bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–11–24
47 papers selected by
Gavin McStay, Liverpool John Moores University
  1. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  2. Hypothyroidism modulates mitochondrial dynamics and mitophagy in the heart of rats under fed and fasting conditions.
  3. Neurotoxicity of Realgar: Crosstalk Between UBXD8-DRP1-Regulated Mitochondrial Fission and PINK1-Parkin-Mediated Mitophagy.
  4. Correction: OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS-STING pathway to mediate GBM immune escape.
  5. Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles.
  6. H3 relaxin ameliorates mitochondrial quality control and apoptosis in cardiomyocytes of type 2 diabetic rats via activation of the AMPK pathway.
  7. Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm.
  8. GRP78 mediates mitochondrial fusion and fission in cigarette smoke-induced inflammatory responses in airway epithelial cells.
  9. Sestrin2 balances mitophagy and apoptosis through the PINK1-Parkin pathway to attenuate severe acute pancreatitis.
  10. Mdivi-1 alleviates nicotine-induced human periodontal ligament cells injury by inhibiting mitochondrial fission and dysfunction through the JNK/Drp1 pathway.
  11. Cardiac effects of OPA1 protein promotion in a transgenic animal model.
  12. Diltiazem Hydrochloride Protects Against Myocardial Ischemia/Reperfusion Injury in a BNIP3L/NIX-Mediated Mitophagy Manner.
  13. Intermittent Hypoxia Impairs Cognitive Function and Promotes Mitophagy and Lysophagy in Obstructive Sleep Apnea-Hypopnea Syndrome Rat Model.
  14. SIRT3 Deficiency Promotes Lung Endothelial Pyroptosis Through Impairing Mitophagy to Activate NLRP3 Inflammasome During Sepsis-Induced Acute Lung Injury.
  15. Melatonin protects porcine oocytes from gossypol-induced meiosis defects via regulation of SIRT1-mediated mitophagy.
  16. Bringing together but staying apart: decisive differences in animal and fungal mitochondrial inner membrane fusion.
  17. Sex and Region-Specific Disruption of Autophagy and Mitophagy in Alzheimer's Disease: Linking Cellular Dysfunction to Cognitive Decline.
  18. Kainate-Induced Reorganization the Dentate Gyrus of the Hippocampus Is Accompanied by Activation of Mitochondrial Fission in the Granular Layer Neurons.
  19. Nrf2 activator tertiary butylhydroquinone enhances neural stem cell differentiation and implantation in Alzheimer's disease by boosting mitochondrial function.
  20. Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy.
  21. A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission.
  22. Irisin reduces senile osteoporosis by inducing osteocyte mitophagy through Ampk activation.
  23. Electroacupuncture improves diabetic cognitive impairment rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
  24. Impaired endothelial function contributes to cardiac dysfunction - role of mitochondrial dynamics.
  25. WAC Facilitates Mitophagy-mediated MSC Osteogenesis and New Bone Formation via Protecting PINK1 from Ubiquitination-Dependent Degradation.
  26. A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.
  27. Microplastics accumulated in breast cancer patients lead to mitophagy via ANXA2-mediated endocytosis and IL-17 signaling pathway.
  28. Non-lethal sonodynamic therapy inhibits high glucose and palmitate-induced macrophage inflammasome activation through mtROS-DRP1-mitophagy pathway.
  29. Exposure to copper and copper-based nanoparticles induces hepatopancreatic mitochondrial dysfunction by triggering mtROS mediated apoptosis and mitophagy in Eriocheir sinensis.
  30. Long-term taurine supplementation regulates brain mitochondrial dynamics in mice.
  31. MST1, a novel therapeutic target for Alzheimer's disease, regulates mitochondrial homeostasis by mediating mitochondrial DNA transcription and the PI3K-Akt-ROS pathway.
  32. Identification of mitophagy-related gene signatures for predicting delayed graft function and renal allograft loss post-kidney transplantation.
  33. Single-cell sequencing unveils mitophagy-related prognostic model for triple-negative breast cancer.
  34. Liang-Ge-San protects against viral infection-induced acute lung injury through inhibiting α7nAChR-mediated mitophagy.
  35. From Mild Cases to Critical Cases of COVID-19: The Role of Genes in Inflammasome and Mitochondrial Dynamics.
  36. ATF4 regulates mitochondrial dysfunction, mitophagy, and autophagy, contributing to corneal endothelial apoptosis under chronic ER stress in Fuchs' dystrophy.
  37. Identification and validation of biomarkers related to mitochondria during ex vivo lung perfusion for lung transplants based on machine learning algorithm.
  38. NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.
  39. MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury.
  40. Air pollutants as modulators of mitochondrial quality control in cardiovascular disease.
  41. Exploring heat shock proteins as therapeutic targets for Parkinson's disease.
  42. Corrigendum to "FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a" [Redox Biol. 70 (2024) 103081].
  43. De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.
  44. Shenling Baizhu San Alleviates Central Fatigue through SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis.
  45. Biological Evaluation of a Rhodium(III) Bipyridylsulfonamide Complex: Effects on Mitochondrial Dynamics and Cytoskeletal Remodeling in Breast Cancer Cells.
  46. Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1[Formula: see text]-Mediated Mitochondrial Autophagy and Apoptosis Pathways.
  47. PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.
  1. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  2. Life Sci. 2024 Nov 15. pii: S0024-3205(24)00844-0. [Epub ahead of print]359 123254
    Hypothyroidism modulates mitochondrial dynamics and mitophagy in the heart of rats under fed and fasting conditions.
    Juliana Santos Romão, Jessika Geisebel Oliveira Neto, Cherley Borba Vieira Andrade, Jorge José Carvalho, Carmen Cabanelas Pazos-Moura, Karen Jesus Oliveira.
       AIMS: Investigate the impact of hypothyroidism on mitochondrial dynamics and mitophagy in the heart under fed and fasting conditions.
    METHODS: Hypothyroidism was induced in male Wistar rats with methimazole (0.03 %) for 21 days. Half of the euthyroid and hypothyroid groups underwent a 48-h fasting. Mitochondrial number and ultrastructure were evaluated by transmission electron microscopy. Fusion, fission, mitophagy, oxidative stress, and mitochondrial oxidative phosphorylation system (OXPHOS) components were analyzed by Western Blot and qPCR.
    RESULTS: Hypothyroidism increased DRP1 activation and the p-DRP1/OPA1 ratio, indicating a shift toward mitochondrial fission over fusion. Under fasting, hypothyroidism prevented the increases in mitochondrial size, elongation, OPA1, and OXPHOS seen in euthyroid fasted rats. Hypothyroidism also raised 4-HNE content, an oxidative stress product, increased mitochondrial injury, and exacerbated fasting-related mitochondrial damage. This was accompanied by elevated Parkin levels in both fed and fasted hypothyroid groups, but without changes in PINK1 levels or Parkin activation. While fasting upregulated Bnip3l and Map1lc3b expression in euthyroid rats, hypothyroidism suppressed this response, though it did not prevent fasting-induced Bnip3 increases.
    CONCLUSIONS: Hypothyroidism increases the activation of mitochondrial fission machinery and oxidative stress, and induces mitochondrial damage without activation of mitophagy proteins, suggesting disrupted mitophagy signaling. It also interferes with fasting-induced mitochondrial dynamics adaptations, highlighting the essential role of thyroid hormones in metabolic adaptation to fasting.
    Keywords:  Autophagy; Fission; Fusion; Mitochondria; Thyroid hormone
    DOI:  https://doi.org/10.1016/j.lfs.2024.123254
  3. Mol Neurobiol. 2024 Nov 21.
    Neurotoxicity of Realgar: Crosstalk Between UBXD8-DRP1-Regulated Mitochondrial Fission and PINK1-Parkin-Mediated Mitophagy.
    Rui Feng, Jieyu Liu, Tiantian Yao, Zhao Yang, Hong Jiang.
      Realgar is a toxic mineral medicine containing arsenic that is present in many traditional Chinese medicines. It has been reported that the abuse of drugs containing realgar has potential neurotoxicity, but its mechanism of toxicity has not been fully clarified. In this study, we demonstrated that arsenic in realgar promoted mitochondrial fission via UBXD8-mediated DRP1 translocation to the mitochondria and activated mitophagy via PINK1-Parkin, resulting in mitochondrial dysfunction and nerve cell death in the rat cortex. We used PC12 cells and treated them with inorganic arsenic (iAs). Mdivi-1, a mitochondrial fission inhibitor, and the siRNA UBXD8 or PINK1 were used as interventions to verify the precise mechanism by which arsenic affects realgar-induced mitochondrial instability. The results revealed that the arsenic in realgar accumulated in the brain and led to neurobehavioral abnormalities in the rats. We demonstrated that arsenic in realgar-induced high expression of UBXD8 promoted the translocation of DRP1 to the mitochondria, where it underwent phosphorylation, which led to the over-fission of the mitochondria and mitochondria-mediated apoptosis. Moreover, the over-fission of the mitochondria activates mitophagy, which is self-protective but only partially alleviates apoptosis and mitochondria dysfunction. Our findings revealed the crosstalk between mitochondrial fission and mitophagy in realgar-induced neurotoxicity. These results highlight the role of the transposition of DRP1 by UBXD8 in realgar-induced mitochondrial dysfunction and provide new ideas and data for the study of the mechanism of realgar-induced neurotoxicity.
    Keywords:  Mitochondrial fission; Mitophagy; Neurotoxicity; Realgar; UBXD8-DRP1 pathway
    DOI:  https://doi.org/10.1007/s12035-024-04635-1
  4. J Immunother Cancer. 2024 Nov 20. pii: e008718corr1. [Epub ahead of print]12(11):
    Correction: OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS-STING pathway to mediate GBM immune escape.
      
    DOI:  https://doi.org/10.1136/jitc-2023-008718corr1
  5. Aging Dis. 2024 Nov 18.
    Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles.
    Tongxiao Luan, Song Hu, Weihong Nie, Jia Liu, Li Jia, Shan Wang, Jing Zhou, Nina An, Yuting Duan, Aohua Wang, Mengru Xu, Yongjun Mao.
      Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPRmt). This response is crucial for maintaining protein homeostasis, facilitating mitochondrial function recovery, promoting cell survival, and ultimately influencing lifespan. Striated muscles play a pivotal role in oxygen supply, movement, and metabolism. The aging of these muscles can lead to heart failure, arrhythmias, and sarcopenia, significantly impacting quality of life and lifespan. Given the intimate connection between UPRmt and striated muscle aging, UPRmt emerges as a potential therapeutic target for mitigating the effects of striated muscle aging. In this review, we delve into the role of UPRmt in striated muscle aging, drawing upon the extant molecular regulatory mechanisms of UPRmt. This exploration may enhance our understanding of the underlying mechanisms of striated muscle aging and aid in the identification of potential drug targets.
    DOI:  https://doi.org/10.14336/AD.2024.1019
  6. Int Immunopharmacol. 2024 Nov 21. pii: S1567-5769(24)02186-6. [Epub ahead of print]144 113664
    H3 relaxin ameliorates mitochondrial quality control and apoptosis in cardiomyocytes of type 2 diabetic rats via activation of the AMPK pathway.
    Jingzhi Wang, Kelaier Yang, Chunnan Liu, Fan Wang, Xinfang Liang, Jinfeng Wu, Siting Hong, Xinhua Yin, Xiaohui Zhang.
