bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024‒09‒15
57 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy.
  2. Mitophagy protects against ferroptosis.
  3. Burkholderia pseudomallei BipD initiates mitophagy to evade killing by hijacking host KLHL9-KLHL13-CUL3 E3 ligase to ubiquitinate IMMT.
  4. Emerging insights into pulmonary hypertension: the potential role of mitochondrial dysfunction and redox homeostasis.
  5. The multifaceted effects of mitochondria in kidney diseases.
  6. Baicalein: A potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement.
  7. Novel imaging tools to study mitochondrial morphology in Caenorhabditis elegans.
  8. CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.
  9. β-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.
  10. Enhancing mitophagy by ligustilide through BNIP3-LC3 interaction attenuates oxidative stress-induced neuronal apoptosis in spinal cord injury.
  11. Parkin plays a crucial role in acute viral myocarditis by regulating mitophagy activity.
  12. Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
  13. LONP1 alleviates ageing-related renal fibrosis by maintaining mitochondrial homeostasis.
  14. N-acetylcysteine, a small molecule scavenger of reactive oxygen species, alleviates cardiomyocyte damage by regulating OPA1-mediated mitochondrial quality control and apoptosis in response to oxidative stress.
  15. DRP1 Association in Inflammation and Metastasis: A Review.
  16. The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death.
  17. Mito-kaede photoactivation and chase experiment for mitophagy: optimizing flux measurement via fluid exchange system.
  18. A bird's eye view of mitochondrial unfolded protein response in cancer: mechanisms, progression and further applications.
  19. Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression.
  20. Chronic Stress-induced Serotonin Impairs Intestinal Epithelial Cell Mitochondrial Biogenesis via the AMPK-PGC-1α Axis.
  21. SIRT1 Regulates Mitochondrial Damage in N2a Cells Treated with the Prion Protein Fragment 106-126 via PGC-1α-TFAM-Mediated Mitochondrial Biogenesis.
  22. Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.
  23. Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery.
  24. Unravelling the anti-apoptotic role of Plasmodium falciparum Prohibitin-2 (PfPhb2) in maintaining mitochondrial homeostasis.
  25. High-concentration hydrogen inhalation mitigates sepsis-associated encephalopathy in mice by improving mitochondrial dynamics.
  26. Cardiotoxicity of Iron and Zinc and Their Association with the Mitochondrial Unfolded Protein Response in Humans.
  27. Multi-omics and Single Cell Sequencing Analyses Reveal Associations of Mitophagy-Related Genes Predicting Clinical Prognosis and Immune Infiltration Characteristics in Osteosarcoma.
  28. Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.
  29. Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
  30. Silencing of PCK1 mitigates the proliferation and migration of vascular smooth muscle cells and vascular intimal hyperplasia by suppressing STAT3/DRP1-mediated mitochondrial fission.
  31. Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
  32. The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.
  33. SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
  34. Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.
  35. Iron chelators as mitophagy agents: Potential and limitations.
  36. Metformin Alleviates Inflammation and Induces Mitophagy in Human Retinal Pigment Epithelium Cells Suffering from Mitochondrial Damage.
  37. The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.
  38. SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer.
  39. Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
  40. Endoplasmic reticulum-mitochondrial encounter structure regulates the mitochondrial morphology, DON biosynthesis and toxisome formation in Fusarium graminearum.
  41. The PI3K/Akt-Nrf2 Signaling Pathway and Mitophagy Synergistically Mediate Hydroxytyrosol to Alleviate Intestinal Oxidative Damage.
  42. Reduced bioenergetics and mitochondrial fragmentation in human primary cytotrophoblasts induced by an EGFR-targeting chemical mixture.
  43. Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis.
  44. Targeted proteomics addresses selectivity and complexity of protein degradation by autophagy.
  45. Editorial on: Canagliflozin mediates mitophagy through the AMPK/PINK1/PARKIN pathway to alleviate isoprenaline-induced cardiac remodelling.
  46. Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
  47. SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway.
  48. Identification of novel mitophagy-related biomarkers for Kawasaki disease by integrated bioinformatics and machine-learning algorithms.
  49. Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials.
  50. Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
  51. Cardioprotective effect of Vitamin D on cardiac hypertrophy through improvement of mitophagy and apoptosis in an experimental rat model of levothyroxine -induced hyperthyroidism.
  52. Visualizing mitochondrial dynamics at the nanoscale.
  53. Transcriptional activation of PINK1 by MyoD1 mediates mitochondrial homeostasis to induce renal calcification in pediatric nephrolithiasis.
  54. The Interplay between Autophagy and Mitochondria in Cancer.
  55. Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.
  56. Up-regulated mitochondrial biogenesis associated with GH/IGF axis in the ovaries of muskrats (Ondatra zibethicus).
  57. Inner Mitochondrial Membrane Peptidase 2-Like Deletion Aggravates Mitochondrial Apoptosis and Inhibits Autophagy After Hyperglycemia Stroke.
  1. Int J Biol Sci. 2024 ;20(11): 4458-4475
    Nuclear receptor subfamily 4 group A member 1 promotes myocardial ischemia/reperfusion injury through inducing mitochondrial fission factor-mediated mitochondrial fragmentation and inhibiting FUN14 domain containing 1-depedent mitophagy.
    Junyan Wang, Haowen Zhuang, Lianqun Jia, Xinyong He, Sicheng Zheng, Kangshou Ji, Kang Xie, Tong Ying, Ying Zhang, Chun Li, Xing Chang.
      This study investigated the mechanism by which NR4A1 regulates mitochondrial fission factor (Mff)-related mitochondrial fission and FUN14 domain 1 (FUNDC1)-mediated mitophagy following cardiac ischemia-reperfusion injury(I/R). Our findings showed that the damage regulation was positively correlated with the pathological fission and pan-apoptosis of myocardial cell mitochondria. Compared with wild-type mice (WT), NR4A1-knockout mice exhibited resistance to myocardial ischemia-reperfusion injury and mitochondrial pathological fission, characterized by mitophagy activation. Results showed that ischemia-reperfusion injury increased NR4A1 expression level, activating mitochondrial fission mediated by Mff and restoring the mitophagy phenotype mediated by FUNDC1. The inactivation of FUNDC1 phosphorylation could not mediate the normalization of mitophagy in a timely manner, leading to an excessive stress response of unfolded mitochondrial proteins and an imbalance in mitochondrial homeostasis. This process disrupted the normalization of the mitochondrial quality control network, leading to accumulation of damaged mitochondria and the activation of pan-apoptotic programs. Our data indicate that NR4A1 is a novel and critical target in myocardial I/R injury that exertsand negative regulatory effects by activating Mff-mediated mito-fission and inhibiting FUNDC1-mediated mitophagy. Targeting the crosstalk balance between NR4A1-Mff-FUNDC1 is a potential approach for treating I/R.
    Keywords:  FUNDC1; Mff; NR4A1; myocardial ischemia-reperfusion injury; pan-apoptosis
    DOI:  https://doi.org/10.7150/ijbs.95853
  2. Nat Cell Biol. 2024 Sep;26(9): 1374
    Mitophagy protects against ferroptosis.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-024-01507-7
  3. Autophagy. 2024 Sep 12.
    Burkholderia pseudomallei BipD initiates mitophagy to evade killing by hijacking host KLHL9-KLHL13-CUL3 E3 ligase to ubiquitinate IMMT.
    Dongqi Nan, Xuhu Mao, Qian Li.
      Burkholderia pseudomallei (B. pseudomallei) is a facultative intracellular parasitic pathogen with multiple immune escape mechanisms. Mitophagy is critical for mitochondrial quality control and function in various biological processes. We reported that B. pseudomallei infection induces mitophagy to promote its intracellular survival by decreasing mitochondrial reactive oxygen species (mtROS). Mechanically, B. pseudomallei infection leads to the rupture of host outer mitochondrial membrane (OMM) by DNM1L/DRP1 (dynamin 1-like). Furthermore, BipD, the type III secretion system (T3SS) needle tip protein of B. pseudomallei, hijacks the host KLHL9 (kelch-like 9)-KLHL13 (kelch-like 13)-CUL3 (cullin 3) E3 ubiquitin ligase complex to promote the K63-linked ubiquitination of IMMT/mitofilin (inner membrane protein, mitochondrial) at the K211 site. Then BipD-initiated mitophagy, via the conventional macroautophagy/autophagy pathway with the receptor SQSTM1 (sequestosome 1) involvement, decreases the mtROS production, which in turn facilitates the intracellular survival of B. pseudomallei. Here, our findings reveal an unexpected function of BipD and the KLHL9-KLHL13-CUL3 E3 ligase complex and suggest a novel mechanism used by bacterial pathogens that hijack host mitophagy for their survival.
    Keywords:  BipD; burkholderia pseudomallei; intracellular survival; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2024.2403125
  4. Mol Cell Biochem. 2024 Sep 10.
    Emerging insights into pulmonary hypertension: the potential role of mitochondrial dysfunction and redox homeostasis.
    Junming Zhang, Huimin Yan, Yan Wang, Xian Yue, Meng Wang, Limin Liu, Pengfei Qiao, Yixuan Zhu, Zhichao Li.
      Pulmonary hypertension (PH) is heterogeneous diseases that can lead to death due to progressive right heart failure. Emerging evidence suggests that, in addition to its role in ATP production, changes in mitochondrial play a central role in their pathogenesis, regulating integrated metabolic and signal transduction pathways. This review focuses on the basic principles of mitochondrial redox status in pulmonary vascular and right ventricular disorders, a series of dysfunctional processes including mitochondrial quality control (mitochondrial biogenesis, mitophagy, mitochondrial dynamics, mitochondrial unfolded protein response) and mitochondrial redox homeostasis. In addition, we will summarize how mitochondrial renewal and dynamic changes provide innovative insights for studying and evaluating PH. This will provide us with a clearer understanding of the initial signal transmission of mitochondria in PH, which would further improve our understanding of the pathogenesis of PH.
    Keywords:  Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitochondrial redox homeostasis; Mitochondrial unfolded protein response; Mitophagy; Pulmonary hypertension
    DOI:  https://doi.org/10.1007/s11010-024-05096-9
  5. Mitochondrion. 2024 Sep 11. pii: S1567-7249(24)00115-6. [Epub ahead of print] 101957
    The multifaceted effects of mitochondria in kidney diseases.
