brain. In recent years, a large amount of evidence has shown that mitochondrial dysfunction plays a direct role in neurodegenerative diseases, which is expected to provide new ideas for the treatment of related diseases. This review will summarize the main mechanisms of mitochondrial dysfunction in neurodegenerative diseases, as well as collating recent advances in the study of mitochondrial disorders and new therapies.
    Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Neurodegenerative diseases; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2024.102577
  62. Toxicol Res (Camb). 2024 Dec;13(6): tfae188
    Proteomics reveals that nanoplastics with different sizes induce hepatocyte apoptosis in mice through distinct mechanisms involving mitophagy dysregulation and cell cycle arrest.
    Yan-Yang Lu, Weizhen Hua, Yiqiong Sun, Lu Lu, Hongyun Ren, Qingyu Huang.
      Nanoplastics (NPs) can penetrate the intestinal barrier of organisms and accumulate in the liver, thereby inducing hepatocyte apoptosis. However, the underlying mechanisms remain incompletely elucidated. This study examined the effects of PS-NPs exposure on hepatocyte apoptosis and revealed the role of cell cycle arrest and mitophagy. The C57BL/6 mice were administered a diet containing 100 nm and 500 nm PS-NPs at a concentration of 0.1 g/kg for 180 days, respectively. TUNEL staining confirmed that 100 nm PS-NPs induced more pronounced apoptosis compared to 500 nm PS-NPs in mouse liver. Mechanistically, proteomic analysis revealed that Pdcd2l, associated with the S phase of cell cycle and apoptosis, exhibited the highest fold changes among all detected proteins in 100 nm and 500 nm PS-NPs exposure groups. Notably, the expression of Tbc1d17, Bcl2l13, and Pgam5 involved in mitophagosome formation in mouse liver was upregulated by 100 nm PS-NPs but not by 500 nm PS-NPs; moreover, mitophagosomes were observed in HepG2 cells exposed to 100 nm PS-NPs. Additionally, 100 nm PS-NPs internalized by HepG2 cells could penetrate lysosomes. The protein levels of Igf2r and Rab7a were altered, and p62 mRNA expression was increased in mouse liver, suggesting 100 nm PS-NPs, but not 500 nm PS-NPs, impaired lysosomal function and subsequently inhibited mitophagy degradation. Collectively, 500 nm PS-NPs induced Pdcd2l-mediated cell cycle arrest, thereby exacerbating hepatocyte apoptosis; while 100 nm PS-NPs not only triggered similar levels of cell cycle arrest as 500 nm PS-NPs, but also disrupted mitophagy, which was also associated with hepatocyte apoptosis.
    Keywords:  Apoptosis; Hepatotoxicity; Mitophagy; Nanoplastics; Proteomics
    DOI:  https://doi.org/10.1093/toxres/tfae188
  63. J Ethnopharmacol. 2024 Nov 09. pii: S0378-8741(24)01302-3. [Epub ahead of print] 119003
    Buyang Huanwu Decoction restores the balance of mitochondrial dynamics after cerebral ischemia-reperfusion through calcium overload reduction by the PKCε-Nampt-Sirt5 axis.
    Zhenyi Liu, Meijuan Yin, Jing Li, Jing Wang, Xiaofei Jin, Xiaohong Zhou, Weijuan Gao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Stroke is a common condition that poses a significant threat to human health. Buyang Huanwu Decoction (BYHWD) is a traditional treatment used for stroke management. However, the exact mechanism by which BYHWD mitigates cerebral ischemia-reperfusion by regulating calcium overload and restoring mitochondrial function is not yet fully understood.
    AIM: The objective of this research was to examine the neuroprotective properties of BYHWD in reducing the damage produced by cerebral ischemia/reperfusion (I/R) injury via the modulation of calcium overload and mitochondrial dynamics (MD).