       PURPOSE: This study aims to explore the protective mechanism of H3 relaxin treatment for type 2 diabetic cardiomyopathy, focusing on its effects on the mitochondrial quality control system and cardiomyocyte apoptosis.
    METHODS: A type 2 diabetes rat model was induced with a high-fat diet and streptozotocin. The treatment group received H3 relaxin for 2 weeks. In cellular studies, H9C2 cardiomyocytes were treated with high glucose and palmitic acid, followed by H3 relaxin, MFN2 lentivirus, and AMPK inhibitor compound C. Mitochondrial quality control, membrane potential, ROS, and apoptosis markers were assessed.
    RESULTS: H3 relaxin improved apoptosis markers, reduced mitochondrial fission (Drp1, Fis1) and mitophagy proteins (parkin, PINK1), and increased mitochondrial fusion proteins (MFN2, OPA1). It restored mitochondrial membrane potential, lowered ROS, and showed anti-apoptotic effects dependent on MFN2. AMPK pathway activation by H3 relaxin was crucial, as compound C largely negated these benefits.
    CONCLUSION: H3 relaxin improves the mitochondrial quality control system and reduces high glucose and palmitic acid-induced apoptosis by upregulating MFN2. This protective effect is achieved through the activation of the AMPK pathway.
    Keywords:  AMPK signalling pathway; Cell apoptosis; Diabetic cardiomyopathy; H3 relaxin; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.intimp.2024.113664
  7. bioRxiv. 2024 Nov 01. pii: 2024.10.30.621201. [Epub ahead of print]
    Deficiency of mitophagy mediator Parkin in aortic smooth muscle cells exacerbates abdominal aortic aneurysm.
    Hui Wang, Mattew Kazaleh, Rachel Gioscia-Ryan, Jessica Millar, Gerard Temprano-Sagrera, Sherri Wood, Fran Van Den Bergh, Muriel G Blin, Kathleen M Wragg, Adrian Luna, Robert B Hawkins, Scott A Soleimanpour, Maria Sabater-Lleal, Chang Shu, Daniel A Beard, Gorav Ailawadi, Jane C Deng, Daniel R Goldstein, Morgan Salmon.
      Abdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.
    DOI:  https://doi.org/10.1101/2024.10.30.621201
  8. Inhal Toxicol. 2024 Nov 20. 1-10
    GRP78 mediates mitochondrial fusion and fission in cigarette smoke-induced inflammatory responses in airway epithelial cells.
    Yong Wang, Ya-Jing Li, Chen-Chen Li, Li Pu, Wan-Li Geng, Fei Gao, Qing Zhang.
       OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation, with cigarette smoke being a major contributor to epithelial injury. Recent studies have shown that abnormal mitochondrial function is closely linked to the onset and progression of airway inflammation. This study aims to explore the role and underlying molecular mechanisms of mitochondrial dynamics in cigarette smoke-induced airway inflammation.
    MATERIALS AND METHODS: Human bronchial epithelial (HBE) cells were exposed to cigarette smoke extract (CSE) to assess the expression of mitochondrial fusion markers MFN2 and OPA1, the fission marker DRP1, and the glucose-regulated protein GRP78. The siRNA and pharmaceutics targeting DRP1, MFN2, and GRP78 were employed. Both cells and supernatants were analyzed for inflammatory factor levels and the related signaling pathways.
    RESULTS: In this study, HBE cells exposed to CSE showed a significant decrease in the proteins MFN2 and OPA1 and an increase in DRP1. The inhibition of DRP1 expression mitigated inflammation while silencing MFN2 exacerbated it. This was similarly corroborated by the use of the DRP1 inhibitor mdivi-1 and the MFN2 activator leflunomide. Additionally, we proved that GRP78 played an important regulatory role as an essential endoplasmic reticulum protein, regulating the mitochondrial fusion/fission process and subsequently activating the NF-κB pathway to regulate airway inflammation.
    DISCUSSION AND CONCLUSION: Taken together, these results suggested that the GRP78-mediated mitochondrial fusion and fission process played a vital role in cigarette smoke-induced airway inflammation and might be a potential therapeutic target in this regard.
    Keywords:  GRP78; Mitochondrial function; airway epithelial; airway inflammation; mitochondrial fusion and fission
    DOI:  https://doi.org/10.1080/08958378.2024.2428163
  9. Cell Signal. 2024 Nov 20. pii: S0898-6568(24)00493-5. [Epub ahead of print] 111518
    Sestrin2 balances mitophagy and apoptosis through the PINK1-Parkin pathway to attenuate severe acute pancreatitis.
    Yuxi Yang, Yiqiu Peng, Yingying Li, Tingjuan Shi, Ning Xu, Yingyi Luan, Chenghong Yin.
      Mitophagy serves as a mitochondrial quality control mechanism to maintain the homeostasis of mitochondria and the intracellular environment. Studies have shown that there is a close relationship between mitophagy and apoptosis. Sestrin2 (Sesn2) is a highly conserved class of stress-inducible proteins that play important roles in reducing oxidative stress damage, inflammation, and apoptosis. However, the potential mechanism of how Sesn2 regulates mitophagy and apoptosis in severe acute pancreatitis (SAP) remains unclear. In the study, RAW264.7 (macrophage cell Line) cellular inflammation model established by lipopolysaccharide (LPS) treatment as well as LPS and CAE-induced SAP mouse model (wild-type and Sen2 Knockout mouse) were used. Our study showed that LPS stimulation significantly increased the level of Sesn2 in RAW264.7 cells, Sesn2 increased mitochondrial membrane potential, decreased inflammation levels, mitochondrial superoxide levels and apoptosis, and also promoted monocyte macrophages toward the M2 anti-inflammatory phenotype, suggesting a protective effect of Sesn2 on mitochondria. Further, Sesn2 increased mitophagy and decreased apoptosis via modulating the PINK1-Parkin signaling. Meanwhile, knockout of Sesn2 exacerbated pancreatic, mitochondrial damage and inflammation in a mouse model of SAP. In addition, the protective effect of Sesn2 against SAP was shown to be associated with mitophagy conducted by the PINK1-Parkin pathway via inhibiting apoptosis. These findings reveal that Sesn2 in balancing mitochondrial autophagy and apoptosis by modulating the PINK1-Parkin signaling may present a new therapeutic strategy for the treatment of SAP.
    Keywords:  apoptosis; mitophagy; monocyte macrophage; sestrin2; severe acute pancreatitis
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111518
  10. Ecotoxicol Environ Saf. 2024 Nov 18. pii: S0147-6513(24)01414-3. [Epub ahead of print]288 117338
    Mdivi-1 alleviates nicotine-induced human periodontal ligament cells injury by inhibiting mitochondrial fission and dysfunction through the JNK/Drp1 pathway.
    Leihua Cui, Meiqiao Chen, Yihong Jin, Huining Wang, Hou Yubo.
       BACKGROUND: Nicotine, a major component of tobacco, is implicated in the pathogenesis of periodontitis. However, the exact mechanisms through which nicotine exerts its harmful effects remain incompletely understood. This study investigates the impact of nicotine-induced mitochondrial fission on human periodontal ligament cells (hPDLCs).
    METHODS: A range of assays, including MTT, immunofluorescence staining, flow cytometry, and western blotting, were utilized to evaluate hPDLC viability, apoptosis, mitochondrial fission, and function.
    RESULTS: Nicotine decreases hPDLC viability in a dose-dependent manner, leading to apoptosis, an elevated BAX/BCL-2 ratio, and cellular injury. Furthermore, nicotine induces phosphorylation of Drp1 at Ser616, which facilitates mitochondrial fission, elevates mitochondrial ROS production, reduces mitochondrial membrane potential, and lowers ATP generation, resulting in mitochondrial dysfunction. Inhibition of Drp1 phosphorylation by Mdivi-1 significantly alleviates mitochondrial fission and dysfunction, reduces nicotine-induced apoptosis, and promotes osteogenic differentiation.
    CONCLUSION: Nicotine activates c-Jun N-terminal kinase (JNK), and the inhibition of JNK activity with SP600125 effectively prevents nicotine-induced mitochondrial fission, enhances cell viability, and inhibits Drp1 phosphorylation.
    Keywords:  Apoptosis; C‑Jun N‑terminal kinase; Human periodontal ligament cells; Mitochondrial fission; Nicotine; Periodontitis; Smoking
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117338
  11. PLoS One. 2024 ;19(11): e0310394
    Cardiac effects of OPA1 protein promotion in a transgenic animal model.
    Kitti Bruszt, Orsolya Horvath, Katalin Ordog, Szilard Toth, Kata Juhasz, Eszter Vamos, Katalin Fekete, Ferenc Gallyas, Kalman Toth, Robert Halmosi, Laszlo Deres.
      Mitochondria form a dynamic network in cells, regulated by the balance between mitochondrial fusion and fission. The inhibition of mitochondrial fission can have positive effects in acute ischemic/reperfusion injury models by preventing the fall in mitochondrial membrane potential associated with fission processes. However, inhibition of fission in chronic models is disadvantageous because it obstructs the elimination of damaged mitochondrial fragments. OPA1, in view of previous results, is a possible therapeutic target as a fusion promoter and structure stabilizer protein. We used transgenic mice in which the OMA1 cleavage sites of OPA1 were deleted. This resulted in a higher representation of L-OPA1 compared to S-OPA1. After genotyping and model validation, all animals were examined by echocardiograph on two occasions, at weeks 11 and 36. Histological samples were taken from hearts to examine mitochondrial morphology and structure remodeling. The signaling pathways related to mitochondrial dynamic processes were evaluated. Cardiomyocytes were isolated from neonatal mice to determine the efficiency of mitochondrial respiration using the SeaHorse assay method. OPA1 protein promotion has a negative effect on systolic function during aging. We confirmed that volume overload and ventricular remodeling did not manifest. The reason behind the loss of pump function might be, at least partly, due to the energy deficit caused by mitochondrial respiratory failure and damage in mitochondrial quality control pathways.
    DOI:  https://doi.org/10.1371/journal.pone.0310394
  12. J Inflamm Res. 2024 ;17 8905-8919
    Diltiazem Hydrochloride Protects Against Myocardial Ischemia/Reperfusion Injury in a BNIP3L/NIX-Mediated Mitophagy Manner.
    Xing Zhou, Quan Lu, Qiu Wang, Wenxin Chu, Jianhao Huang, Jinming Yu, Yuechou Nong, Wensheng Lu.
       Background: Mitochondrial calcium uptake-induced mitophagy may play an essential role in myocardial ischemia/reperfusion (MI/R) injury. Diltiazem hydrochloride (DIL), a traditional calcium channel blocker, can alleviate MI/R injury by blocking calcium overload. However, whether the protective mechanism of DIL involves mitophagy remains elusive. This study aimed to clarify the underlying molecular mechanism by which DIL ameliorates MI/R injury by downregulating mitophagy in vivo and in vitro.
    Methods: Thirty rats were randomized into three groups: the sham, MI/R, and MI/R+DIL (1 mg/kg) groups (n = 10/per group). MI/R injury was induced by ligating the left anterior descending (LAD) artery for 30 min followed by 60 min of reperfusion in vivo. H9C2 cells were selected to establish an oxygen-glucose deprivation/recovery (OGD/R) model to simulate MI/R injury in vitro. The potential mechanism by which DIL alleviates MI/R injury was analyzed based on tissue morphology, mitophagy-related gene transcription, and protein expression.