    Jia-Le Xue, Jia-Ling Ji, Yan Zhou, Yao Zhang, Bi-Cheng Liu, Rui-Xia Ma, Zuo-Lin Li.
      Mitochondria serve as the primary site for aerobic respiration within cells, playing a crucial role in maintaining cellular homeostasis. To maintain homeostasis and meet the diverse demands of the cells, mitochondria have evolved intricate systems of quality control, mainly including mitochondrial dynamics, mitochondrial autophagy (mitophagy) and mitochondrial biogenesis. The kidney, characterized by its high energy requirements, is particularly abundant in mitochondria. Interestingly, the mitochondria display complex behaviors and functions. When the kidney is suffered from obstructive, ischemic, hypoxic, oxidative, or metabolic insults, the dysfunctional mitochondrial derived from the defects in the mitochondrial quality control system contribute to cellular inflammation, cellular senescence, and cell death, posing a threat to the kidney. However, in addition to causing injury to the kidney in several cases, mitochondria also exhibit protective effect on the kidney. In recent years, accumulating evidence indicated that mitochondria play a crucial role in adaptive repair following kidney diseases caused by various etiologies. In this article, we comprehensively reviewed the current understanding about the multifaceted effects of mitochondria on kidney diseases and their therapeutic potential.
    Keywords:  Kidney diseases; Mitochondria; Mitochondrial quality control system; Treatment strategy
    DOI:  https://doi.org/10.1016/j.mito.2024.101957
  6. J Pharm Anal. 2024 Aug;14(8): 100968
    Baicalein: A potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement.
    Na Liu, Xin Cui, Wenhui Yan, Tingli Guo, Zhuanzhuan Wang, Xiaotong Wei, Yuzhuo Sun, Jieyun Liu, Cheng Xian, Weina Ma, Lina Chen.
      There is increasing evidence that the activation of glucagon-like peptide-1 receptor (GLP-1R) can be used as a therapeutic intervention for cognitive disorders. Here, we have screened GLP-1R targeted compounds from Scutellaria baicalensis, which revealed baicalein is a potential GLP-1R small-molecule agonist. Mitophagy, a selective autophagy pathway for mitochondrial quality control, plays a neuroprotective role in multiple cognitive impairment diseases. We noticed that Glp1r knock-out (KO) mice present cognitive impairment symptoms and appear worse in spatial learning memory and learning capacity in Morris water maze (MWM) test than their wide-type (WT) counterparts. Our mechanistic studies revealed that mitophagy is impaired in hippocampus tissue of diabetic mice and Glp1r KO mice. Finally, we verified that the cognitive improvement effects of baicalein on diabetic cognitive dysfunction occur through the enhancement of mitophagy in a GLP-1R-dependent manner. Our findings shed light on the importance of GLP-1R for cognitive function maintenance, and revealed the vital significance of GLP-1R for maintaining mitochondrial homeostasis. Furthermore, we identified the therapeutic potential of baicalein in the treatment of cognitive disorder associated with diabetes.
    Keywords:  Cell membrane chromatography; Cognitive disorder; Diabetes; GLP-1R agonist; Mitophagy
    DOI:  https://doi.org/10.1016/j.jpha.2024.100968
  7. Life Sci Alliance. 2024 Nov;pii: e202402918. [Epub ahead of print]7(11):
    Novel imaging tools to study mitochondrial morphology in Caenorhabditis elegans.
    Miriam Valera-Alberni, Pallas Yao, Silvia Romero-Sanz, Anne Lanjuin, William B Mair.
      Mitochondria exhibit a close interplay between their structure and function. Understanding this intricate relationship requires advanced imaging techniques that can capture the dynamic nature of mitochondria and their impact on cellular processes. However, much of the work on mitochondrial dynamics has been performed in single celled organisms or in vitro cell culture. Here, we introduce novel genetic tools for live imaging of mitochondrial morphology in the nematode Caenorhabditis elegans, addressing a pressing need for advanced techniques in studying organelle dynamics within live intact multicellular organisms. Through a comprehensive analysis, we directly compare our tools with existing methods, demonstrating their advantages for visualizing mitochondrial morphology and contrasting their impact on organismal physiology. We reveal limitations of conventional techniques, whereas showcasing the utility and versatility of our approaches, including endogenous CRISPR tags and ectopic labeling. By providing a guide for selecting the most suitable tools based on experimental goals, our work advances mitochondrial research in C. elegans and enhances the strategic integration of diverse imaging modalities for a holistic understanding of organelle dynamics in living organisms.
    DOI:  https://doi.org/10.26508/lsa.202402918
  8. Redox Biol. 2024 Sep 06. pii: S2213-2317(24)00322-7. [Epub ahead of print]76 103344
    CARM1 phosphorylation at S595 by p38γ MAPK drives ROS-mediated cellular senescence.
    Yena Cho, Yong Kee Kim.
      CARM1 is predominantly localized in the nucleus and plays a pivotal role in maintaining mitochondrial homeostasis by regulating gene expression. It suppresses mitochondrial biogenesis by downregulating PGC-1α and TFAM expression, while promoting mitochondrial fission through increased DNM1L expression. Under oxidative stress, CARM1 translocates to the cytoplasm, where it directly methylates DRP1 and accelerates mitochondrial fission, enhancing reactive oxygen species (ROS) production. Cytoplasmic localization of CARM1 is facilitated by its phosphorylation at S595 by ROS-activated p38γ MAPK, creating a positive feedback loop. Consequently, cytoplasmic CARM1 contributes to cellular senescence by altering mitochondrial dynamics and increasing ROS levels. This observation was supported by the increased cytoplasmic CARM1 levels and disrupted mitochondrial dynamics in the transformed 10T1/2 cells. Moreover, CARM1 inhibitors not only inhibit the proliferation of cancer cells but also induce apoptotic death in senescent cells. These findings highlight the potential of CARM1 inhibitors, particularly those targeting cytoplasmic functions, as novel strategies for eliminating cancer and senescent cells.
    Keywords:  CARM1; Mitochondrial homeostasis; ROS; Senescence; p38γ MAPK
    DOI:  https://doi.org/10.1016/j.redox.2024.103344
  9. Gastroenterol Rep (Oxf). 2024 ;12 goae084
    β-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.
    Shuyun Wu, Huiling Liu, Jiazhi Yi, Minyi Xu, Jie Jiang, Jin Tao, Bin Wu.
      Background: Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. β-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear.Methods: Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay.
    Results: We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2.
    Conclusions: Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.
    Keywords:  intestinal barrier; mitochondrial dysfunction; mitofusion2; mitophagy; β-arrestin1
    DOI:  https://doi.org/10.1093/gastro/goae084
  10. Int J Biol Sci. 2024 ;20(11): 4382-4406
    Enhancing mitophagy by ligustilide through BNIP3-LC3 interaction attenuates oxidative stress-induced neuronal apoptosis in spinal cord injury.
    Hui Yao, Chaoyang Cai, Weijun Huang, Caizhen Zhong, Tianlun Zhao, Jiawei Di, Juliang Tang, Depeng Wu, Mao Pang, Lei He, Limin Rong, Bin Liu.
      Mitophagy selectively eliminates damaged or dysfunctional mitochondria, playing a crucial role in maintaining mitochondrial quality control. However, it remains unclear whether mitophagy can be fully activated and how it evolves after SCI. Our RNA-seq analysis of animal samples from sham and 1, 3, 5, and 7 days post-SCI indicated that mitophagy was indeed inhibited during the acute and subacute early stages. In vitro experiments showed that this inhibition was closely related to excessive production of reactive oxygen species (ROS) and the downregulation of BNIP3. Excessive ROS led to the blockage of mitophagy flux, accompanied by further mitochondrial dysfunction and increased neuronal apoptosis. Fortunately, ligustilide (LIG) was found to have the ability to reverse the oxidative stress-induced downregulation of BNIP3 and enhance mitophagy through BNIP3-LC3 interaction, alleviating mitochondrial dysfunction and ultimately reducing neuronal apoptosis. Further animal experiments demonstrated that LIG alleviated oxidative stress and mitophagy inhibition, rescued neuronal apoptosis, and promoted tissue repair, ultimately leading to improved motor function. In summary, this study elucidated the state of mitophagy inhibition following SCI and its potential mechanisms, and confirmed the effects of LIG-enhanced mitophagy through BNIP3-LC3, providing new therapeutic targets and strategies for repairing SCI.
    Keywords:  ROS; ligustilide; mitochondrial autophagy; neuronal apoptosis; non-ubiquitination process; spinal cord injury
    DOI:  https://doi.org/10.7150/ijbs.98051
  11. Theranostics. 2024 ;14(13): 5303-5315
    Parkin plays a crucial role in acute viral myocarditis by regulating mitophagy activity.
    Yixuan Qiu, Jing Xu, Yilian Chen, Yihao Wu, Yuan-Nan Lin, Weike Liu, Zhening Wang, Yuqing Wu, Xinge Qian, Yue-Chun Li.
      Rationale: Parkin (an E3 ubiquitin protein ligase) is an important regulator of mitophagy. However, the role of Parkin in viral myocarditis (VMC) remains unclear. Methods: Coxsackievirus B3 (CVB3) infection was induced in mice to create VMC. Cardiac function and inflammatory response were evaluated by echocardiography, histological assessment, and molecular analyses. AAV9 (adeno-associated virus 9), transmission electron microscopy (TEM) and western blotting were used to investigate the mechanisms by which Parkin regulates mitophagy and cardiac inflammation. Results: Our data indicated that Parkin- and BNIP3 (BCL2 interacting protein 3 like)-mediated mitophagy was activated in VMC mice and neonatal rat cardiac myocytes (NRCMs) infected with CVB3, which blocked autophagic flux by inhibiting autophagosome-lysosome fusion. Parkin silencing aggravated mortality and accelerated the development of cardiac dysfunction in CVB3-treated mice. While silencing of Parkin did not significantly increase inflammatory response through activating NF-κB pathway and production of inflammatory cytokines post-VMC, the mitophagy activity were reduced, which stimulated the accumulation of damaged mitochondria. Moreover, Parkin silencing exacerbated VMC-induced apoptosis. We consistently found that Parkin knockdown disrupted mitophagy activity and inflammatory response in NRCMs. Conclusion: This study elucidated the important role of Parkin in maintaining cardiac function and inflammatory response by regulating mitophagy activity and the NF-κB pathway during acute VMC. Although the functional impact of mitophagy remains unclear, our findings suggest that Parkin silencing may accelerate VMC development.