    METHODS: MCAO/R model success was evaluated via PSI laser scatter flowmetry. The neurological function scores were assessed. The cerebral infarct (CI) volume was detected via TTC staining. NeuN expression was detected via immunohistochemistry, and degenerated neurons were observed via FJC staining. The mitochondrial permeability transition pore (mPTP), the mitochondrial membrane potential (MMP), and ATP were detected. The reactive oxygen species (ROS) content and the NAD+/NADH ratio were determined. The glutamate (Glu) and glutamine (Gln) contents as well as the Ca2+ concentration were determined. The expression of PKCε, p-PKCε, namely, Sirt5, GLS, Drp1, p-Drp1 616, Fis1, Opa1, and Mfn2 was determined via Western blotting. Immunohistochemistry was used to detect p-PKCε, which is expressed at high levels. Immunofluorescence was used to detect p-Drp1 616, Opa1 and Sirt5 fluorescence intensity.
    RESULTS: BYHWD treatment enhanced neurological function, decreased the amount of CI, mitigated neuronal damage, decreased mPTP opening, restored the MMP, increased ATP synthesis, and decreased the ROS content after brain I/R. It also increased PKCε, p-PKCε, Sirt5, GLS, Opa1 and Mfn2 expression; downregulated p-Drp1 616, Drp1 and Fis1 expression; elevated the NAD+/NADH ratio and Gln content; and decreased the Glu content and Ca2+ concentration. The effects of BYHWD were reversed by the administration of the PKCε inhibitor εV1-2. BYHWD administration led to increased PKCε mRNA expression.
    CONCLUSIONS: BYHWD modulates MD by diminishing calcium overload through the PKCε-Nampt-Sirt5 axis, which restores mitochondrial function and mitigates brain I/R damage.
    Keywords:  BYHWD; Nampt; PKCε; Sirt5; cerebral ischemia-reperfusion injury; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.jep.2024.119003
  64. Stem Cell Res Ther. 2024 Nov 10. 15(1): 412
    Pretreatment with growth differentiation factor 15 augments cardioprotection by mesenchymal stem cells in myocardial infarction by improving their survival.
    Xinran Huang, Xiaoting Liang, Qian Han, Ying Shen, Jiaqi Chen, Ziqi Li, Jie Qiu, Xiaoyan Gao, Yimei Hong, Fang Lin, Weifeng Li, Xin Li, Yuelin Zhang.
       BACKGROUND: The clinical application of mesenchymal stem cells (MSCs) in myocardial infarction (MI) is severely hampered by their poor survival. Pretreatment is a key strategy that has been adopted to promote their therapeutic efficacy. This study aimed to investigate the benefit of growth differentiation factor 15-pretreated MSCs (GDF15-MSCs) in enhancing cardiac repair following MI and to determine the underlying mechanisms.
    METHODS: MSCs with or without GDF15 pretreatment were exposed to serum deprivation and hypoxia (SD/H) challenge. Apoptosis of MSCs was assessed by TUNEL staining. The conditioned media (CM) of MSCs and GDF15-MSCs was collected by centrifugation. MSCs and GDF15-MSCs were transplanted into the peri-infarct region in a mouse model of MI. Cardiac function, fibrosis and MSC survival were examined 4 weeks after MSC transplantation.
    RESULTS: Pretreatment with GDF15 greatly reduced SD/H-induced apoptosis of MSCs via inhibition of reactive oxygen species (ROS) generation by attenuating mitochondrial fission. Mechanistically, GDF15 pretreatment ameliorated mitochondrial fission of MSCs under SD/H challenge by activating the AMPK pathway. These effects were partially abrogated by AMPK inhibitor. Pretreatment with GDF15 also promoted paracrine effects of MSCs in vitro, evidenced by improving tube formation of HUVECs, and inhibited the apoptosis of cardiomyocytes induced by SD/H. At 4 weeks after transplantation, compared with MSCs, GDF15 pretreatment strongly promoted the survival of MSCs in the ischemic heart with consequent enhanced cardiac function, reduced cardiac fibrosis and increased angiogenesis.
    CONCLUSIONS: Our study showed that pretreatment with GDF15 promoted the cardioprotective effects of MSCs in MI via regulation of pro-survival signaling and paracrine actions. GDF15 pretreatment is an effective approach to enhance the therapeutic efficacy of MSCs in ischemic heart disease.