    Results: According to histological and immunohistochemical evaluations, DIL significantly alleviated myocardial damage in vivo. Moreover, DIL significantly increased cell viability, attenuated OGD/R-induced apoptosis, and inhibited mitochondrial autophagy in vitro. Mechanistically, DIL attenuated mitochondrial autophagy through the upregulation of dual-specificity protein phosphatase 1 (DUSP1) and the downregulation of c-Jun N-terminal kinase (JNK) and Bcl2 interacting protein 3-like (BNIP3L, also known as NIX) expression.
    Conclusion: Diltiazem hydrochloride protects against myocardial ischemia/reperfusion injury in a BNIP3L/NIX-mediated mitophagy manner in vivo and in vitro.
    Keywords:  calcium channel blockers; diltiazem hydrochloride; mitophagy; myocardial infarction; myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.2147/JIR.S493037
  13. Mol Biotechnol. 2024 Nov 16.
    Intermittent Hypoxia Impairs Cognitive Function and Promotes Mitophagy and Lysophagy in Obstructive Sleep Apnea-Hypopnea Syndrome Rat Model.
    Jizu Ling, BoWen Li, XinHui Yuan, WenKai Yang, KeYang Sun.
      Autophagy regulates intermittent hypoxia (IH)-induced obstructive sleep apnea-hypopnea syndrome (OSAHS). We investigated the effects of IH and its withdrawal on cognitive function, autophagy, and lysophagy in OSAHS. An OSAHS rat model was established, and rats were divided into five groups: normoxia control, IH-4w (4-week IH), IH-6w (6-week IH), IH-8w (8-week IH), and IH-8w + 4w (8-week IH and 4-week normoxia). The cognitive behavior; mitochondrial and lysosomal morphology of the hippocampal tissue; mitochondrial respiratory function, permeability, and membrane potential; lysosomal function; autophagy- and lysophagy-related protein levels; and hypoxia-associated autophagy gene expression in rats were assessed. The cognitive function of rats in the IH-4w, IH-6w, and IH-8w groups was significantly impaired. In IH-8w cells, mitochondrial function was damaged with swollen morphology and decreased quantity, respiration, permeability, and membrane potential, along with significantly increased mitophagy-related protein ATG5 and LC3II/LC3 levels and decreased p62 levels. Expression of hypoxia-associated autophagy genes Becn1, Hif1, Bnip3, Bnip3l, and Fundc1 was significantly higher in the IH-8w group. Significantly increased LAMP2, CTSB, and ACP2 levels in IH-8w cells further indicated impaired lysosomal function. Lysophagy-related protein LAMP1, LC3II/LC3I, and TFEB levels were significantly increased in the IH-8w group, whereas p62 level was significantly decreased. The above listed evidence indicated damage to the mitochondria and lysosomes, as well as stimulation of mitophagy and lysophagy in IH-treatment OSAHS rat model. After withdrawing IH and culturing for 4 weeks in normal conditions, the cognitive function of rats improved, and mitophagy and lysophagy decreased. Our findings indicate that IH impairs cognitive function and promotes mitophagy and lysophagy in an OSAHS rat model, and IH withdrawal recovered the above effects.
    Keywords:  Cognitive function; Hippocampus; Lysophagy; Mitophagy; Obstructive sleep apnea–hypopnea syndrome
    DOI:  https://doi.org/10.1007/s12033-024-01319-y
  14. Mol Cell Biol. 2024 Nov 18. 1-16
    SIRT3 Deficiency Promotes Lung Endothelial Pyroptosis Through Impairing Mitophagy to Activate NLRP3 Inflammasome During Sepsis-Induced Acute Lung Injury.
    Congmin Yan, Xin Lin, Jingting Guan, Wengang Ding, Ziyong Yue, Zhiqiang Tang, Xiangqi Meng, Bo Zhao, Zhiqiang Song, Dongmei Li, Tao Jiang.
      Acute lung injury (ALI) is a major cause of death in bacterial sepsis due to endothelial inflammation and endothelial permeability defects. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of sepsis-induced ALI. Sirtuin 3 (SIRT3) is a histone protein deacetylase involved in preservation of mitochondrial function, which has been demonstrated in our previous study. Here, we investigated the effects of SIRT3 deficiency on impaired mitophagy to promote lung endothelial cells (ECs) pyroptosis during sepsis-induced ALI. We found that 3-TYP aggravated sepsis-induced ALI with increased lung ECs pyroptosis and enhanced NLRP3 activation. Mitochondrial reactive oxygen species (mtROS) and extracellular mitochondrial DNA (mtDNA) released from damaged mitochondria could be exacerbated in SIRT3 deficiency, which further elicit NLRP3 inflammasome activation in lung ECs during sepsis-induced ALI. Furthermore, Knockdown of SIRT3 contributed to impaired mitophagy via downregulating Parkin, which resulted in mitochondrial dysfunction. Moreover, pharmacological inhibition NLRP3 or restoration of SIRT3 attenuates sepsis-induced ALI and sepsis severity in vivo. Taken together, our results demonstrated SIRT3 deficiency facilitated mtROS production and cytosolic release of mtDNA by impaired Parkin-dependent mitophagy, promoting to lung ECs pyroptosis through the NLRP3 inflammasome activation, which providing potential therapeutic targets for sepsis-induced ALI.
    Keywords:  Acute lung injury; SIRT3; mitophagy; pyroptosis; sepsis
    DOI:  https://doi.org/10.1080/10985549.2024.2426282
  15. Food Chem Toxicol. 2024 Nov 19. pii: S0278-6915(24)00688-4. [Epub ahead of print] 115122
    Melatonin protects porcine oocytes from gossypol-induced meiosis defects via regulation of SIRT1-mediated mitophagy.
    Xiaoli Su, Yijing He, Heran Li, Tianhang Yu, Qinfeng Sun, Miaoyu Chen, Biao Zhang, Weihan Wang, Shiqiang Ju, Qiao Li.
      Cottonseed meal (CSM) is an ideal source of protein feed ingredients. However, the gossypol contained in it has toxic effects on animals, limiting its use in livestock production. The underlying mechanisms remain largely unknown. This study aimed to investigate the adverse effects of gossypol exposure and assess whether melatonin, a natural antioxidant, could alleviate oocyte damage induced by gossypol. Porcine cumulus oocyte complexes (COCs) were treated with gossypol alone or co-treated with melatonin for 44 h during in vitro maturation. The results demonstrated that gossypol exposure induced oxidative stress and mitochondrial dysfunction, leading to oocyte maturation failure. Conversely, melatonin co-treatment mitigated these detrimental effects, by promoting oocyte mitophagy, as evidenced by the upregulation of PINK1, Parkin, and LC3 expressions, along with the downregulation of P62. Further investigation revealed that gossypol treatment significantly decreased SIRT1 protein expression, while melatonin co-treatment markedly increased it. Using the SIRT1 inhibitor Ex527 confirmed that melatonin enhances mitophagy through SIRT1, improving mitochondrial function and rescuing oocyte maturation. This study revealed the potential harm of gossypol on mammalian reproductive health, provided experimental reference for the protective effect of melatonin, and provided theoretical basis for the effective prevention and treatment of reproductive damage caused by gossypol.
    Keywords:  Gossypol; Melatonin; Mitophagy; Porcine oocytes; SIRT1
    DOI:  https://doi.org/10.1016/j.fct.2024.115122
  16. Biol Rev Camb Philos Soc. 2024 Nov 18.
    Bringing together but staying apart: decisive differences in animal and fungal mitochondrial inner membrane fusion.
    Hassan Hashimi, Ondřej Gahura, Tomáš Pánek.
      Mitochondria are dynamic and plastic, undergoing continuous fission and fusion and rearrangement of their bioenergetic sub-compartments called cristae. These fascinating processes are best understood in animal and fungal models, which are taxonomically grouped together in the expansive Opisthokonta supergroup. In opisthokonts, crista remodelling and inner membrane fusion are linked by dynamin-related proteins (DRPs). Animal Opa1 (optical atrophy 1) and fungal Mgm1 (mitochondrial genome maintenance 1) are tacitly considered orthologs because their similar mitochondria-shaping roles are mediated by seemingly shared biochemical properties, and due to their presence in the two major opisthokontan subdivisions, Holozoa and Holomycota, respectively. However, molecular phylogenetics challenges this notion, suggesting that Opa1 and Mgm1 likely had separate, albeit convergent, evolutionary paths. Herein, we illuminate disparities in proteolytic processing, structure, and interaction network that may have bestowed on Opa1 and Mgm1 distinct mechanisms of membrane remodelling. A key disparity is that, unlike Mgm1, Opa1 directly recruits the mitochondrial phospholipid cardiolipin to remodel membranes. The differences outlined herein between the two DRPs could have broader impacts on mitochondrial morphogenesis. Outer and inner membrane fusion are autonomous in animals, which may have freed Opa1 to repurpose its intrinsic activity to remodel cristae, thereby regulating the formation of respiratory chain supercomplexes. More significantly, Opa1-mediated crista remodelling has emerged as an integral part of cytochrome c-regulated apoptosis in vertebrates, and perhaps in the cenancestor of animals. By contrast, outer and inner membrane fusion are coupled in budding yeast. Consequently, Mgm1 membrane-fusion activity is inextricable from its role in the biogenesis of fungal lamellar cristae. These disparate mitochondrial DRPs ultimately may have contributed to the different modes of multicellularity that have evolved within Opisthokonta.
    Keywords:  Mgm1; Opa1; apoptosis; cristae; dynamin‐related protein; membrane remodelling; mitochondrial dynamics; phylogeny
    DOI:  https://doi.org/10.1111/brv.13168
  17. bioRxiv. 2024 Oct 31. pii: 2024.10.30.621097. [Epub ahead of print]
    Sex and Region-Specific Disruption of Autophagy and Mitophagy in Alzheimer's Disease: Linking Cellular Dysfunction to Cognitive Decline.
    Aida Adlimoghaddam, Fariba Fayazbakhsh, Mohsen Mohammadi, Zeinab Babaei, Amir Barzegar Behrooz, Farhad Tabasi, Teng Guan, Iman Beheshti, Mahmoud Aghaei, Daniel J Klionsky, Benedict C Albensi, Saeid Ghavami.
      Macroautophagy and mitophagy are critical processes in Alzheimer's disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagy (LC3B-II, SQSTM1) and mitophagy (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement). Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects. Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research.
    Abstract Figure:
    DOI:  https://doi.org/10.1101/2024.10.30.621097
  18. Bull Exp Biol Med. 2024 Nov 22.
    Kainate-Induced Reorganization the Dentate Gyrus of the Hippocampus Is Accompanied by Activation of Mitochondrial Fission in the Granular Layer Neurons.
    D N Voronkov, A V Egorova, E N Fedorova, M S Ryabova, A K Pavlova, A V Stavrovskaya, V S Sukhorukov.
      The reorganization of the dentate gyrus of the hippocampus and changes in mitochondrial fission were evaluated using the kainate model of temporal lobe epilepsy. In 28 days after administration of 0.5 μg kainic acid, disturbances in the distribution of neuronal precursors in the subgranular zone of the hippocampus, thickening of the granular layer, and an increase in the content of synaptophysin in the molecular layer were detected. The observed changes were accompanied by an increase in the content of mitochondrial fission regulator protein Drp1 (dynamin related protein) and modification of the mitochondrial network in granular neurons of the dentate gyrus. These observations indicate a significant role of Drp1 in pathological rearrangements of the hippocampus during epileptogenesis and allow considering it as a potential target for pharmacological agents.