    Keywords:  NF-κB pathway; Parkin; inflammation; mitophagy; viral myocarditis
    DOI:  https://doi.org/10.7150/thno.97675
  12. Mol Neurobiol. 2024 Sep 09.
    Disruption of Mitochondrial Quality Control in Inherited Metabolic Disorders.
    Manuela Bianchin Marcuzzo, Josyane de Andrade Silveira, Emílio L Streck, Jerry Vockley, Guilhian Leipnitz.
      Inherited metabolic disorders (IMDs) are genetic disorders often characterized by the accumulation of toxic metabolites in patient tissues and bodily fluids. Although the pathophysiologic effect of these metabolites and their direct effect on cellular function is not yet established for many of these disorders, animal and cellular studies have shown that mitochondrial bioenergetic dysfunction with impairment of citric acid cycle activity and respiratory chain, along with secondary damage induced by oxidative stress are prominent in some. Mitochondrial quality control, requiring the coordination of multiple mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy, is responsible for the correction of such defects. For inborn errors of enzymes located in the mitochondria, secondary abnormalities in quality control this organelle could play a role in their pathophysiology. This review summarizes preclinical data (animal models and patient-derived cells) on mitochondrial quality control disturbances in selected IMDs.
    Keywords:  Biogenesis; Fission; Fusion; Inherited Metabolic Disorders; Mitochondrial Quality Control; Mitophagy
    DOI:  https://doi.org/10.1007/s12035-024-04467-z
  13. J Cell Mol Med. 2024 Sep;28(17): e70090
    LONP1 alleviates ageing-related renal fibrosis by maintaining mitochondrial homeostasis.
    Congxiao Zhang, Siman Shen, Li Xu, Man Li, Binyao Tian, Li Yao, Xinwang Zhu.
      Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed in vitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.
    Keywords:  LONP1; ageing; m6A methyltransferase METTL3; mitochondrial homeostasis; renal fibrosis
    DOI:  https://doi.org/10.1111/jcmm.70090
  14. J Thorac Dis. 2024 Aug 31. 16(8): 5323-5336
    N-acetylcysteine, a small molecule scavenger of reactive oxygen species, alleviates cardiomyocyte damage by regulating OPA1-mediated mitochondrial quality control and apoptosis in response to oxidative stress.
    Junyi Zheng, Lili Zhao, Yuanyuan Liu, Mengying Chen, Xukun Guo, Jixiang Wang.
      Background: Oxidative stress-induced mitochondrial damage is the major cause of cardiomyocyte dysfunction. Therefore, the maintenance of mitochondrial function, which is regulated by mitochondrial quality control (MQC), is necessary for cardiomyocyte homeostasis. This study aimed to explore the underlying mechanisms of N-acetylcysteine (NAC) function and its relationship with MQC.Methods: A hydrogen peroxide-induced oxidative stress model was established using H9c2 cardiomyocytes treated with or without NAC prior to oxidative stress stimulation. Autophagy with light chain 3 (LC3)-green fluorescent protein (GFP) assay, reactive oxygen species (ROS) with the 2',7'-dichlorodi hydrofluorescein diacetate (DCFH-DA) fluorescent, lactate dehydrogenase (LDH) release assay, adenosine triphosphate (ATP) content assay, and a mitochondrial membrane potential detection were used to evaluate mitochondrial dynamics in H2O2-treated H9c2 cardiomyocytes, with a focus on the involvement of MQC regulated by NAC. Cell apoptosis was analyzed using caspase-3 activity assay and Annexin V-fluorescein isothiocyanate (V-FITC)/propidium iodide (PI) double staining.
    Results: We observed that NAC improved cell viability, reduced ROS levels, and partially restored optic atrophy 1 (OPA1) protein expression under oxidative stress. Following transfection with a specific OPA1-small interfering RNA, the mitophagy, mitochondrial dynamics, mitochondrial functions, and cardiomyocyte apoptosis were evaluated to further explore the mechanisms of NAC. Our results demonstrated that NAC attenuated cardiomyocyte apoptosis via the ROS/OPA1 axis and protected against oxidative stress-induced mitochondrial damage via the regulation of OPA1-mediated MQC.
    Conclusions: NAC ameliorated the injury to H9c2 cardiomyocytes caused by H2O2 by promoting the expression of OPA1, consequently improving mitochondrial function and decreasing apoptosis.
    Keywords:  N-acetylcysteine (NAC); cardiomyocyte; mitochondrial quality control (MQC); mitophagy; optic atrophy 1 (OPA1)
    DOI:  https://doi.org/10.21037/jtd-24-927
  15. Curr Drug Targets. 2024 Sep 06.
    DRP1 Association in Inflammation and Metastasis: A Review.
    Parmar Keshri Nandan, Anica Tholath Job, Tamizhselvi Ramasamy.
      In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on aging, human health, and other advanced findings in metabolic functions. The latest finding shows that metabolic interventions are a leading cause of several diseases, which has sparked interest in finding new therapeutic treatments. Apart from this, the unique inheritance of genetic material from mother to offspring can help scientists find ways to prevent mitochondrial inherited diseases. Additionally, the anti-aging benefits of controlling mitochondrial functions are also being researched. The present study aims to provide a cohesive overview of the latest findings in mitochondrial research, focusing on the role of DRP1 (Dynamin- related protein 1), a member of the GTPase family, in mediating mitochondrial fission. The first section of this paper provides a concise explanation of how DRP1 controls processes such as mitophagy and mitochondrial fission. Subsequently, the paper delves into the topic of inflammation, discussing the current findings regarding the inflammatory response mediated by DRP1. Finally, the role of mitochondrial fission mediated by DRP1 in cancer is examined, reviewing ongoing research on various types of cancer and their recurrence. Moreover, this review also covers the epigenetic regulation of mitochondrial fission. The studies were selected, and evaluated, and the information was collected to present an overview of the key findings. By exploring various aspects of research and potential links, we hope to contribute to a deeper understanding of the intricate relationship between the fields of cancer research and inflammation studies with respect to mitochondrial- based research.
    Keywords:  GTPase; cytokine.; inflammation; metastasis; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.2174/0113894501304751240819111831
  16. Cancers (Basel). 2024 Sep 02. pii: 3060. [Epub ahead of print]16(17):
    The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death.
    Shu-Hao Chang, Kai-Cheng Chuang, Zheng-Yi Li, Mao-Chia Chang, Kuang-Ting Liu, Chien-Sheng Hsu, Shi-Wei Huang, Mu-Chi Chung, Shih-Chung Wang, Yi-Ju Chen, Jeng-Jer Shieh.
      Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.
    Keywords:  Mcl-1; ROS; imiquimod; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/cancers16173060
  17. Biotechniques. 2024 Sep 11. 1-13
    Mito-kaede photoactivation and chase experiment for mitophagy: optimizing flux measurement via fluid exchange system.
    Hiroyuki Morinaga, Yoh Sugawara, Yoshinori Kitagawa, Jingyuan Chen, Nobuo Yasuda, Hiroki Ogata, Yoshihiro Yamaguchi, Masao Kaneki, Joseph A Jeevendra Martyn, Shingo Yasuhara.
      Modulating autophagy and mitophagy, vital cellular quality control systems, offer therapeutic potential for critical illnesses. However, limited drug screening options hinder progress. We present a novel assay using the photoswitchable fluorescent reporter, mito-Kaede, to quantify mitophagy flux. Mito-Kaede's superior UV-induced photoconversion and brightness post-conversion make it ideal for prolonged mitochondrial dynamics tracking. Its specificity in responding to mitophagy, confirmed by parkin-knockout cells, adds value. When coupled with a custom fluid exchange system, enabling efficient medium changes, precise mitophagy observations become feasible. This mitophagy assay, alongside our methodological insights, can decipher mitophagy's role in pathology and supports drug screening efforts.
    Keywords:  CCCP; Parkin; assay; autophagy; fluorescent microscopy; mito-Kaede; mitophagy; photoactivation; photoconversion; time-lapse
    DOI:  https://doi.org/10.1080/07366205.2024.2372955
  18. Cell Death Dis. 2024 Sep 11. 15(9): 667
    A bird's eye view of mitochondrial unfolded protein response in cancer: mechanisms, progression and further applications.
    Xinyu Zhang, Yumei Fan, Ke Tan.
      Mitochondria are essential organelles that play critical roles in energy metabolism, apoptosis and various cellular processes. Accumulating evidence suggests that mitochondria are also involved in cancer development and progression. The mitochondrial unfolded protein response (UPRmt) is a complex cellular process that is activated when the protein-folding capacity of the mitochondria is overwhelmed. The core machinery of UPRmt includes upstream regulatory factors, mitochondrial chaperones and proteases. These components work together to eliminate misfolded proteins, increase protein-folding capacity, and restore mitochondrial function. Recent studies have shown that UPRmt is dysregulated in various cancers and contributes to tumor initiation, growth, metastasis, and therapeutic resistance. Considering the pivotal role of the UPRmt in oncogenesis, numerous compounds and synthetic drugs targeting UPRmt-related components induce cancer cell death and suppress tumor growth. In this review, we comprehensively summarize recent studies on the molecular mechanisms of UPRmt activation in C. elegans and mammals and elucidate the conceptual framework, functional aspects, and implications of the UPRmt for cancer therapy. In summary, we paint a developmental landscape of the UPRmt in different types of cancer and offer valuable insights for the development of novel cancer treatment strategies by targeting the UPRmt.
    DOI:  https://doi.org/10.1038/s41419-024-07049-y
  19. Neoplasia. 2024 Sep 10. pii: S1476-5586(24)00096-4. [Epub ahead of print]57 101055
    Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression.
    Xiang Li, Zongqi Wang, Bixi Gao, Kun Dai, Jiang Wu, Kecheng Shen, Guangzhao Li, Xiaowang Niu, Xin Wu, Longyuan Li, Haitao Shen, Haiying Li, Zhengquan Yu, Zhong Wang, Gang Chen.