    Keywords:  Cell survival; Growth differentiation factor 15; Mesenchymal stem cells; Mitochondrion; Myocardial infarction
    DOI:  https://doi.org/10.1186/s13287-024-04030-6
  65. ACS Pharmacol Transl Sci. 2024 Nov 08. 7(11): 3540-3558
    Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.
    Hasham Shafi, Andrea J Lora, Haley M Donow, Saurabh Aggarwal, Panfeng Fu, Ting Wang, Heidi M Mansour.
      Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.
    DOI:  https://doi.org/10.1021/acsptsci.4c00436
  66. FEBS J. 2024 Nov 14.
    Mitochondria: great balls of fire.
    Howard T Jacobs, Pierre Rustin, Paule Bénit, Dan Davidi, Mügen Terzioglu.
      Recent experimental studies indicate that mitochondria in mammalian cells are maintained at temperatures of at least 50 °C. While acknowledging the limitations of current experimental methods and their interpretation, we here consider the ramifications of this finding for cellular functions and for evolution. We consider whether mitochondria as heat-producing organelles had a role in the origin of eukaryotes and in the emergence of homeotherms. The homeostatic responses of mitochondrial temperature to externally applied heat imply the existence of a molecular heat-sensing system in mitochondria. While current findings indicate high temperatures for the innermost compartments of mitochondria, those of the mitochondrial surface and of the immediately surrounding cytosol remain to be determined. We ask whether some aspects of mitochondrial dynamics and motility could reflect changes in the supply and demand for mitochondrial heat, and whether mitochondrial heat production could be a factor in diseases and immunity.
    Keywords:  cold‐shock; eukaryote origins; heat‐shock; homeothermy; immunity; mitochondria; mitochondrial disease; mitochondrial dynamics; temperature gradients; thermogenesis
    DOI:  https://doi.org/10.1111/febs.17316
  67. Int J Biochem Cell Biol. 2024 Nov 08. pii: S1357-2725(24)00182-1. [Epub ahead of print] 106689
    Mitochondrial E3 ligase TRIM71 affects mitochondrial complex assembly and sensitizes dopaminergic neuronal cells to apoptosis in Parkinson's Disease (PD).
    Shanikumar Goyani, Shatakshi Shukla, Minal Mane, M V Saranga, Nisha Chandak, Anjali Shinde, Fatema Currim, Jyoti Singh, Rajesh Singh.
      Parkinson's Disease (PD) is a chronic neurodegenerative disorder that impacts the substantia niagra region of the midbrain leading to impaired motor as well as non-motor symptoms of the central nervous system (CNS). Mitochondrial dysfunction has been characterized as the primary cause of dopaminergic neuronal loss, however, the molecular mechanisms leading to mitochondrial dysfunction are not completely understood. PARKIN, E3 ubiquitin ligase, plays a crucial role in maintaining mitochondrial quality control, albeit the role of other E3 ligases in regulating mitochondrial functions is not understood. In the current study, we explored the implication of TRIM71, E3 ubiquitin ligase, in the modulation of mitochondrial functions and neuronal death in PD stress conditions induced by rotenone and 6-OHDA. Ectopic expression of TRIM71 in SH-SY5Y dopaminergic neuronal cells sensitizes to PD stress-induced cell death, while its knock-down rescues neuronal cell death. TRIM71 turnover is enhanced in neurons under PD stress conditions. TRIM71 predominantly localizes on the outer mitochondrial membrane and translocation increases during PD stress conditions. TRIM71 regulates mitochondrial complex I and IV assembly and activity. TRIM71 knock-down decreases mitochondrial ROS and enhances ATP level as well as mitochondrial membrane potential in PD stress conditions. TRIM71-mediated mitochondrial ROS and cell death were rescued by mitoTEMPO, a mitochondrial-targeted antioxidant. Altogether, the evidence strongly suggests TRIM71-mediated modulation of mitochondrial functions and neuronal apoptosis in PD stress conditions.
    Keywords:  Parkinson’s disease; ROS; TRIM71; cell death; mitochondria
    DOI:  https://doi.org/10.1016/j.biocel.2024.106689
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