    Keywords:  kainic acid; hippocampal sclerosis; mitochondrial fission; Drp1
    DOI:  https://doi.org/10.1007/s10517-024-06289-4
  19. Brain Res. 2024 Nov 18. pii: S0006-8993(24)00596-1. [Epub ahead of print] 149341
    Nrf2 activator tertiary butylhydroquinone enhances neural stem cell differentiation and implantation in Alzheimer's disease by boosting mitochondrial function.
    Long Lin, Jiameng Li, Zhengtao Yu, Jun He, You Li, Junwen Jiang, Ying Xia.
       AIMS: To investigate the effects of Nrf2 agonist tertiary butylhydroquinone (TBHQ)-stimulated neural stem cells (NSCs) transplantation (NSC(TBHQ)) on neuronal damage and cognitive deficits in an AD model and its underlying principles.
    METHODS: BHQ-treated NSCs were examined with or without Aβ1-42 to investigate the effects of TBHQ on the proliferation and differentiation functions. The mitophagy inhibitor Cyclosporine A (CSA) was used to explore the regulation of mitophagy by TBHQ. The no-, ethanol-, and TBHQ-treated NSCs were transplanted into the bilateral hippocampal region of model mice to explore the effects of NSC(TBHQ) on neuronal, cognitive, and mitochondrial functional impairments in mice.
    RESULTS: TBHQ reversed the Aβ1-42-caused inhibition on NSC proliferation and differentiation, as well as on levels of mitochondrial membrane potential, adenosine triphosphate (ATP), and mitochondrial fusion-associated proteins. TBHQ alleviated the Aβ1-42-induced increase in apoptosis, mitochondrial damage, mitochondria-derived reactive oxygen species (mtROS), and mitochondrial fission-related proteins. TBHQ activated the Parkin, Beclin, LC3II/I, and COXIV expression, while inhibiting the p62 expression. CSA reversed the effects of TBHQ on NSC proliferation and differentiation. After NSC(TBHQ) transplantation, it not only further extended the dwell time in the target quadrant and shorten the time and distance for finding the hidden platform, but also further decreased the Aβ and p-Tau/Tau levels, while increasing the expression of NeuN. The effects of NSC(TBHQ) transplantation on mitochondrial function were consistent with the in vitro experiments.
    CONCLUSIONS: The study shows that NSC(TBHQ) intensifies the beneficial impact of NSCs transplantation on cognitive impairment and neuronal damage in AD models, likely due to TBHQ's role in promoting NSCs growth and differentiation via mitophagy, thus laying a theoretical foundation for improving NSCs transplantation for AD.
    Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Neural stem cells; Nrf2; TBHQ
    DOI:  https://doi.org/10.1016/j.brainres.2024.149341
  20. J Adv Res. 2024 Nov 14. pii: S2090-1232(24)00471-5. [Epub ahead of print]
    Astragaloside IV alleviates septic myocardial injury through DUSP1-Prohibitin 2 mediated mitochondrial quality control and ER-autophagy.
    Junyan Wang, Xiangyi Pu, Haowen Zhuang, Zhijiang Guo, Mengyuan Wang, Huaihong Yang, Chun Li, Xing Chang.
       INTRODUCTION: Septic cardiomyopathy (SCM) is a complication of myocardial injury in patients with severe sepsis.
    OBJECTIVES: This study highlights the potential of Astragaloside IV(AS) in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2-related mitochondria-ER interaction.
    METHODS: Dual specificity phosphatase-1 (DUSP1)/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) /DUSP1 transgenic mice (DUSP1/PHB2TG) were used to generate LPS-induced sepsis models. The pathological mechanism by which AS-IV improves heart injury was detected using cardiac ultrasound, fluorescence staining, transmission electron microscopy, and western blotting. After siRNA treatment of cardiomyocytes with DUSP-1/PHB2, changes in mitochondrial function and morphology were determined using qPCR, western blotting, ELISA, and laser confocal microscopy, and the targeted therapeutic effects of AS-IV were further examined.
    RESULTS: SCM treatment leads to severe mitochondrial dysfunction. However, Astragaloside IV (AS) treatment normalizes mitochondrial homeostasis and ER function. Notably, the protective effect was blocked in DUSP1/Prohibitin 2 cardiomyocyte-specific knockout mice (DUSP1/PHB2CKO) but remained unaffected in DUSP1 transgenic mice (DUSP1/PHB2TG).
    CONCLUSION: This study highlights the potential of AS in the treatment of septic cardiomyopathy and provides a reference for developing cardioprotective drugs targeting DUSP1-PHB2 related mitochondria-ER interaction.
    Keywords:  DUSP1; ER autophagy；Astragaloside IV; Mitochondrial quality control; PHB2; Septic myocardial injury
    DOI:  https://doi.org/10.1016/j.jare.2024.10.030
  21. PLoS Comput Biol. 2024 Nov 18. 20(11): e1012596
    A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission.
    Anna K Leinheiser, Colleen C Mitchell, Ethan Rooke, Stefan Strack, Chad E Grueter.
      Mitochondrial hyperfission in response to cellular insult is associated with reduced energy production and programmed cell death. Thus, there is a critical need to understand the molecular mechanisms coordinating and regulating the complex process of mitochondrial fission. We develop a nonlinear dynamical systems model of dynamin related protein one (Drp1)-dependent mitochondrial fission and use it to identify parameters which can regulate the total fission rate (TFR) as a function of time. The TFR defined from a nondimensionalization of the model undergoes a Hopf bifurcation with bifurcation parameter [Formula: see text] where [Formula: see text] is the total concentration of mitochondrial fission factor (Mff) and k+ and k- are the association and dissociation rate constants between oligomers on the outer mitochondrial membrane. The variable μ can be thought of as the maximum build rate over the disassembling rate of oligomers. Though the nondimensionalization of the system results in four dimensionless parameters, we found the TFR and the cumulative total fission (TF) depend strongly on only one, μ. Interestingly, the cumulative TF does not monotonically increase as μ increases. Instead it increases with μ to a certain point and then begins to decrease as μ continues to increase. This non-monotone dependence on μ suggests interventions targeting k+, k-, or [Formula: see text] may have a non-intuitive impact on the fission mechanism. Thus understanding the impact of regulatory parameters, such as μ, may assist future therapeutic target selection.
    DOI:  https://doi.org/10.1371/journal.pcbi.1012596
  22. iScience. 2024 Nov 15. 27(11): 111042
    Irisin reduces senile osteoporosis by inducing osteocyte mitophagy through Ampk activation.
    Honghan Li, Deqing Luo, Wei Xie, Wenbin Ye, Jinlong Chen, Paolo Alberton, Mingzhu Zhang, Eryou Feng, Denitsa Docheva, Dasheng Lin.
      Irisin, an exercise-induced myokine, is known to be able to regulate bone metabolism. However, the underlying mechanisms regarding the effects of irisin on senile osteoporosis have not been fully elucidated. Here, we demonstrated that irisin can inhibit bone mass loss and bone microarchitecture alteration in senile osteoporosis mouse model. In addition, irisin has effects on bone remodeling that is in favor of bone formation. Remarkably, irisin induced autophagy in osteocytes demonstrated by increased LC3-positive osteocytes, and increased autophagy-related genes and proteins. In vitro analysis revealed that Irisin can prevent mitochondrial oxidative damage. Furthermore, irisin can obviously induce osteocyte mitophagy and increased phosphorylation of Ampk and Ulk1. Inhibition of Ampk signaling recapitulated the biological effect of irisin loss, accompanied by the markedly lower expression of Ulk1. Taken together, our findings show that irisin reduces age-related bone loss by inducing osteocyte mitophagy via Ampk-dependent activation of Ulk1.
    Keywords:  Biological sciences; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.111042
  23. Metab Brain Dis. 2024 Nov 19. 40(1): 14
    Electroacupuncture improves diabetic cognitive impairment rats by suppressing NLRP3 inflammasome activation via induction of mitophagy.
    Xia Ge, Lele Zhang, Min Ye, Aihua Fei, Ling Wang, Aihong Yuan.
      Diabetic cognitive impairment pose a significant threat to public health in our aging society. However, the underlying molecular mechanisms have not been fully elucidated, which warrants further investigation. This study aimed to investigate the effects of electroacupuncture on cognitive impairment and its associated mechanisms. The diabetes model was induced via intraperitoneal injection of streptozotocin (STZ) into Sprague-Dawley rats combined with a high-fat and high-sugar diet. The learning and memory abilities of the rats were assessed using behavioral tests. Electron microscopy and hematoxylin-eosin (H&E) staining were used to identify the histological changes of neurons in the CA1 area of the rat hippocampal CA1. An examination of related indicators was performed by Western blotting including NLRP3 inflammasome-associated proteins Caspase-1, IL-18, IL1β, NLRP3, and P62, and mitophagy-related proteins Pink1, LC3, and Parkin. After modeling, rats displayed impaired learning and memory functions. The administration of electroacupuncture treatment alleviated diabetic cognitive impairment, described as shorter escape latency and an increased frequency of platform crossings. The damaged morphological and ultrastructural changes of neurons in rat hippocampal CA1 area can be alleviated through electroacupuncture treatment. Furthermore, in-depth studies suggest that electroacupuncture treatment can suppress NLRP3 inflammasome activation through induction of Pink1, LC3 and Parkin expression. Electroacupuncture treatment can attenuate NLRP3 inflammasome activation by promoting mitophagy, eventually improving cognitive impairment in (STZ)-treated rats with a high-fat die.
    Keywords:  Diabetic cognitive impairment; Electroacupuncture; Mitophagy; NLRP3 inflammasome activation
    DOI:  https://doi.org/10.1007/s11011-024-01464-y
  24. Am J Physiol Heart Circ Physiol. 2024 Nov 19.
    Impaired endothelial function contributes to cardiac dysfunction - role of mitochondrial dynamics.
    Cristhian A Gutierrez-Huerta, Giovanni Quiroz-Delfi, Fathima Dhilhani Mohammed Faleel, Andreas Beyer.
      The endothelial microvasculature is essential for the regulation of vasodilation and vasoconstriction, and improved functioning of the endothelium is linked to improved outcomes for individuals with coronary artery disease (CAD). People with endothelial dysfunction exhibit a loss of NO-mediated vasodilation, achieving vasodilation instead through mitochondria-derived H2O2. Mitochondrial dynamics is an important autoregulatory mechanism that contributes to mitochondrial and endothelial homeostasis and plays a role in formation of reactive oxygen species (ROS), including H2O2. Dysregulation of mitochondrial dynamics leads to increased ROS production, decreased ATP production, impaired metabolism, activation of pathological signal transduction, impaired calcium sensing, and inflammation. We hypothesize that dysregulation of endothelial mitochondrial dynamics plays a crucial role in the endothelial microvascular dysfunction seen in individuals with CAD. Therefore, proper regulation of endothelial mitochondrial dynamics may be a suitable treatment for individuals with endothelial microvascular dysfunction and we furthermore postulate that improving this microvascular dysfunction will directly improve outcomes for those with CAD.
    Keywords:  endothelial cell biology; endothelial microvasculature; microcirculation; mitochondrial dynamics
    DOI:  https://doi.org/10.1152/ajpheart.00531.2024
  25. Adv Sci (Weinh). 2024 Nov 18. e2404107
    WAC Facilitates Mitophagy-mediated MSC Osteogenesis and New Bone Formation via Protecting PINK1 from Ubiquitination-Dependent Degradation.