      BACKGROUND: Glioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies.METHODS: We conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment.
    RESULTS: Our research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models.
    CONCLUSION: This study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.
    Keywords:  Glioblastoma; Heat shock factor 1; Heat shock protein 60; Mitochondrial heat shock protein 70; Mitochondrial unfolded protein response; SUMOylation
    DOI:  https://doi.org/10.1016/j.neo.2024.101055
  20. Int J Biol Sci. 2024 ;20(11): 4476-4495
    Chronic Stress-induced Serotonin Impairs Intestinal Epithelial Cell Mitochondrial Biogenesis via the AMPK-PGC-1α Axis.
    Ding Yang, Yan Sun, Pei Wen, Yaoxing Chen, Jing Cao, Xuelin Sun, Yulan Dong.
      Chronic stress is closely associated with gastrointestinal disorders. However, the impact of stress-related neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) on the intestines under chronic stress conditions remains poorly understood. This study aims to elucidate the mechanisms by which 5-HT affects mitochondrial biogenesis and intestinal barrier integrity during chronic stress. Employing a chronic restraint stress (CRS) mouse model, we observed elevated intestinal 5-HT levels, altered colonic mucosal structure, and disrupted tight junctions. The increase in 5-HT was associated with up-regulated serotonin synthesis enzymes and downregulated serotonin reuptake transporters, indicating an imbalance in serotonin homeostasis imbalance caused by chronic stress. Furthermore, serotonin exacerbated oxidative stress and impaired tight junction protein expression, highlighting its role in promoting intestinal barrier dysfunction. Experiments with cells in vitro demonstrated that 5-HT impairs mitochondrial biogenesis by inhibiting the AMPK-PGC-1α axis via 5-HT7 receptors and the cAMP-PKA pathway. Pharmacological inhibition of serotonin synthesis or 5-HT7 receptors alleviated the intestinal barrier damage caused by 5-HT and chronic stress, restoring mitochondrial biogenesis. These findings provide compelling evidence that serotonin exacerbates chronic stress-induced intestinal barrier disruption by inhibiting the AMPK-PGC-1α axis, paving the way for novel therapeutic interventions targeting the detrimental effects of serotonin on the intestine, particularly under chronic stress conditions.
    Keywords:  5-HT7 receptor; AMPK-PGC-1α axis; chronic stress; intestinal barrier; mitochondrial biogenesis; serotonin
    DOI:  https://doi.org/10.7150/ijbs.97275
  21. Int J Mol Sci. 2024 Sep 07. pii: 9707. [Epub ahead of print]25(17):
    SIRT1 Regulates Mitochondrial Damage in N2a Cells Treated with the Prion Protein Fragment 106-126 via PGC-1α-TFAM-Mediated Mitochondrial Biogenesis.
    Mengyang Zhao, Jie Li, Zhiping Li, Dongming Yang, Dongdong Wang, Zhixin Sun, Pei Wen, Fengting Gou, Yuexin Dai, Yilan Ji, Wen Li, Deming Zhao, Lifeng Yang.
      Mitochondrial damage is an early and key marker of neuronal damage in prion diseases. As a process involved in mitochondrial quality control, mitochondrial biogenesis regulates mitochondrial homeostasis in neurons and promotes neuron health by increasing the number of effective mitochondria in the cytoplasm. Sirtuin 1 (SIRT1) is a NAD+-dependent deacetylase that regulates neuronal mitochondrial biogenesis and quality control in neurodegenerative diseases via deacetylation of a variety of substrates. In a cellular model of prion diseases, we found that both SIRT1 protein levels and deacetylase activity decreased, and SIRT1 overexpression and activation significantly ameliorated mitochondrial morphological damage and dysfunction caused by the neurotoxic peptide PrP106-126. Moreover, we found that mitochondrial biogenesis was impaired, and SIRT1 overexpression and activation alleviated PrP106-126-induced impairment of mitochondrial biogenesis in N2a cells. Further studies in PrP106-126-treated N2a cells revealed that SIRT1 regulates mitochondrial biogenesis through the PGC-1α-TFAM pathway. Finally, we showed that resveratrol resolved PrP106-126-induced mitochondrial dysfunction and cell apoptosis by promoting mitochondrial biogenesis through activation of the SIRT1-dependent PGC-1α/TFAM signaling pathway in N2a cells. Taken together, our findings further describe SIRT1 regulation of mitochondrial biogenesis and improve our understanding of mitochondria-related pathogenesis in prion diseases. Our findings support further investigation of SIRT1 as a potential target for therapeutic intervention of prion diseases.
    Keywords:  SIRT1; mitochondrial biogenesis; mitochondrial quality control; prion disease; resveratrol
    DOI:  https://doi.org/10.3390/ijms25179707
  22. Cell Rep Med. 2024 Sep 04. pii: S2666-3791(24)00436-1. [Epub ahead of print] 101715
    Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury.
    Preethy S Sridharan, Yeojung Koh, Emiko Miller, Di Hu, Suwarna Chakraborty, Sunil Jamuna Tripathi, Teresa R Kee, Kalyani Chaubey, Edwin Vázquez-Rosa, Sarah Barker, Hui Liu, Rose A León-Alvarado, Kathryn Franke, Coral J Cintrón-Pérez, Matasha Dhar, Min-Kyoo Shin, Margaret E Flanagan, Rudolph J Castellani, Tamar Gefen, Marina Bykova, Lijun Dou, Feixiong Cheng, Brigid M Wilson, Hisashi Fujioka, David E Kang, Jung-A A Woo, Bindu D Paul, Xin Qi, Andrew A Pieper.
      Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers chronic neurodegeneration persisting 17 months later, equivalent to many human decades. We show that increased mitochondrial fission after mouse TBI is related to increased brain levels of mitochondrial fission 1 protein (Fis1) and that brain Fis1 is also elevated in human TBI. Pharmacologically preventing Fis1 from binding its mitochondrial partner, dynamin-related protein 1 (Drp1), for 2 weeks after TBI normalizes the balance of mitochondrial fission/fusion and prevents chronically impaired mitochondrial bioenergetics, oxidative damage, microglial activation and lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, and cognitive impairment. Delaying treatment until 8 months after TBI offers no protection. Thus, time-sensitive inhibition of acutely elevated mitochondrial fission may represent a strategy to protect human TBI patients from chronic neurodegeneration.
    Keywords:  Drp1; Fis1; blood-brain barrier; mitochondria; mitochondrial fission; mitochondrial fusion; neurodegeneration; neuroprotection; oxidative stress; traumatic brain injury
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101715
  23. bioRxiv. 2024 Aug 28. pii: 2024.08.28.609967. [Epub ahead of print]
    Reconstitution of BNIP3/NIX-mediated autophagy reveals two pathways and hierarchical flexibility of the initiation machinery.
    Elias Adriaenssens, Stefan Schaar, Annan S I Cook, Jan F M Stuke, Justyna Sawa-Makarska, Thanh Ngoc Nguyen, Xuefeng Ren, Martina Schuschnig, Julia Romanov, Grace Khuu, Michael Lazarou, Gerhard Hummer, James H Hurley, Sascha Martens.
      Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. While the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here, we demonstrate that transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex. This latter pathway is employed by the BNIP3/NIX receptors to trigger mitophagy. Additionally, other transmembrane mitophagy receptors, including FUNDC1 and BCL2L13, exclusively use the FIP200/ULK1 complex, while FKBP8 and the ER-phagy receptor TEX264 are capable of utilizing both pathways to initiate autophagy. Our study defines the molecular rules for initiation by transmembrane cargo receptors, revealing remarkable flexibility in the assembly and activation of the autophagy machinery, with significant implications for therapeutic interventions.
    DOI:  https://doi.org/10.1101/2024.08.28.609967
  24. Mitochondrion. 2024 Sep 06. pii: S1567-7249(24)00114-4. [Epub ahead of print] 101956
    Unravelling the anti-apoptotic role of Plasmodium falciparum Prohibitin-2 (PfPhb2) in maintaining mitochondrial homeostasis.
    Shilpi Jain, Monika Narwal, Md Omair Anwar, Neha Prakash, Asif Mohmmed.
      The functional mitochondrion is vital for the propagation of the malaria parasite in the human host. Members of the SPFH protein family, Prohibitins (PHBs), are known to play crucial roles in maintaining mitochondrial homeostasis and cellular functions. Here, we have functionally characterized the homologue of the Plasmodium falciparumProhibitin-2 (PfPhb2) protein. A transgenic parasite line, generated using the selection-linked integration (SLI) strategy for C-terminal tagging, was utilized for cellular localization as well as for inducible knock-down of PfPhb2. We show that PfPhb2 localizes in the parasite mitochondrion during the asexual life cycle. Inducible knock-down of PfPhb2 by GlmS ribozyme caused no significant effect on the growth and multiplication of parasites. However, depletion of PfPhb2 under mitochondrial-specific stress conditions, induced by inhibiting the essential mitochondrial AAA-protease, ClpQ protease, results in enhanced inhibition of parasite growth, mitochondrial ROS production, mitochondrial membrane potential loss and led to mitochondrial fission/fragmentation, ultimately culminating in apoptosis-like cell-death. Further, PfPhb2 depletion renders the parasites more susceptible to mitochondrial targeting drug proguanil. These data suggest the functional involvement of PfPhb2 along with ClpQ protease in stabilization of various mitochondrial proteins to maintain mitochondrial homeostasis and functioning. Overall, we show that PfPhb2 has an anti-apoptotic role in maintaining mitochondrial homeostasis in the parasite.
    Keywords:  AAA-protease; Cell death; Cellular stress; Mitochondrial homeostasis; Plasmodium; Prohibitins
    DOI:  https://doi.org/10.1016/j.mito.2024.101956
  25. CNS Neurosci Ther. 2024 Sep;30(9): e70021
    High-concentration hydrogen inhalation mitigates sepsis-associated encephalopathy in mice by improving mitochondrial dynamics.
    Yan Cui, Shuqi Meng, Nannan Zhang, Jingya Liu, Lina Zheng, Wanjie Ma, Yu Song, Zhiwei Wang, Yuehao Shen, Jianfeng Liu, Keliang Xie.