    Shuai Fan, Jinteng Li, Guan Zheng, Ziyue Ma, Xiaoshuai Peng, Zhongyu Xie, Wenjie Liu, Wenhui Yu, Jiajie Lin, Zepeng Su, Peitao Xu, Peng Wang, Yanfeng Wu, Huiyong Shen, Guiwen Ye.
      Osteogenic differentiation of mesenchymal stem cells (MSCs) plays a pivotal role in the pathogenesis and treatment of bone-related conditions such as osteoporosis and bone regeneration. While the WW domain-containing coiled-coil adaptor (WAC) protein is primarily associated with transcriptional regulation and autophagy, its involvement in MSC osteogenesis remains unclear. Here, the data reveal that the levels of WAC are diminished in both osteoporosis patients and osteoporosis mouse models. It plays a pivotal function in facilitating MSC osteogenesis and enhancing new bone formation both in vitro and in vivo. Mechanistically, WAC promotes MSC osteogenesis by protecting PINK1, a crucial initiator of mitophagy, from ubiquitination-dependent degradation thereby activating mitophagy. Interestingly, WAC interacts with the TM domains of PINK1 and prevents the K137 site from ubiquitination modification. The study elucidates the mechanism by which WAC modulates MSC osteogenesis, binds to PINK1 to protect it from ubiquitination, and identifies potential therapeutic targets for osteoporosis and bone defect repair.
    Keywords:  PINK1; WAC; mesenchymal stem cell; mitophagy; osteogenesis
    DOI:  https://doi.org/10.1002/advs.202404107
  26. bioRxiv. 2024 Oct 31. pii: 2024.10.30.621078. [Epub ahead of print]
    A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.
    Rajesh Angireddy, Bhanu Chandra Karisetty, Kaitlin A Katsura, Abdias Díaz, Svathi Murali, Sarina Smith, Laura Ohl, Kelly Clark, Andrew V Kossenkov, Elizabeth J K Bhoj.
       Background and Objectives: TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the TBCK gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies.
    Methods: We employed a human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons and astrocytes, to understand the role of TBCK in mTORC1 activity and neuronal autophagy and cellular mechanisms of pathology. We used shRNA technology to knockdown TBCK in ReNcells.
    Results: These data showed that loss of TBCK did not inhibit mTORC1 activity in neither NPC nor neurons. Additionally, analysis of eight patient-derived cells and TBCK knock down HeLa cells showed that mTORC1 inhibition is inconsistent across different patients and cell types. We showed that TBCK knockdown in ReNcells affected NPC differentiation to neurons and astrocytes. Specifically, differentiation defects are coupled to cell cycle defects in NPC and increased cell death during differentiation. RNAseq analysis indicated the downregulation of several different neurodevelopmental and differentiation pathways. We observed a higher number of LC3-positive vesicles in the soma and neurites of TBCK knockdown cells. Further, TBCK knockdown altered mitochondrial dynamics and membrane potential in NPC, neurons and astrocytes. We found partial mitochondrial rescue with the mitochondrial fission inhibitor mdivi- 1.
    Discussion: This work outlines a new Human Cell Model for TBCK-related neurodegeneration and the essential role of mitochondrial health and partial rescue with mitochondrial fission inhibitor. This data, along with human neurons and astrocytes, illuminate mechanisms of neurodegeneration and provide a possible novel therapeutic avenue for affected patients.
    DOI:  https://doi.org/10.1101/2024.10.30.621078
  27. Environ Pollut. 2024 Nov 17. pii: S0269-7491(24)02038-4. [Epub ahead of print]364(Pt 2): 125321
    Microplastics accumulated in breast cancer patients lead to mitophagy via ANXA2-mediated endocytosis and IL-17 signaling pathway.
    Ziying Tian, Boni Ding, Yilin Guo, Jieyu Zhou, Su Jiang, Jiaxue Lu, Nan Li, Xiao Zhou, Wenling Zhang.
      Breast cancer (BC) is the most common malignancy in women and the leading cause of cancer death. Microplastics (MPs) are plastic fragments with a diameter of less than 5 mm, easily ingested by organisms. Although MPs have been reported to enter the human body through diet, surgery, etc., whether MPs accumulate in BC and their effects have been largely unknown. Our study revealed a significant accumulation of MPs in BC patient samples. MPs pull-down experiments and mass spectrometry (MS) studies showed that MPs bound to annexin A2 (ANXA2) and were endocytosed into cells. This process resulted in mitochondrial damage and subsequent induction of mitophagy. Furthermore, after binding to ANXA2, MPs regulated mitophagy by inhibiting IL-17 exocytosis. These findings revealed the mechanism of toxic effects of MPs in patients with BC, clarified the molecular mechanism of ANXA2-IL-17 signaling pathway causing mitochondrial damage by MPs, and suggested the potential toxic effects and toxicological mechanisms of MPs.
    Keywords:  ANXA2; Breast cancer; IL-17 signaling pathway; Microplastics; Mitophagy
    DOI:  https://doi.org/10.1016/j.envpol.2024.125321
  28. FASEB J. 2024 Nov 30. 38(22): e70178
    Non-lethal sonodynamic therapy inhibits high glucose and palmitate-induced macrophage inflammasome activation through mtROS-DRP1-mitophagy pathway.
    Jiayu Wang, Yicheng Shen, Heyu Chen, Jinwei Guan, Zhitao Li, Xianna Liu, Shuyuan Guo, Linxin Wang, Baoyue Yan, Chenrun Jin, He Li, Tian Guo, Yun Sun, Weihua Zhang, Zhiguo Zhang, Ye Tian, Zhen Tian.
      Obesity plays a crucial role in the development and progression of type 2 diabetes mellitus (T2DM) by causing excessive release of free fatty acid from adipose tissue, which in turn leads to systemic infiltration of macrophages. In individuals with T2DM, the infiltration of macrophages into pancreatic islets results in islet inflammation that impairs beta cell function, as evidenced by increased apoptosis and decreased glucose-stimulated insulin secretion. The present study aimed to investigate the effects of non-lethal sonodynamic therapy (NL-SDT) on bone marrow-derived macrophages (BMDMs) exposed to high glucose and palmitic acid (HG/PA). These findings indicate that NL-SDT facilitates the expression of DRP1 through the transient production of mitochondrial ROS, which subsequently promotes mitophagy. This mitophagy was shown to limit the activation of the NLRP3 inflammasome and the secretion of IL-1β in BMDMs exposed to HG/PA. In co-culture experiments, beta cells exhibited significant dysfunction when interacting with HG/PA-treated BMDMs. However, this dysfunction was markedly alleviated when the BMDMs had undergone NL-SDT treatment. Moreover, NL-SDT was found to lower blood glucose levels and elevate serum insulin concentrations in db/db mice. Furthermore, NL-SDT effectively reduced the infiltration of F4/80-positive macrophages and the expression of CASP1 within islets. These findings provide fundamental insights into the mechanisms through which NL-SDT may serve as a promising approach for the treatment of T2DM.
    Keywords:  beta cell; inflammasome; macrophage; mitochondrial quality control; sonodynamic therapy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1096/fj.202402008R
  29. Sci Total Environ. 2024 Nov 14. pii: S0048-9697(24)07733-7. [Epub ahead of print] 177576
    Exposure to copper and copper-based nanoparticles induces hepatopancreatic mitochondrial dysfunction by triggering mtROS mediated apoptosis and mitophagy in Eriocheir sinensis.
    Xinping Guo, Minghao Shen, Su Jiang, Xiumei Xing, Cong Zhang, Shaowu Yin, Kai Zhang.
      Copper (Cu) is an important metal pollutant commonly found in aquatic environment owing to its inherent bioaccumulation and biomagnification potentials and long-term persistence in environmental compartments. The application of novel fabricated copper nanoparticles (Cu-NPs) has led to cytotoxicity in aquatic animals. However, the differences in underlying toxicity mechanisms between Cu-NPs and waterborne Cu (such as CuSO4) remain unelucidated. Herein, the mechanisms underlying the CuSO4/Cu-NPs-mediated perturbation of the hepatopancreatic mitochondrial function at different concentrations were investigated and compared. After exposing Eriocheir sinensis to 0 (control), 5, 50, and 500 μg/L CuSO4 and 10 μg/L Cu-NPs for 21 days, hepatopancreases were retrieved. The results revealed that Cu-NPs or CuSO4 (50 and 500 μg/L) induced ultrastructural damage following a time-dose effect, as indicated by swelling and degeneration of the lumen of hepatic tubules. Excess CuSO4 or Cu-NPs exposure decreased the antioxidative capacity and led to the over-accumulation of mitochondrial ROS. Moreover, the mitochondrial membrane potential (ΔΨm) was reduced and apoptosis induced. Additionally, both CuSO4 and Cu-NPs increased the numbers of mitophagosomes and the mRNA and protein levels of LC3B, and triggered mitophagy through PRKN-independent pathway; however, mostly the BNIP3L/Beclin1 pathway was involved in excess CuSO4-induced mitophagy. Altogether, this study provides a basis for exploring Cu-mediated potential mitochondrial autophagy activation mechanisms and their effects on environmental toxicity.
    Keywords:  Apoptosis; Cu-NPs; CuSO(4); Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.177576
  30. Basic Clin Pharmacol Toxicol. 2024 Nov 18.
    Long-term taurine supplementation regulates brain mitochondrial dynamics in mice.
    Heresh Rezaei, Hong-Wei Wang, Weishun Tian, Jing Zhao, Asma Najibi, Socorro Retana-Márquez, Elahe Rafiei, Ayeh Rowhanirad, Samira Sabouri, Mohammadreza Kiafar, Rahil Fazlinezhad, Amir Mohammad Niknahad, Fatemeh Evazzadeh, Seyedeh Tayebeh Anousheh, Mohammad Mehdi Ommati, Hossein Niknahad, Reza Heidari.
       BACKGROUND: Taurine (TAU) is the most abundant non-protein amino acid in the central nervous system (CNS). However, the molecular mechanism of TAU in the CNS is still poorly understood. Meanwhile, disruption in mitochondrial dynamics is evident in CNS disorders. This study aimed to investigate the effect of TAU on mitochondrial dynamics.
    METHODS: TAU (0.25, 0.5 and 1% in drinking water) was administered to young mice for six months. Several memory/cognition parameters and indices of anxiety/depression were assessed. Meanwhile, various mitochondrial indices and the expression/activity of genes involved in mitochondrial biogenesis and dynamics (Akt, CREB, NRF1, TFAM, PGC-1α, Mfn1, Mfn2, UCP2, PINK1, OPA1, Drp1 and Fis1) were examined.
    RESULTS: TAU significantly enhanced memory performance, suppressed anxiety and depression-like behaviour, increased mitochondrial biogenesis/dynamics and improved mitochondrial indices. It should be mentioned that there was no significant difference between different concentrations of TAU in changing most brain mitochondrial dynamic biomarkers in the current study.
    CONCLUSIONS: These findings offer more insights into the molecular mechanism for TAU's action in the CNS. However, there is a need for further research to confirm these effects in humans. Overall, this study suggests the potential application of TAU in various neurological disorders and the need for clinical studies on the effects of this amino acid in the brain.
    Keywords:  amino acid; cognition; dementia; hippocampus; memory; neurodegenerative diseases
    DOI:  https://doi.org/10.1111/bcpt.14101
  31. J Transl Med. 2024 Nov 22. 22(1): 1056
    MST1, a novel therapeutic target for Alzheimer's disease, regulates mitochondrial homeostasis by mediating mitochondrial DNA transcription and the PI3K-Akt-ROS pathway.