      BACKGROUND: Sepsis-associated encephalopathy (SAE) is a neuronal injury with poor prognosis. Mitochondrial dysfunction is critical in SAE development, and hydrogen gas (H2) has a protective effect on septic mice. This study aimed to investigate the effect of high concentration (67%) of H2 on SAE and whether it is related to mitochondrial biogenesis and mitochondrial dynamics.METHODS: A mouse sepsis model was induced by cecal ligation and puncture. The mice inhalated 67% H2 for 1 h at 1 and 6 h post-surgery, respectively. The 7-day survival rate was recorded. Cognitive function was assessed using the Y-maze test and Morris water maze test. Serum inflammatory factors, antioxidant enzymes, as well as mitochondrial function indexes including mitochondrial membrane potential (MMP) and ATP in the hippocampal tissue were evaluated 24 h after surgery. Mitochondrial dynamic proteins (DRP1 and MFN2) and biosynthetic proteins (PGC-1α, NRF2, and TFAM) in the hippocampal tissue were detected. Moreover, the morphology of mitochondria was observed by transmission electron microscopy.
    RESULTS: Inhalation of 67% H2 improved the 7-day survival rates and recognition memory function of septic mice, alleviated brain antioxidant enzyme activity (SOD and CAT), and reduced serum proinflammatory cytokine levels. H2 inhalation also enhanced the expression of MFN2 and mitochondrial biogenesis-related factors (PGC-1α, NRF2, and TFAM) and decreased the expression of fission protein (DRP1), leading to improvement in mitochondrial function, as evidenced by MMP and ATP levels.
    CONCLUSIONS: Inhalation of high concentration (67%) of H2 in septic mice improved the survival rate and reduced neuronal injury. Its mechanism might be mediated by enhancing mitochondrial biogenesis and mitochondrial dynamics.
    Keywords:  hydrogen; mitochondrial biogenesis; mitochondrial dynamics; sepsis‐associated encephalopathy
    DOI:  https://doi.org/10.1111/cns.70021
  26. Int J Mol Sci. 2024 Sep 06. pii: 9648. [Epub ahead of print]25(17):
    Cardiotoxicity of Iron and Zinc and Their Association with the Mitochondrial Unfolded Protein Response in Humans.
    Vid Mirosevic, Tomo Svagusa, Natalija Matic, Kresimir Maldini, Mario Siljeg, Davor Milicic, Hrvoje Gasparovic, Igor Rudez, Ana Sepac, Lucija Gojmerac, Ana Kulic, Petra Bakovic, Filip Sedlic.
      This study was designed to examine the association between myocardial concentrations of the trace elements Cu, Fe, Mn, Mo, and Zn and the expression of mitochondrial unfolded protein response (UPRmt) elements and the age of patients who received heart transplantation or a left-ventricular assist device (ageHTx/LVAD). Inductively coupled plasma mass spectrometry was used to determine the concentration of Cu, Fe, Mn, Mo, and Zn in the myocardium of control subjects and patients undergoing heart transplantation or left-ventricular assist device (LVAD) implantation. We used ELISA to quantify the expression of UPRmt proteins and 4-Hydroxynonenal (4-HNE), which served as a marker of oxidative-stress-induced lipid peroxidation. Concentrations of Cu, Mn, Mo, and Zn were similar in the control and heart failure (HF) myocardium, while Fe showed a significant decrease in the HF group compared to the control. A higher cumulative concentration of Fe and Zn in the myocardium was associated with reduced ageHTx/LVAD, which was not observed for other combinations of trace elements or their individual effects. The trace elements Cu, Mn, and Zn showed positive correlations with several UPRmt proteins, while Fe had a negative correlation with UPRmt effector protease YME1L. None of the trace elements correlated with 4-HNE in the myocardium. The concentrations of the trace elements Mn and Zn were significantly higher in the myocardium of patients with dilated cardiomyopathy than in patients with ischemic cardiomyopathy. A higher cumulative concentration of Fe and Zn in the myocardium was associated with a younger age at which patients received heart transplantation or LVAD, potentially suggesting an acceleration of HF. A positive correlation between myocardial Cu, Mn, and Zn and the expression of UPRmt proteins and a negative correlation between myocardial Fe and YME1L expression suggest that these trace elements exerted their actions on the human heart by interacting with the UPRmt. An altered generation of oxidative stress was not an underlying mechanism of the observed changes.
    Keywords:  cardiomyopathy; heart failure; mitochondrial unfolded protein response; oxidative stress; trace elements
    DOI:  https://doi.org/10.3390/ijms25179648
  27. Mol Biotechnol. 2024 Sep 12.
    Multi-omics and Single Cell Sequencing Analyses Reveal Associations of Mitophagy-Related Genes Predicting Clinical Prognosis and Immune Infiltration Characteristics in Osteosarcoma.
    Shengquan Ren, Rongfang Pan, Zhengdan Wang.
      Despite recent advances in clinical treatments, identifying high-risk osteosarcoma (OS) patients remains an unresolved clinical challenge. Mitophagy, a specialized form of cellular autophagy, selectively reduces the number of mitochondria or repairs their abnormal functions in response to external stress, thereby ensuring mitochondrial quality and maintaining mitochondrial function. Mitophagy plays a crucial role in cancer development, including processes such as mitochondrial repair, homeostasis maintenance, and tumor metabolism. However, its impact on OS has not yet been reported. In this study, we collected 58 mitophagy-related genes (MPRGs) from the TARGET and GEO databases and bioinformatically screened for those associated with OS prognosis. By LASSO-multivariable Cox regression algorithm, we subsequently developed a novel scoring system, the MPRG score, and validated its significance in predicting OS prognosis. Immune landscape analysis showed patients in the low MPRG group had a higher immune infiltration level than those in the high MPRG group. Drug sensitivity differences highlighted the potential need for alternative therapeutic strategies based on MPRG scoring system. The distribution characteristics of the MPRG signature in different cell subtypes of OS were explored by single-cell sequencing analyses. In vitro experiments further confirmed the abnormal expression of screened targets in OS. Our findings highlight the role of mitophagy in OS and its potential as a therapeutic target.
    Keywords:  Drug sensitivity; Immunoinfiltration characteristic; Mitophagy; Molecular subtype; Osteosarcoma; Single cell sequencing analysis
    DOI:  https://doi.org/10.1007/s12033-024-01280-w
  28. Autophagy. 2024 Sep 12. 1-19
    Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.
    Jie Sun, Jie Ding, Han Yue, Binbin Xu, Akrit Sodhi, Kang Xue, Hui Ren, Jiang Qian.
      Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year; preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced BNIP3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, BNIP3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1α protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses BNIP3-induced UM progression and metastasis in vitro and in vivo. Collectively, these observations demonstrate a novel mechanism whereby BNIP3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that BNIP3 could be an important therapeutic target to prevent metastasis in patients with UM.Abbreviations: AOD: average optical density; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine; CoCl2: cobalt chloride; GEPIA: Gene Expression Profiling Interactive Analysis; HIF1A: hypoxia inducible factor 1, alpha subunit; IHC: immunohistochemistry; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; TCGA: The Cancer Genome Atlas; UM: uveal melanoma.
    Keywords:  BNIP3; HIF1A; glycolysis; mitophagy; oxidative phosphorylation; uveal melanoma
    DOI:  https://doi.org/10.1080/15548627.2024.2395142
  29. J Vis Exp. 2024 Aug 23.
    Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
    Alyssa C Vadovsky, Melissa Quinn, Tianyi Xia, Yan Levitsky, Jason N Bazil.
      Mitochondrial isolation has been practiced for decades, following procedures established by pioneers in the fields of molecular biology and biochemistry to study metabolic impairments and disease. Consistent mitochondrial quality is necessary to properly investigate mitochondrial physiology and bioenergetics; however, many different published isolation methods are available for researchers. Although different experimental strategies require different isolation methods, the basic principles and procedures are similar. This protocol details a method capable of extracting well-coupled mitochondria from a variety of tissue sources, including small animals and cells. The steps outlined include organ dissection, mitochondrial purification, protein quantification, and various quality control checks. The primary quality control metric used to identify high-quality mitochondria is the respiratory control ratio (RCR). The RCR is the ratio of the respiratory rate during oxidative phosphorylation to the rate in the absence of ADP. Alternative metrics are discussed. While high RCR values relative to their tissue source are obtained using this protocol, several steps can be optimized to suit the individual needs of researchers. This procedure is robust and has consistently resulted in isolated mitochondria with above-average RCR values across animal models and tissue sources.
    DOI:  https://doi.org/10.3791/67093
  30. Acta Biochim Biophys Sin (Shanghai). 2024 Sep 12.
    Silencing of PCK1 mitigates the proliferation and migration of vascular smooth muscle cells and vascular intimal hyperplasia by suppressing STAT3/DRP1-mediated mitochondrial fission.
    Li Zhang, Yingmei Chen, Quanrong Pan, Shizheng Fang, Zhongjian Zhang, Jia Wang, Yongjian Yang, Dachun Yang, Xiongshan Sun.
      The pathological proliferation and migration of vascular smooth muscle cells (VSMCs) are key processes during vascular neointimal hyperplasia (NIH) and restenosis. Phosphoenolpyruvate carboxy kinase 1 (PCK1) is closely related to a variety of malignant proliferative diseases. However, the role of PCK1 in VSMCs has rarely been investigated. This study aims to examine the role of PCK1 in the proliferation and migration of VSMCs and vascular NIH after injury. In vivo, extensive NIH and increased expression of PCK1 within the neointima are observed in injured arteries. Interestingly, the administration of adeno-associated virus-9 (AAV-9) carrying Pck1 short hairpin RNA (sh Pck1) significantly attenuates NIH and stenosis of the vascular lumen. In vitro, Pck1 small interfering RNA (si Pck1)-induced PCK1 silencing inhibits VSMC proliferation and migration. Additionally, silencing of PCK1 leads to reduced expression of dynamin-related protein 1 (DRP1) and attenuated mitochondrial fission. Lentivirus-mediated DRP1 overexpression markedly reverses the inhibitory effects of PCK1 silencing on VSMC proliferation, migration, and mitochondrial fission. Finally, PCK1 inhibition attenuates the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Activation of STAT3 abolishes the suppressive effects of PCK1 silencing on DRP1 expression, mitochondrial fission, proliferation, and migration in VSMCs. In conclusion, PCK1 inhibition attenuates the mitochondrial fission, proliferation, and migration of VSMCs by inhibiting the STAT3/DRP1 axis, thereby suppressing vascular NIH and restenosis.
    Keywords:  dynamin-related protein 1; mitochondrial fission; neointimal hyperplasia; phosphoenolpyruvate carboxyl kinase 1; vascular smooth muscle cells
    DOI:  https://doi.org/10.3724/abbs.2024154
  31. Chem Sci. 2024 Aug 28.
    Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology.
    Wakana Yamada, Shusuke Tomoshige, Sho Nakamura, Shinichi Sato, Minoru Ishikawa.
      Dysfunction of mitochondria is implicated in various diseases, including cancer and neurodegenerative disorders, but drug discovery targeting mitochondria and mitochondrial proteins has so far made limited progress. Targeted protein degradation (TPD) technologies represented by proteolysis targeting chimeras (PROTACs) are potentially applicable for this purpose, but most existing TPD approaches leverage the ubiquitin-proteasome system or lysosomes, which are absent in mitochondria, and TPD in mitochondria (mitoTPD) remains little explored. Herein, we describe the design and synthesis of a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. This compound successfully induced the degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix. Furthermore, in cells overexpressing mSA fused to short transmembrane protein 1 (mSA-STMP1), which enhances mitochondrial fission, our mitochondrial mSA degrader restored the mitochondrial morphology by reducing the level of mSA-STMP1. A preliminary structure-activity relationship study indicated that a longer linker length enhances the degradation activity towards mSA. These findings highlight the potential of mitoTPD as a tool for drug discovery targeting mitochondria and for research in mitochondrial biology, as well as the utility of mSA as a degradation tag for mitochondrial protein.
    DOI:  https://doi.org/10.1039/d4sc03145h
  32. iScience. 2024 Sep 20. 27(9): 110710
    The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.
    Cheng-Liang Kuo, Ying-Chen Lin, Yu Kang Lo, Yu-Zhi Lu, Ananth Ponneri Babuharisankar, Hui-Wen Lien, Han-Yu Chou, Alan Yueh-Luen Lee.
      Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.
    Keywords:  Cancer; Immune response; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110710
  33. Mol Cell Neurosci. 2024 Sep 10. pii: S1044-7431(24)00054-X. [Epub ahead of print]131 103969
    SUMOylation modulates mitochondrial dynamics in an in vitro rotenone model of Parkinson's disease.
    Ericks Sousa Soares, Letícia Yoshitome Queiroz, Ellen Gerhardt, Rui Daniel S Prediger, Tiago Fleming Outeiro, Helena Iturvides Cimarosti.
      SUMOylation is a post-translational modification essential for various biological processes. SUMO proteins bind to target substrates in a three-step enzymatic pathway, which is rapidly reversible by the action of specific proteases, known as SENPs. Studies have shown that SUMOylation is dysregulated in several human disorders, including neurodegenerative diseases that are characterized by the progressive loss of neurons, mitochondrial dysfunction, deficits in autophagy, and oxidative stress. Considering the potential neuroprotective roles of SUMOylation, the aim of this study was to investigate the effects of SENP3 knockdown in H4 neuroglioma cells exposed to rotenone, an in vitro model of cytotoxicity that mimics dopaminergic loss in Parkinson's disease (PD). The current data show that SENP3 knockdown increases SUMO-2/3 conjugates, which is accompanied by reduced levels of the mitochondrial fission protein Drp1 and increased levels of the mitochondrial fusion protein OPA1. Of high interest, SENP3 knockdown prevented rotenone-induced superoxide production and cellular death. Taken together, these findings highlight the importance of SUMOylation in maintaining mitochondrial homeostasis and the neuroprotective potential of this modification in PD.
    Keywords:  Mitochondria; Parkinson's disease; SENP3 knockdown; SUMOylation
    DOI:  https://doi.org/10.1016/j.mcn.2024.103969
  34. Autophagy. 2024 Sep 08. 1-20
    Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.
    Tzu-Lin Lee, Wen-Chi Shen, Ya-Chun Chen, Tsai-Chun Lai, Shu-Rung Lin, Shu-Wha Lin, I-Shing Yu, Yen-Hsiu Yeh, Tsai-Kun Li, I-Ta Lee, Chiang-Wen Lee, Yuh-Lien Chen.
      Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Mir221 and Mir222. The present study investigated the effects of PM exposure on I/R-induced cardiac injury through mitophagy and apoptosis, as well as the potential role of Mir221 and Mir222 in ADSC-Exos. Wild-type, mir221- and mir222-knockout (KO), and Mir221- and Mir222-overexpressing transgenic (TG) mice were intratracheally injected with PM (10 mg/kg). After 24 h, mice underwent left coronary artery ligation for 30 min, followed by 3 h of reperfusion (I/R). H9c2 cardiomyocytes were cultured under 1% O2 for 6 h, then reoxygenated for 12 h (hypoxia-reoxygenation [H/R]). PM aggravated I/R (or H/R) cardiac injury by increasing ROS levels and causing mitochondrial dysfunction, which increased the expression of mitochondrial fission-related proteins (DNM1L/Drp1 and MFF) and mitophagy-related proteins (BNIP3 and MAP1LC3B/LC3B) in vivo and in vitro. Treatment with ADSC-Exos or Mir221- and Mir222-mimics significantly reduced PM+I/R-induced cardiac injury. Importantly, ADSC-Exos contain Mir221 and Mir222, which directly targets BNIP3, MAP1LC3B/LC3B, and BBC3/PUMA, decreasing their expression and ultimately reducing cardiomyocyte mitophagy and apoptosis. The present data showed that ADSC-Exos treatment regulated mitophagy and apoptosis through the Mir221 and Mir222-BNIP3-MAP1LC3B-BBC3/PUMA pathway and significantly reduced the cardiac damage caused by PM+I/R. The present study revealed the novel therapeutic potential of ADSC-Exos in alleviating PM-induced exacerbation of myocardial I/R injury.Abbreviation: ADSC-Exos: adipose-derived stem cell exosomes; AL: autolysosome; ATP: adenosine triphosphate; BBC3/PUMA: BCL2 binding component 3; BNIP3: BCL2/adenovirus E1B interacting protein 3; CASP3: caspase 3; CASP9: caspase 9; CDKN1B/p27: cyclin dependent kinase inhibitor 1B; CVD: cardiovascular disease; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DHE: dihydroethidium; DNM1L/Drp1: dynamin 1-like; EF: ejection fraction; FS: fractional shortening; H/R: hypoxia-reoxygenation; I/R: ischemia-reperfusion; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; miRNA: microRNA; NAC: N-acetylcysteine; OCR: oxygen consumption rate; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PM: particulate matter; PRKAA1/AMPK: protein kinase AMP-activated catalytic subunit alpha 1; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TRP53/p53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.
    Keywords:  ADSC-exosomes; Mir221 and Mir222; cardiomyocyte; ischemia/reperfusion injury; mitophagy; particulate matter
    DOI:  https://doi.org/10.1080/15548627.2024.2395799
  35. Biomed Pharmacother. 2024 Sep 11. pii: S0753-3322(24)01292-7. [Epub ahead of print]179 117407
    Iron chelators as mitophagy agents: Potential and limitations.
    Tereza Brogyanyi, Zdeněk Kejík, Kateřina Veselá, Petr Dytrych, David Hoskovec, Michal Masařik, Petr Babula, Robert Kaplánek, Tomáš Přibyl, Jaroslav Zelenka, Tomáš Ruml, Martin Vokurka, Pavel Martásek, Milan Jakubek.
      Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.
    Keywords:  Cancer; Cardiovascular diseases; Iron chelators; Iron heomeostais; Mitophagy; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.biopha.2024.117407
  36. Cells. 2024 Aug 27. pii: 1433. [Epub ahead of print]13(17):
    Metformin Alleviates Inflammation and Induces Mitophagy in Human Retinal Pigment Epithelium Cells Suffering from Mitochondrial Damage.
    Maija Toppila, Sofia Ranta-Aho, Kai Kaarniranta, Maria Hytti, Anu Kauppinen.
      Mitochondrial malfunction, excessive production of reactive oxygen species (ROS), deficient autophagy/mitophagy, and chronic inflammation are hallmarks of age-related macular degeneration (AMD). Metformin has been shown to activate mitophagy, alleviate inflammation, and lower the odds of developing AMD. Here, we explored the ability of metformin to activate mitophagy and alleviate inflammation in retinal pigment epithelium (RPE) cells. Human ARPE-19 cells were pre-treated with metformin for 1 h prior to exposure to antimycin A (10 µM), which induced mitochondrial damage. Cell viability, ROS production, and inflammatory cytokine production were measured, while autophagy/mitophagy proteins were studied using Western blotting and immunocytochemistry. Metformin pre-treatment reduced the levels of proinflammatory cytokines IL-6 and IL-8 to 42% and 65% compared to ARPE-19 cells exposed to antimycin A alone. Metformin reduced the accumulation of the autophagy substrate SQSTM1/p62 (43.9%) and the levels of LC3 I and II (51.6% and 48.6%, respectively) after antimycin A exposure. Metformin also increased the colocalization of LC3 with TOM20 1.5-fold, suggesting active mitophagy. Antimycin A exposure increased the production of mitochondrial ROS (226%), which was reduced by the metformin pre-treatment (84.5%). Collectively, metformin showed anti-inflammatory and antioxidative potential with mitophagy induction in human RPE cells suffering from mitochondrial damage.
    Keywords:  AMD; RPE; autophagy; inflammation; metformin; mitochondrial ROS
    DOI:  https://doi.org/10.3390/cells13171433
  37. Cardiovasc Toxicol. 2024 Sep 12.
    The Worsening of Myocardial Ischemia-Reperfusion Injury in Uremic Cardiomyopathy is Further Aggravated by PM2.5 Exposure: Mitochondria Serve as the Central Focus of Pathology.
    Bhavana Sivakumar, Gino A Kurian.