    Dongqing Cui, Haixia Liu, Lili Cao, Xiaowei Du, Dingxin Liu, Zhiping Liu, Tong Wang, Hui Yang, Xiaolei Zheng, Zhaohong Xie, Shunliang Xu, Jianzhong Bi, Ping Wang.
       BACKGROUND: Alzheimer's disease (AD) is a prevalent irreversible neurodegenerative condition marked by gradual cognitive deterioration and neuronal loss. The mammalian Ste20-like kinase (MST1)-Hippo pathway is pivotal in regulating cell apoptosis, immune response, mitochondrial function, and oxidative stress. However, the association between MST1 and mitochondrial function in AD remains unknown. Therefore, this study investigates the effect of MST1 on neuronal damage and cognitive impairment by regulating mitochondrial homeostasis in AD.
    METHODS: In this study, 4- and 7-month-old 5xFAD mice were selected to simulate the early and middle stages of AD, respectively; age-matched wild-type mice served as controls for comparative analysis. Adeno-associated virus (AAV) was injected into the hippocampus of mice. Four weeks post-injection, cognitive function, neuronal damage indicators, and mitochondrial morphology, dynamics, oxidative stress, ATP, and apoptosis-related indicators were evaluated. Additionally, RNA-sequencing was performed on the hippocampal tissue of 5xFAD mice and MST1-knockdown 5xFAD mice. Subsequently, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on differentially expressed genes to elucidate the potential mechanism of MST1. In vitro studies were performed to investigate the effects of MST1 on SH-SY5Y model cell viability and mitochondrial function and validate the potential underlying molecular mechanisms.
    RESULTS: MST1 overexpression accelerated neuronal degeneration and cognitive deficits in vivo while promoting oxidative stress and mitochondrial damage. Similarly, in vitro, MST1 overexpression facilitated apoptosis and mitochondrial dysfunction. MST1 knockdown and chemical inactivation reduced cognitive decline, mitochondrial dysfunction, and neuronal degeneration. Mechanistically, MST1 regulated the transcription of mitochondrial genes, including MT-ND4L, MT-ATP6, and MT-CO2, by binding to PGC1α. Moreover, MST1 influenced cellular oxidative stress through the PI3K-Akt-ROS pathway, ultimately disrupting mitochondrial homeostasis and mediating cell damage.
    CONCLUSIONS: Cumulatively, these results suggest that MST1 primarily regulates mitochondrial DNA transcription levels by interacting with PGC1α and modulates cellular oxidative stress through the PI3K-Akt-ROS pathway, disrupting mitochondrial homeostasis. This discovery can be exploited to potentially enhance mitochondrial energy metabolism pathways by targeting MST1, offering novel potential therapeutic targets for treating AD.
    Keywords:  Alzheimer’s disease; MST1; Mitochondrial homeostasis; Oxidative phosphorylation (OXPHOS); PI3K-Akt signaling pathway
    DOI:  https://doi.org/10.1186/s12967-024-05852-x
  32. Transpl Immunol. 2024 Nov 14. pii: S0966-3274(24)00164-3. [Epub ahead of print]87 102148
    Identification of mitophagy-related gene signatures for predicting delayed graft function and renal allograft loss post-kidney transplantation.
    Kaifeng Mao, Fenwang Lin, Yige Pan, Zhenquan Lu, Bingfeng Luo, Yifei Zhu, Jiaqi Fang, Junsheng Ye.
       BACKGROUND: Ischemia-reperfusion injury (IRI) is an unavoidable consequence post-kidney transplantation, which inevitably leads to kidney damage. Numerous studies have demonstrated that mitophagy is implicated in human cancers. However, the function of mitophagy in kidney transplantation remains poorly understood. This study aims to develop mitophagy-related gene (MRGs) signatures to predict delayed graft function (DGF) and renal allograft loss post-kidney transplantation.
    METHODS: Differentially expressed genes (DEGs) were identified and intersected with the MRGs to obtain mitophagy-related DEGs (MRDEGs). Functional enrichment analyses were conducted. Subsequently, random forest and SVM-RFE machine learning were employed to identify hub genes. The DGF diagnostic prediction signature was constructed using LASSO regression analysis. The renal allograft prognostic prediction signature was developed through univariate Cox and LASSO regression analysis. In addition, ROC curves, immunological characterization, correlation analysis, and survival analysis were performed.
    RESULTS: Nineteen MRDEGs were obtained by intersecting 61 DEGs with 4897 MRGs. Seven hub genes were then identified through machine learning. Subsequently, a five-gene DGF diagnostic prediction signature was established, with ROC curves indicating its high diagnostic value for DGF. Immune infiltration analysis revealed that many immune cells were more abundant in the DGF group compared to the Immediate Graft Function (IGF) group. A two-gene prognostic signature was developed, which accurately predicted renal allografts prognosis.
    CONCLUSIONS: The mitophagy-related gene signatures demonstrated high predictive accuracy for DGF and renal allograft loss. Our study may provide new perspectives on prognosis and treatment strategies post-kidney transplantation.
    Keywords:  Delayed graft function (DGF); Ischemia-reperfusion injury (IRI); Kidney transplantation; Mitophagy-related genes (MRGs); Prognostic signatures
    DOI:  https://doi.org/10.1016/j.trim.2024.102148
  33. Front Immunol. 2024 ;15 1489444
    Single-cell sequencing unveils mitophagy-related prognostic model for triple-negative breast cancer.
    Peikai Ding, Shengbin Pei, Zheng Qu, Yazhe Yang, Qiang Liu, Xiangyi Kong, Zhongzhao Wang, Jing Wang, Yi Fang.
       Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking hormone receptors and HER2 expression, leading to limited treatment options and poor prognosis. Mitophagy, a selective autophagy process targeting damaged mitochondria, plays a complex role in cancer progression, yet its prognostic significance in TNBC is not well understood.
    Methods: This study utilized single-cell RNA sequencing data from the TCGA and GEO databases to identify mitophagy-related genes (MRGs) associated with TNBC. A prognostic model was developed using univariate Cox analysis and LASSO regression. The model was validated across multiple independent cohorts, and correlations between MRG expression, immune infiltration, and drug sensitivity were explored.
    Results: Nine key MRGs were identified and used to stratify TNBC patients into high-risk and low-risk groups, with the high-risk group showing significantly worse survival outcomes. The model demonstrated strong predictive accuracy across various datasets. Additionally, the study revealed a correlation between higher MRG expression levels and increased immune cell infiltration, as well as potential responsiveness to specific chemotherapeutic agents.
    Conclusion: The mitophagy-related prognostic model offers a novel method for predicting outcomes in TNBC patients and highlights the role of mitophagy in influencing the tumor microenvironment, with potential applications in personalized treatment strategies.
    Keywords:  immunoassay; mitophagy; prognostic model; single-cell sequencing; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1489444
  34. Phytomedicine. 2024 Nov 10. pii: S0944-7113(24)00888-2. [Epub ahead of print]135 156231
    Liang-Ge-San protects against viral infection-induced acute lung injury through inhibiting α7nAChR-mediated mitophagy.
    Jingtao Yu, Zibin Lu, Bing Chen, Xuemei He, Wei Zhao, Huihui Cao, Yuhua Li, Gefei Peng, Jinying Ou, Qinhai Ma, Linzhong Yu, Junshan Liu.
       BACKGROUND: Acute lung injury (ALI) is the main cause of death in clinical respiratory virus infection. Liang-Ge-San (LGS), a famous traditional Chinese formula, has been proved to be effective in treating ALI caused by lipopolysaccharide. However, the effects of LGS on ALI induced by viral infections remain uncertain.
    PURPOSE: To investigate the effect and mechanism of action of LGS on viral infection-induced ALI.
    METHODS: The inhibitory effects of LGS on virus-induced inflammation in vitro were evaluated by qRT-PCR and ELISA. The protein expression of α7nAChR was examined by Western blotting. α7nAChR was inhibited by the transfection of siRNA or methyllycaconitine citrate (MLA, an α7nAChR inhibitor) to investigate the role of α7nAChR in the anti-inflammatory effect of LGS. Adoptive culture and co-culture systems of macrophages RAW264.7 and alveolar epithelial cells MLE-12 were established to mimic their interaction. Western blotting, immunofluorescence, flow cytometry and transmission electron microscopy were used to examine the effects of LGS on mitophagy inhibition. In vivo, ALI mouse models induced by SARS-CoV-2, H1N1 or Poly(I:C) infection were established to explore the therapeutic effect and mechanism of LGS.
    RESULTS: LGS reduced the release of IL-6, TNF-α and IL-1β and increased the expression of α7nAChR in virus-infected RAW264.7 cells. The blockage of α7nAChR counteracted the anti-inflammatory effect of LGS. Moreover, LGS significantly inhibited autophagy in MLE-12 cells induced by Poly(I:C) in adoptive culture and co-culture systems of RAW264.7 and MLE-12 cells, which could be attenuated after the inhibition of α7nAChR in RAW264.7 cells by decreasing the secretion of IL-6, TNF-α and IL-1β. Further study showed that LGS suppressed TNF-α-induced mitochondrial damage and mitophagy by inhibiting the generation of ROS in MLE-12 cells. In vivo, LGS significantly prolonged the survival time, alleviated pathological injury and acute inflammation of ALI mice induced by SARS-CoV-2, H1N1 or Poly(I:C) infection which were associated with the inhibition of α7nAChR-mediated mitophagy.
    CONCLUSION: This study first demonstrates that LGS inhibits virus infection-induced inflammation in RAW246.7 cells by increasing the expression of α7nAChR, thereby inhibiting mitophagy induction in MLE-12 cells to alleviate ALI. This work indicates that LGS may serve as a candidate drug for treating ALI/ARDS caused by viral infection.
    Keywords:  Acute lung injury; Inflammation; Liang–Ge–San; Mitophagy; Respiratory virus; α7nAChR
    DOI:  https://doi.org/10.1016/j.phymed.2024.156231
  35. Iran J Allergy Asthma Immunol. 2024 Jul 27. 23(4): 393-402
    From Mild Cases to Critical Cases of COVID-19: The Role of Genes in Inflammasome and Mitochondrial Dynamics.
    Azam Kia, Vahideh Hajhasan, Mona Nadi, Azam Samei, Sadeq Azimzadeh Jamalkandi, Shahram Parvin, Ali Saffaie, Pedram Basirjafar, Jafar Salimian, Azam Samei.
      The coronavirus disease 2019 (CVOID-19) has varied clinical manifestations including mild to severe acute respiratory symptoms. Inflammasome complex and mitochondria play an important role in initiating inflammatory responses and could potentially be affected by this infection. To study the inflammasome and mitochondrial fission and fusion gene expression levels in COVID-19 patients, we designed this experiment. The inflammasome and mitochondrial gene expression profiles were determined by real-time polymerase chain reaction in the peripheral blood of 70 hospitalized CVOID-19 patients with mild to moderate symptoms (HOSP) and 30 ICU patients with severe symptoms (ICU) compared to 20 healthy controls (HC). The results indicated that the expression of the dynamin-related protein-1 was extremely suppressed in HOSP while it came back to the normal range in the ICU group. However, the expression of fission 1 protein had a non-significant increase in HOSP and a decrease in the ICU group. The mitofusin-1 and dominant optic atrophy genes showed high expression levels (10-fold) and (70-fold), respectively, in the HOSP group. However, mitofusin-2 significantly decreased in both groups. Although leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase activating and recruitment domain genes dramatically increased in both groups (10 and 4-fold), other inflammasome genes declined in both groups. Finally, Nuclear factor kappa-light-chain-enhancer of activate d B cells (NF-κB) extremely decreased, and Intreleukine-1 showed high expression in ICU patients (3-fold). CVOID-19 infection suppresses the fission genes and elevates the fusion gene expression in mitochondria, and it can cause activation of the inflammasome via the NLRP3 pathway.