      Uremic cardiomyopathy (UC) represents a complex syndrome characterized by different cardiac complications, including systolic and diastolic dysfunction, left ventricular hypertrophy, and diffuse fibrosis, potentially culminating in myocardial infarction (MI). Revascularization procedures are often necessary for MI management and can induce ischemia reperfusion injury (IR). Despite this clinical relevance, the role of fine particulate matter (PM2.5) in UC pathology and the underlying subcellular mechanisms governing this pathology remains poorly understood. Hence, we investigate the impact of PM2.5 exposure on UC susceptibility to IR injury. Using a rat model of adenine-induced chronic kidney disease (CKD), the animals were exposed to PM2.5 at 250 µg/m3 for 3 h daily over 21 days. Subsequently, hearts were isolated and subjected to 30 min of ischemia followed by 60 min of reperfusion to induce IR injury. UC hearts exposed to PM2.5 followed by IR induction (Adenine + PM_IR) exhibited significantly impaired cardiac function and increased cardiac injury (increased infarct size and apoptosis). Analysis at the subcellular level revealed reduced mitochondrial copy number, impaired mitochondrial bioenergetics, decreased expression of PGC1-α (a key regulator of mitochondrial biogenesis), and compromised mitochondrial quality control mechanisms. Additionally, increased mitochondrial oxidative stress and perturbation of the PI3K/AKT/AMPK signaling axis were evident. Our findings therefore collectively indicate that UC myocardium when exposed to PM2.5 is more vulnerable to IR-induced injury, primarily due to severe mitochondrial impairment.
    Keywords:  Mitochondria; Myocardial ischemia reperfusion injury; Oxidative stress; PM2.5 ; Uremic cardiomyopathy
    DOI:  https://doi.org/10.1007/s12012-024-09920-y
  38. Mol Med. 2024 Sep 12. 30(1): 147
    SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer.
    Xuehua Wei, Xiangpeng Xiong, Pingping Wang, Shufang Zhang, Dongxian Peng.
      BACKGROUND: The complex interplay between Sirtuin 1 (SIRT1) and FOXO3 in endometrial cancer (EC) remains understudied. This research aims to unravel the interactions of deacetylase SIRT1 and transcription factor FOXO3 in EC, focusing on their impact on mitophagy and hormone resistance.METHODS: High-throughput sequencing, cell experiments, and bioinformatics tools were employed to investigate the roles and interactions of SIRT1 and FOXO3 in EC. Co-immunoprecipitation (Co-IP) assay was used to assess the interaction between SIRT1 and FOXO3 in RL95-2 cells. Functional assays were used to assess cell viability, proliferation, migration, invasion, apoptosis, and the expression of related genes and proteins. A mouse model of EC was established to evaluate tumor growth and hormone resistance under different interventions. Immunohistochemistry and TUNEL assays were used to assess protein expression and apoptosis in tumor tissues.
    RESULTS: High-throughput transcriptome sequencing revealed a close association between SIRT1, FOXO3, and EC development. Co-IP showed a protein-protein interaction between SIRT1 and FOXO3. Overexpression of SIRT1 enhanced FOXO3 deacetylation and activity, promoting BNIP3 transcription and PINK1/Parkin-mediated mitophagy, which in turn promoted cell proliferation, migration, invasion, and inhibited apoptosis in vitro, as well as increased tumor growth and hormone resistance in vivo. These findings highlighted SIRT1 as an upstream regulator and potential therapeutic target in EC.
    CONCLUSION: This study reveals a novel molecular mechanism underlying the functional relevance of SIRT1 in regulating mitophagy and hormone resistance through the deacetylation of FOXO3 in EC, thereby providing valuable insights for new therapeutic strategies.
    Keywords:  BNIP3/PINK1/Parkin signaling pathway; Deacetylation modification; Endometrial cancer; FOXO3; Hormone resistance; Mitophagy; SIRT1
    DOI:  https://doi.org/10.1186/s10020-024-00915-7
  39. Adv Sci (Weinh). 2024 Sep 12. e2401856
    Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.
    Lihao Jin, Dingyi Gan, Wentao He, Na Wu, Shuchenlu Xiang, Yinsheng Wei, Gilbert Eriani, Yanchun Ji, Min-Xin Guan, Meng Wang.
      Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.
    Keywords:  apoptosis; leber's hereditary optic neuropathy; mitochondrial tRNA mutation; mitophagy; phenotypic expression
    DOI:  https://doi.org/10.1002/advs.202401856
  40. Microbiol Res. 2024 Sep 03. pii: S0944-5013(24)00293-3. [Epub ahead of print]289 127892
    Endoplasmic reticulum-mitochondrial encounter structure regulates the mitochondrial morphology, DON biosynthesis and toxisome formation in Fusarium graminearum.
    Jichang Song, Yige Li, Ziyang Zhang, Xinlong Gao, Shengxue Li, Jie Zhang, Mingguo Zhou, Yabing Duan.
      The endoplasmic reticulum-mitochondrial encounter structure (ERMES) complex is known to play crucial roles in various cellular processes. However, its functional significance in filamentous fungi, particularly its impact on deoxynivalenol (DON) biosynthesis in Fusarium graminearum, remains inadequately understood. In this study, we aimed to investigate the regulatory function of the ERMES complex in F. graminearum. Our findings indicate significant changes in mitochondrial morphology of ERMES mutants, accompanied by decreased ATP content and ergosterol production. Notably, the toxisome formation in the ERMES mutant ΔFgMDM10 was defective, resulting in a substantial reduction in DON biosynthesis. This suggests a pivotal role of ERMES in toxisome formation, as evidenced by the pronounced inhibition of toxisome formation when ERMES was disrupted by boscalid. Furthermore, ERMES deficiencies were shown to diminish the virulence of F. graminearum towards host plants significantly. In conclusion, our results suggest ERMES is an important regulator of mitochondrial morphology, DON biosynthesis, and toxisome formation in F. graminearum.
    Keywords:  DON; ERMES; Fusarium graminearum; Mitochondrial morphology; Toxisome
    DOI:  https://doi.org/10.1016/j.micres.2024.127892
  41. Int J Biol Sci. 2024 ;20(11): 4258-4276
    The PI3K/Akt-Nrf2 Signaling Pathway and Mitophagy Synergistically Mediate Hydroxytyrosol to Alleviate Intestinal Oxidative Damage.
    Xiaobin Wen, Shanlong Tang, Fan Wan, Ruqing Zhong, Liang Chen, Hongfu Zhang.
      Oxidative stress is a major pathogenic factor in many intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). The Nrf2 signaling pathway and mitophagy can reduce reactive oxygen species (ROS) and alleviate oxidative stress, but their relationship is unclear. Hydroxytyrosol (HT), a polyphenolic compound abundant in olive oil, has strong antioxidant activity and may help treat these diseases. We used pigs as a model to investigate HT's effect on intestinal oxidative damage and its mechanisms. Diquat (DQ) induced oxidative stress and impaired intestinal barrier function, which HT mitigated. Mechanistic studies in IPEC-J2 cells showed that HT protected against oxidative damage by activating the PI3K/Akt-Nrf2 signaling pathway and promoting mitophagy. Our study highlighted the synergistic relationship between Nrf2 and mitophagy in mediating HT's antioxidant effects. Inhibition studies confirmed that disrupting either pathway compromised HT's protective effects. Maintaining redox balance through Nrf2 and mitophagy is important for eliminating excess ROS. Nrf2 increases antioxidant enzymes to clear existing ROS, while mitophagy removes damaged mitochondria and reduces ROS generation. This study demonstrates that these pathways collaboratively modulate the antioxidant effects of HT, with neither being dispensable. Targeting Nrf2 and mitophagy could be a promising strategy for treating oxidative stress-related intestinal diseases, with HT as a potential treatment.
    Keywords:  Hydroxytyrosol; Intestinal health; Mitophagy; Nrf2 signaling pathway; Oxidative stress
    DOI:  https://doi.org/10.7150/ijbs.97263
  42. Chemosphere. 2024 Sep 07. pii: S0045-6535(24)02199-4. [Epub ahead of print] 143301
    Reduced bioenergetics and mitochondrial fragmentation in human primary cytotrophoblasts induced by an EGFR-targeting chemical mixture.
    Anita A Waye, Elvis Ticiani, Zinat Sharmin, Vanessa Perez Silos, Thilini Perera, Alex Tu, Irina A Buhimschi, Carlos A Murga-Zamalloa, Ying S Hu, Almudena Veiga-Lopez.
      Exposures to complex environmental chemical mixtures during pregnancy reach and target the feto-placental unit. This study investigates the influence of environmental chemical mixtures on placental bioenergetics. Recognizing the essential role of the epidermal growth factor receptor (EGFR) in placental development and its role in stimulating glycolysis and mitochondrial respiration in trophoblast cells, we explored the effects of chemicals known to disrupt EGFR signaling on cellular energy production. Human primary cytotrophoblasts (hCTBs) and a first-trimester extravillous trophoblast cell line (HTR-8/SVneo) were exposed to a mixture of EGFR-interfering chemicals, including atrazine, bisphenol S, niclosamide, PCB-126, PCB-153, and trans-nonachlor. An RNA sequencing approach revealed that the mixture altered the transcriptional signature of genes involved in cellular energetics. Next, the impact of the mixture on cellular bioenergetics was evaluated using a combination of mitochondrial and glycolytic stress tests, ATP production, glucose consumption, lactate synthesis, and super-resolution imaging. The chemical mixture did not alter basal oxygen consumption but diminished the maximum respiratory capacity in a dose-dependent manner, indicating a disruption of mitochondrial function. The respiratory capacity and ATP production were increased by EGF, while the Chem-Mix reduced both EGF- and non-EGF-mediated oxygen consumption rate in hCTBs. A similar pattern was observed in the glycolytic medium acidification, with EGF increasing the acidification, and the Chem-Mix blocking EGF-induced glycolytic acidification. Furthermore, direct stochastic optical reconstruction microscopy (dSTORM) imaging demonstrated that the Chem-Mix led to a reduction of the mitochondrial network architecture, with findings supported by a decrease in the abundance of OPA1, a mitochondrial membrane GTPase involved in mitochondrial fusion. In conclusion, we demonstrated that a mixture of EGFR-disrupting chemicals alters mitochondrial remodeling, resulting in disturbed cellular bioenergetics, reducing the capacity of human cytotrophoblast cells to generate energy. Future studies should investigate the mechanism by which mitochondrial dynamics are disrupted and the pathological significance of these findings.