    Keywords:  Corona disease 2019 (COVID-19); Inflammasome; Mitochondria
    DOI:  https://doi.org/10.18502/ijaai.v23i4.16213
  36. bioRxiv. 2024 Nov 15. pii: 2024.11.14.623646. [Epub ahead of print]
    ATF4 regulates mitochondrial dysfunction, mitophagy, and autophagy, contributing to corneal endothelial apoptosis under chronic ER stress in Fuchs' dystrophy.
    Saba Qureshi, Stephanie Lee, Lukas Ritzer, Stefan Y Kim, William Steidl, Gayle Joliet Krest, Anisha Kasi, Varun Kumar.
       Purpose: Endoplasmic reticulum (ER) stress, mitochondrial dysfunction, mitophagy/autophagy are known to contribute independently to corneal endothelial (CE) apoptosis in Fuchs' endothelial corneal dystrophy (FECD). However, the role of a well-studied specific ER stress pathway (PERK-ATF4-CHOP) in regulating mitochondrial dysfunction, mitophagy/autophagy, and apoptosis is unknown. The purpose of this study is to explore the role of ATF4 in regulating mitochondrial dysfunction and mitophagy/autophagy, leading to CEnC apoptosis in FECD.
    Methods: Human corneal endothelial cell line (HCEnC-21T), Fuchs' corneal endothelial cell line (F35T), and primary human corneal endothelial cells were treated with ER stressor tunicamycin (0.01, 0.1, 1, 10 μg/mL) for 24 and/or 48 hours. ATF4 siRNA was used to knock down ATF4 in 21T cell line and primary corneal endothelial cells. Cell viability was measured using an MTT assay (10 μg/mL tunicamycin for 24 hours). Mitochondrial bioenergetics was analyzed by measuring mitochondria membrane potential (MMP) loss using TMRE assay and ATP production using mitochondrial complex V assay kit at 48 hours post tunicamycin. Mitochondrial-mediated intrinsic apoptotic pathway proteins, mitophagy, and autophagy marker proteins were analyzed using Western blotting (10 μg/mL tunicamycin for 24 hours). ATF4 +/- and ATF4 +/+ mice were irradiated with UVA to assess pro-apoptotic ER stress and corneal endothelial cell death in vivo .
    Results: F35T cell line had a significantly increased expression of ER stress pathway molecules (eIF2α, ATF4, CHOP) and mitochondrial-mediated intrinsic apoptotic molecules (cleaved PARP, caspase 9, caspase 3) along with mitochondrial fragmentation compared to 21T cells at the baseline, which further increased after treatment with tunicamycin. Mitochondrial membrane potential also significantly decreased in F35T compared to 21T after tunicamycin. ATF4 knockdown after tunicamycin significantly attenuated pro-apoptotic ER and mitochondrial stress molecules, rescued MMP loss, and reduced mitochondrial fragmentation in the 21T cell line and primary corneal endothelial cells. ATF4 knockdown post tunicamycin treatment also downregulated altered/excessive Parkin-mediated mitophagy and Akt/mTOR-mediated autophagy pathway with reduction of caspases, leading to increased cellular viability. ATF4+/-mice had significantly increased CE numbers with improved cellular morphology and decreased CHOP expression compared to ATF4+/+ post-UVA.
    Conclusions: Pro-apoptotic ATF4 induction under tunicamycin-induced ER stress disrupts mitochondrial bioenergetics and dynamics, leading to activation of excessive autophagy/mitophagy. ATF4-induced activation of CHOP plays a key role in switching excessive autophagy to CEnC apoptosis. This study highlights the importance of ATF4 in ER-mitochondrial crosstalk and its contribution to CEnC apoptosis in FECD.
    DOI:  https://doi.org/10.1101/2024.11.14.623646
  37. Gene. 2024 Nov 15. pii: S0378-1119(24)00978-8. [Epub ahead of print]936 149097
    Identification and validation of biomarkers related to mitochondria during ex vivo lung perfusion for lung transplants based on machine learning algorithm.
    Zhi-Chang Yang, Wen-Yuan Lu, Zhen-Yang Geng, Yang Zhao, Xiao-Ming Chen, Tong Zheng, Ji-Ze Wu, Kai-Jun Huang, Hao-Xiang Yuan, Yang Yang.
       BACKGROUND: Ex vivo lung perfusion (EVLP) is a critical strategy to rehabilitate marginal donor lungs, thereby increasing lung transplantation (LTx) rates. Ischemia-reperfusion (I/R) injury inevitably occurs during LTx. Exploring the common mechanisms between EVLP and I/R may unveil new treatment targets to enhance LTx outcomes.
    METHODS: We obtained datasets from the public Gene Expression Omnibus (GEO) for EVLP (GSE127055 and GSE127057) and I/R (GSE145989) processes. We performed analysis of differentially expressed genes (DEGs) and Gene Set Enrichment Analysis (GSEA). Mitochondrial genes were sourced from the MitoCarta 3.0 database. Hub mitochondrial-related DEGs (MitoDEGs) were identified using a combination of protein-protein interaction networks and machine learning methods, which were further validated in cell and mice models of EVLP.
    RESULTS: GSEA analysis of DEGs following EVLP and I/R revealed significant inhibition of mitochondrial function pathways, encompassing mitochondrial central dogma, mtRNA metabolism, OXPHOS assembly factors, metals and cofactors, and heme synthesis and processing processes. Machine learning algorithms including Random Forest, LASSO, and XGBoost identified five downregulated genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) as hub MitoDEGs for both EVLP and I/R processes. We confirmed the reduced expression of these hub MitoDEGs in endothelial cells during EVLP and observed mitochondrial damage in endothelial cells characterized by swollen morphology and cristae disappearance.
    CONCLUSIONS: Imbalance in mitochondrial homeostasis is a shared pathological process during EVLP and I/R-induced lung injury. The identified hub mitochondrial-related genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) suggest promising therapeutic targets for lung injury during LTx. The downregulation of these genes indicates a significant disruption in mitochondrial function. This study provides potential mitochondrial-related therapeutic targets for I/R-induced lung injury and for donor lung repair during EVLP procedure in LTx.
    Keywords:  Ex vivo lung perfusion; Ischemia–reperfusion; Lung transplantation; Machine learning algorithms; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.gene.2024.149097
  38. JCI Insight. 2024 Nov 19. pii: e180409. [Epub ahead of print]
    NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.
    Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen.
      Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.
    Keywords:  Autophagy; Bone marrow differentiation; Development; Metabolism; Osteoporosis
    DOI:  https://doi.org/10.1172/jci.insight.180409
  39. Stem Cell Res Ther. 2024 Nov 19. 15(1): 438
    MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury.
    Kaiting Zhuang, Wenjuan Wang, Xumin Zheng, Xinru Guo, Cheng Xu, Xuejing Ren, Wanjun Shen, Qiuxia Han, Zhe Feng, Xiangmei Chen, Guangyan Cai.
       BACKGROUND: The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study attempted to dissect the role of hUC-MSCs therapy in modulating mitochondrial elongation-related senescence by hUC-MSCs therapy in post-AKI.
    METHODS: Initially, a unilateral renal ischemia-reperfusion (uIRI) model was established in C57 mice. Subsequently, lentivirus-transfected hUC-MSCs were given by subcapsular injection. Two weeks after transplantation, histochemical staining, and transmission electron microscopy were used to assess the efficacy of hUC-MSCs in treating renal senescence, fibrosis, and mitochondrial function. To further investigate the mitochondrial regulation of hUC-MSCs secretion, hypoxic HK-2 cells were built. Finally, antibodies of HGF and its receptor were used within the hUC-MSCs supernatant.
    RESULTS: Unopposed mitochondrial fusion, renal senescence, and renal interstitial fibrosis were successively identified after uIRI in mice. Then, the efficacy of hUC-MSCs after uIRI was confirmed. Subsequently, inhibiting hUC-MSCs-derived HGF significantly compromises the efficacy of hUC-MSCs and leads to ineffectively curbing mitochondrial elongation, accompanying insufficient control of elevated PKA and inhibitory phosphorylation of drp1 (Drp1pSer637). As a result, the treatment efficacy of renal senescence and fibrosis alleviation was also weakened. Furthermore, similar results were obtained with antibodies blocking HGF or cMet in hypoxic HK-2 cells treated with hUC-MSCs-condition medium for further proving. Uncurbed mitochondrial elongation induced by PKA and Drp1pSer637 was inhibited by hUC-MSCs derived HGF but reversed in the activation or overexpression of PKA.
    CONCLUSIONS: The research concluded that hUC-MSCs-derived HGF can inhibit PKA-Drp1pSer637-mitochondrial elongation via its receptor cMet to alleviate renal senescence and fibrosis in post-AKI.
    Keywords:  Hepatocyte growth factor (HGF); Mesenchymal stem cells (MSCs); Mitochondrial elongation; Renal premature senescence
    DOI:  https://doi.org/10.1186/s13287-024-04041-3
  40. Physiol Rep. 2024 Nov;12(22): e70118
    Air pollutants as modulators of mitochondrial quality control in cardiovascular disease.
    Kit Neikirk, Chanel Harris, Han Le, Ashton Oliver, Bryanna Shao, Kaihua Liu, Heather K Beasley, Sydney Jamison, Jeanne A Ishimwe, Annet Kirabo, Antentor Hinton.
      It is important to understand the effects of environmental factors such as air pollution on mitochondrial structure and function, especially when these changes increase cardiovascular disease risk. Although lifestyle choices directly determine many mitochondrial diseases, increasingly, it is becoming clear that the structure and function of mitochondria may be affected by pollutants found in the atmosphere (e.g., gases, pesticides herbicide aerosols, or microparticles). To date, the role of such agents on mitochondria and the potential impact on cardiovascular fitness is neglected. Here we offer a review of airborne stressors and pollutants, that may contribute to impairments in mitochondrial function and structure to cause heart disease.
    Keywords:  cardiovascular disease; environment; mitochondria; pollutants; toxicology
    DOI:  https://doi.org/10.14814/phy2.70118
  41. Biochem Pharmacol. 2024 Nov 17. pii: S0006-2952(24)00633-6. [Epub ahead of print]230(Pt 3): 116633
    Exploring heat shock proteins as therapeutic targets for Parkinson's disease.
    Xiang Li, Wenjun Wang, Shi Pan, Xueqin Cao, Elizabeth Rosalind Thomas, Mingyu Xie, Chunxiang Zhang, Jianming Wu.
      Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein (α-syn). Promoting the degradation of misfolded proteins has been shown to be an effective approach to alleviate PD. This review highlights the roles of specific heat shock proteins (HSPs) in modulating α-syn aggregation and neuronal survival. HSP27 prevents glycosylation-induced α-syn aggregation, disrupts copper ion interactions, inhibits mitochondrial apoptosis, and prevents dopaminergic neuronal cell death. HSP70 alleviates dopaminergic neuronal damage by promoting mitophagy and preventing neuronal apoptosis. HSC70 plays a critical role in chaperone-mediated autophagy and facilitates lysosomal degradation. GRP78 mitigates abnormal protein aggregation. The HSP70-HSP40-HSP110 system is capable of degrading α-syn amyloid fibers. Inhibition of HSP90 expression protects neurons. Further research should prioritize developing regulators of HSPs as treatments for PD. While HSPs offer promise in PD management, their complex roles necessitate cautious therapeutic development to harness their potential. Understanding the specific roles of different HSPs will be essential to developing effective therapies for α-syn clearance.
    Keywords:  HSPs; Mitophagy; Parkinson’ disease; Unfolded protein response; α-syn
    DOI:  https://doi.org/10.1016/j.bcp.2024.116633
  42. Redox Biol. 2024 Nov 21. pii: S2213-2317(24)00408-7. [Epub ahead of print] 103430
    Corrigendum to "FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a" [Redox Biol. 70 (2024) 103081].
    Miyesaier Abudureyimu, Xuanming Luo, Lingling Jiang, Xuejuan Jin, Cuizhen Pan, Wei Yu, Junbo Ge, Yingmei Zhang, Jun Ren.
      
    DOI:  https://doi.org/10.1016/j.redox.2024.103430
  43. Hum Mol Genet. 2024 Nov 20. pii: ddae166. [Epub ahead of print]
    De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.
    Priyanka Sandal, Chian Ju Jong, Ronald A Merrill, Grace J Kollman, Austin H Paden, Eric G Bend, Jennifer Sullivan, Rebecca C Spillmann, Vandana Shashi, Anneke T Vulto-van Silfhout, Rolph Pfundt, Bert B A de Vries, Pan P Li, Louise S Bicknell, Stefan Strack.
      The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T). In addition to moderate to severe intellectual disability and developmental delay, affected individuals presented with seizures, microcephaly, aggression, hypotonia, as well as broad-based or stiff gait. We used biochemical and cellular assays, including a novel luciferase complementation assay to interrogate PP2A holoenzyme assembly and activity, as well as deregulated mitochondrial dynamics as possible pathogenic mechanisms. Cell-based assays documented impaired ability of PPP2R2B missense variants to incorporate into the PP2A holoenzyme, localize to mitochondria, induce fission of neuronal mitochondria, and dephosphorylate the mitochondrial fission enzyme dynamin-related protein 1. AlphaMissense-based pathogenicity prediction suggested that an additional seven unreported missense variants may be pathogenic. In conclusion, our studies identify loss-of-function at the PPP2R2B locus as the basis for syndromic intellectual disability with developmental delay. They also extend PPP2R2B-related pathologies from neurodegenerative (SCA12) to neurodevelopmental disorders and suggests that altered mitochondrial dynamics may contribute to mechanisms.
    Keywords:  cerebellar ataxias; dynamin-related protein 1; mitochondrial dynamics; neurodevelopmental disorders; protein phosphatase 2A
    DOI:  https://doi.org/10.1093/hmg/ddae166
  44. J Ethnopharmacol. 2024 Nov 19. pii: S0378-8741(24)01409-0. [Epub ahead of print] 119110
    Shenling Baizhu San Alleviates Central Fatigue through SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis.
    Ruochong Wang, Yan Liu, Yang Jiang, Yawen Zhang, Yifei Zhang, Binshi Wang, Haixin Lu, Hui Su, Wenyong Liao, Leilei Liu, Feng Li, Weiyue Zhang, Shuran Ma.
       ETHNOPHARMACOLOGICAL RELEVANCE: Shenling Baizhu San (SLBZS) is a Traditional Chinese Medicine (TCM) formula composed of 10 medicinal herbs, historically used to strengthen the spleen, replenish qi, and alleviate fatigue-related symptoms. SLBZS originates from the 'Taiping Huimin Heji Ju Fang' of the Song Dynasty. Central fatigue (CF), a subtype of fatigue, is considered in TCM to be closely associated with spleen deficiency. However, there is currently a lack of research on SLBZS's therapeutic effects on CF and the pharmacological mechanisms underlying its potential benefits.
    AIM OF THE STUDY: This study aims to assess the effects of SLBZS on CF in rats induced by the Modified Multiple Platform Method (MMPM) and to elucidate the underlying mechanisms, focusing on mitochondrial biogenesis and SIRT1/PGC-1α pathway regulation.
    MATERIALS AND METHODS: CF was induced in male Wistar rats using MMPM, involving intermittent sleep deprivation over 21 days. SLBZS was administered at low(LSLBZS), medium(MSLBZS), and high doses(HSLBZS). Chemical components of SLBZS were identified and quantified using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS). Behavioral tests evaluated physical performance, emotional state, and cognitive function, while serum biochemical markers, mitochondrial morphology, and the protein and gene expression levels of the SIRT1/PGC-1α pathway were analyzed to explore underlying mechanisms.
    RESULTS: A total of 141 main compounds in SLBZS were identified, comprising various components such as flavonoids, phenylpropanoids, terpenoids, among others. SLBZS significantly improved physical performance, alleviated negative emotions, and enhanced cognitive function in CF rats. Biochemically, SLBZS increased serum ATP levels and reduced fatigue-related markers. Mitochondrial analysis demonstrated that SLBZS reversed mitochondrial degeneration, increased mitochondrial number, and increased mtDNA copy number in the hippocampus. Furthermore, SLBZS upregulated SIRT1 /PGC-1α pathway expression at both the protein and gene levels in the hippocampus. Notably, the HSLBZS group demonstrated particularly pronounced effects.
    CONCLUSION: SLBZS significantly alleviates CF symptoms enhances mitochondrial function via upregulating the SIRT1/PGC-1α pathway, positioning it as a promising alternative for CF management by addressing both its physiological and symptomatic aspects.
    Keywords:  Central Fatigue; Modified Multiple Platform Method; PGC-1α; SIRT1; Shenling Baizhu San; Traditional Chinese medicine; mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.jep.2024.119110
  45. J Med Chem. 2024 Nov 22.
    Biological Evaluation of a Rhodium(III) Bipyridylsulfonamide Complex: Effects on Mitochondrial Dynamics and Cytoskeletal Remodeling in Breast Cancer Cells.
    Irena Audzeyenka, Agnieszka Piwkowska, Dorota Rogacka, Mariusz Makowski, Mateusz Kowalik.
      Rhodium(III) complexes have gained attention for their anticancer potential. In this study, we investigated a rhodium(III) bipyridylsulfonamide complex (2) and its ligand (L) for their effects on breast cancer (SKBr3) and noncancerous mammary cells (HB2). Both compounds significantly reduced oxidative phosphorylation (OXPHOS) and mitochondrial function in SKBr3 cells while sparing HB2 cells. Compound 2 also increased glycolysis in both lines, suggesting a metabolic shift. Mitochondrial size and shape were altered, particularly in SKBr3 cells. Additionally, both compounds reduced cancer cell migration by disrupting actin cytoskeleton organization and the Rac1/VASP signaling pathway. These findings suggest that the rhodium(III) bipyridylsulfonamide complex selectively impairs mitochondrial dynamics and cell migration in cancer cells while sparing healthy cells, providing insight into its mechanism of action and toward its use as targeted anticancer therapy. This study lays the groundwork for future in vivo studies and further optimization of these metal-based therapeutics for clinical applications.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02284
  46. Am J Chin Med. 2024 Nov 19. 1-23
    Ginsenoside Rh4 Ameliorates Cisplatin-Induced Intestinal Toxicity via PGC-1[Formula: see text]-Mediated Mitochondrial Autophagy and Apoptosis Pathways.
    Wei Liu, Meng Sun, Wen-Ting Wang, Jian Song, Chun-Mei Wang, Neng-Yan Mou, Tian-Qi Shao, Zhi-Hong Zhang, Meng-Yang Wang, Hai-Ming Sun.
      Cisplatin-evoked profound gastrointestinal symptomatology is one of the most common side effects of chemotherapy drugs, causing further gastrointestinal cell and intestinal mucosal injury. Ginsenoside Rh4 (G-Rh4), an active component extracted from red ginseng, possesses beneficial anti-oxidative and anti-apoptosis effects. This study aimed to assess the effectiveness of pharmacological intervention with G-Rh4 mitigating intestinal toxicity evoked by cisplatin in a murine model and in IEC-6 cells in vitro. Following oral administration for 10 days, G-Rh4 (10[Formula: see text]mg/kg and 20[Formula: see text]mg/kg) significantly increased the indicators of diamine oxidase (DAO) affected by cisplatin (20[Formula: see text]mg/kg) in mice, and histopathological analysis further indicated that G-Rh4 could effectively improve intestinal tissue morphology, as well as the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 [Formula: see text] (PGC-1[Formula: see text] pathway and autophagy-related proteins. Moreover, in vitro experiments demonstrated that G-Rh4 exerted a concentration-dependent increase in cell viability, while also inhibiting cytotoxicity and abnormal rise of reactive oxygen species (ROS). Notably, ROS also activate PGC-1[Formula: see text] protein and mediate the occurrence of mitochondrial autophagy and apoptosis pathways. The molecular docking approach was employed to dock G-Rh4 with PGC-1[Formula: see text] and AMPK, revealing a binding energy of [Formula: see text]7.3[Formula: see text]kcal/mol and [Formula: see text]8.1[Formula: see text]kcal/mol and indicating a tight interaction between the components and the target. G-Rh4 could reduce the expression of autophagy-related protein p62/p53, reduce the accumulation of autophagy products, and promote the flow of autophagy. In conclusion, G-Rh4 exerted protective effects against cisplatin-induced intestinal toxicity, at least partially through PGC-1[Formula: see text]-mediated autophagy and apoptosis.
    Keywords:  Apoptosis; Autophagy; Cisplatin; Ginsenoside Rh4; Intestinal Toxicity; PGC-1[Formula: see text]
    DOI:  https://doi.org/10.1142/S0192415X24500848
  47. J Cell Biol. 2024 Dec 02. pii: e202407193. [Epub ahead of print]223(12):
    PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.
    Ravi Chidambaram, Kamal Kumar, Smriti Parashar, Gowsalya Ramachandran, Shuliang Chen, Susan Ferro-Novick.
      Here, we report that the RTN3L-SEC24C endoplasmic reticulum autophagy (ER-phagy) receptor complex, the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L, and the FIP200 autophagy initiating protein, target mutant proinsulin (Akita) condensates for lysosomal delivery at ER tubule junctions. When delivery was blocked, Akita condensates accumulated in the ER. In exploring the role of tubulation in these events, we unexpectedly found that loss of the Parkinson's disease protein, PINK1, reduced peripheral tubule junctions and blocked ER-phagy. Overexpression of the PINK1 kinase substrate, DRP1, increased junctions, reduced Akita condensate accumulation, and restored lysosomal delivery in PINK1-depleted cells. DRP1 is a dual-functioning protein that promotes ER tubulation and severs mitochondria at ER-mitochondria contact sites. DRP1-dependent ER tubulating activity was sufficient for suppression. Supporting these findings, we observed PINK1 associating with ER tubules. Our findings show that PINK1 shapes the ER to target misfolded proinsulin for RTN3L-SEC24C-mediated macro-ER-phagy at defined ER sites called peripheral junctions. These observations may have important implications for understanding Parkinson's disease.
    DOI:  https://doi.org/10.1083/jcb.202407193
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