    Keywords:  bioenergetics; chemical mixture; mitochondria; placenta
    DOI:  https://doi.org/10.1016/j.chemosphere.2024.143301
  43. J Pharm Anal. 2024 Aug;14(8): 100933
    Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis.
    Yini Bao, Qiyuan Shan, Keda Lu, Qiao Yang, Ying Liang, Haodan Kuang, Lu Wang, Min Hao, Mengyun Peng, Shuosheng Zhang, Gang Cao.
      Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing a major public health challenge worldwide. The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear, and effective treatments are still lacking. Renal tubular epithelial cells (RTECs) maintain kidney function, and their dysfunction has emerged as a critical contributor to renal fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system (UPS), autophagy, mitochondrial homeostasis (mitophagy and mitochondrial metabolism), endoplasmic reticulum (ER, unfolded protein response), and lysosomes. Failures in the cellular quality control of RTECs, including DNA, protein, and organelle damage, exert profibrotic functions by leading to senescence, defective autophagy, ER stress, mitochondrial and lysosomal dysfunction, apoptosis, fibroblast activation, and immune cell recruitment. In this review, we summarize recent advances in understanding the role of quality control components and intercellular crosstalk networks in RTECs, within the context of renal fibrosis.
    Keywords:  Autophagy; Mitochondria; Quality control; Renal fibrosis; Renal tubular epithelial cells; Telomere homeostasis
    DOI:  https://doi.org/10.1016/j.jpha.2024.01.001
  44. Autophagy. 2024 Sep 08.
    Targeted proteomics addresses selectivity and complexity of protein degradation by autophagy.
    Alexandre Leytens, Rocío Benítez-Fernández, Carlos Jiménez-García, Carole Roubaty, Michael Stumpe, Patricia Boya, Jörn Dengjel.
      Macroautophagy/autophagy is a constitutively active catabolic lysosomal degradation pathway, often found dysregulated in human diseases. It is often considered to act in a cytoprotective manner and is commonly upregulated in cells undergoing stress. Its initiation is regulated at the protein level and does not require de novo protein synthesis. Historically, autophagy has been regarded as non-selective; however, it is now clear that different stimuli can lead to the selective degradation of cellular components via selective autophagy receptors (SARs). Due to its selective nature and the existence of multiple degradation pathways potentially acting in concert, monitoring of autophagy flux, i.e. selective autophagy-dependent protein degradation, should address this complexity. Here, we introduce a targeted proteomics approach monitoring abundance changes of 37 autophagy-related proteins covering process-relevant proteins such as the initiation complex and the Atg8-family protein lipidation machinery, as well as most known SARs. We show that proteins involved in autophagosome biogenesis are upregulated and spared from degradation under autophagy-inducing conditions in contrast to SARs, in a cell-line dependent manner. Classical bulk stimuli such as nutrient starvation mainly induce degradation of ubiquitin-dependent soluble SARs and not of ubiquitin-independent, membrane-bound SARs. In contrast, treatment with the iron chelator deferiprone leads to the degradation of ubiquitin-dependent and -independent SARs linked to mitophagy and reticulophagy/ER-phagy. Our approach is automatable and supports large-scale screening assays paving the way to (pre)clinical applications and monitoring of specific autophagy flux.
    Keywords:  ER-phagy; mass spectrometry; mitophagy; parallel reaction monitoring; reticulophagy; selective autophagy receptors
    DOI:  https://doi.org/10.1080/15548627.2024.2396792
  45. J Cardiovasc Pharmacol. 2024 Aug 30.
    Editorial on: Canagliflozin mediates mitophagy through the AMPK/PINK1/PARKIN pathway to alleviate isoprenaline-induced cardiac remodelling.
    Alfredo Caturano, Davide Nilo, Roberto Nilo, Vincenzo Russo, Marcellino Monda, Luca Rinaldi, Raffaele Marfella, Ferdinando Carlo Sasso.
      
    DOI:  https://doi.org/10.1097/FJC.0000000000001629
  46. iScience. 2024 Sep 20. 27(9): 110683
    Spastin regulates ER-mitochondrial contact sites and mitochondrial homeostasis.
    Amelie Raby, Sonia Missiroli, Peggy Sanatine, Dominique Langui, Julien Pansiot, Nissai Beaude, Lucie Vezzana, Rachelle Saleh, Martina Marinello, Mireille Laforge, Paolo Pinton, Ana Buj-Bello, Andrea Burgo.
      Mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) emerged to play critical roles in numerous cellular processes, and their dysregulation has been associated to neurodegenerative disorders. Mutations in the SPG4 gene coding for spastin are among the main causes of hereditary spastic paraplegia (HSP). Spastin binds and severs microtubules, and the long isoform of this protein, namely M1, spans the outer leaflet of ER membrane where it interacts with other ER-HSP proteins. Here, we showed that overexpressed M1 spastin localizes in ER-mitochondria intersections and that endogenous spastin accumulates in MERCs. We demonstrated in different cellular models that downregulation of spastin enhances the number of MERCs, alters mitochondrial morphology, and impairs ER and mitochondrial calcium homeostasis. These effects are associated with reduced mitochondrial membrane potential, oxygen species levels, and oxidative metabolism. These findings extend our knowledge on the role of spastin in the ER and suggest MERCs deregulation as potential causes of SPG4-HSP disease.
    Keywords:  Biological sciences; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2024.110683
  47. FASEB J. 2024 Sep;38(17): e70011
    SCUBE3 promotes osteogenic differentiation and mitophagy in human bone marrow mesenchymal stem cells through the BMP2/TGF-β signaling pathway.
    Hongyu Chen, Xiaoyong Wu, Yinan Lan, Xijie Zhou, Ye Zhang, Long Long, Yuliang Zhong, Zhengan Hao, Weijun Zhang, DeTing Xue.
      In clinical settings, addressing large bone defects remains a significant challenge for orthopedic surgeons. The use of genetically modified bone marrow mesenchymal stem cells (BMSCs) has emerged as a highly promising approach for these treatments. Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a multifunctional secreted glycoprotein, the role of which remains unclear in human hBMSCs. This study used various experimental methods to elucidate the potential mechanism by which SCUBE3 influences osteogenic differentiation of hBMSCs in vitro. Additionally, the therapeutic efficacy of SCUBE3, in conjunction with porous GeLMA microspheres, was evaluated in vivo using a mouse bone defect model. Our findings indicate that SCUBE3 levels increase significantly during early osteogenic differentiation of hBMSCs, and that reducing SCUBE3 levels can hinder this differentiation. Overexpressing SCUBE3 elevated osteogenesis gene and protein levels and enhanced calcium deposition. Furthermore, treatment with recombinant human SCUBE3 (rhSCUBE3) protein boosted BMP2 and TGF-β expression, activated mitophagy in hBMSCs, ameliorated oxidative stress, and restored osteogenic function through SMAD phosphorylation. In vivo, GELMA/OE treatment effectively accelerated bone healing in mice. In conclusion, SCUBE3 fosters osteogenic differentiation and mitophagy in hBMSCs by activating the BMP2/TGF-β signaling pathway. When combined with engineered hydrogel cell therapy, it could offer valuable guidance for the clinical management of extensive bone defects.
    Keywords:  BMP2; HBMSCs; SCUBE3; TGF‐β; mitophagy; osteogenic differentiation
    DOI:  https://doi.org/10.1096/fj.202400991R
  48. Transl Pediatr. 2024 Aug 31. 13(8): 1439-1456
    Identification of novel mitophagy-related biomarkers for Kawasaki disease by integrated bioinformatics and machine-learning algorithms.
    Yan Wang, Ying Liu, Nana Wang, Zhiheng Liu, Guanghui Qian, Xuan Li, Hongbiao Huang, Wenyu Zhuo, Lei Xu, Jiaying Zhang, Haitao Lv, Yang Gao.
      Background: Kawasaki disease (KD) is a systemic vasculitis primarily affecting the coronary arteries in children. Despite growing attention to its symptoms and pathogenesis, the exact mechanisms of KD remain unclear. Mitophagy plays a critical role in inflammation regulation, however, its significance in KD has only been minimally explored. This study sought to identify crucial mitophagy-related biomarkers and their mechanisms in KD, focusing on their association with immune cells in peripheral blood.Methods: This research used four datasets from the Gene Expression Omnibus (GEO) database that were categorized as the merged and validation datasets. Screening for differentially expressed mitophagy-related genes (DE-MRGs) was conducted, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A weighted gene co-expression network analysis (WGCNA) identified the hub module, while machine-learning algorithms [random forest-recursive feature elimination (RF-RFE) and support vector machine-recursive feature elimination (SVM-RFE)] pinpointed the hub genes. Receiver operating characteristic (ROC) curves were generated for these genes. Additionally, the CIBERSORT algorithm was used to assess the infiltration of 22 immune cell types to explore their correlations with hub genes. Interactions between transcription factors (TFs), genes, and Gene-microRNAs (miRNAs) of hub genes were mapped using the NetworkAnalyst platform. The expression difference of the hub genes was validated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).
    Results: Initially, 306 DE-MRGs were identified between the KD patients and healthy controls. The enrichment analysis linked these MRGs to autophagy, mitochondrial function, and inflammation. The WGCNA revealed a hub module of 47 KD-associated DE-MRGs. The machine-learning algorithms identified cytoskeleton-associated protein 4 (CKAP4) and serine-arginine protein kinase 1 (SRPK1) as critical hub genes. In the merged dataset, the area under the curve (AUC) values for CKAP4 and SRPK1 were 0.933 [95% confidence interval (CI): 0.901 to 0.964] and 0.936 (95% CI: 0.906 to 0.966), respectively, indicating high diagnostic potential. The validation dataset results corroborated these findings with AUC values of 0.872 (95% CI: 0.741 to 1.000) for CKAP4 and 0.878 (95% CI: 0.750 to 1.000) for SRPK1. The CIBERSORT analysis connected CKAP4 and SRPK1 with specific immune cells, including activated cluster of differentiation 4 (CD4) memory T cells. TFs such as MAZ, SAP30, PHF8, KDM5B, miRNAs like hsa-mir-7-5p play essential roles in regulating these hub genes. The qRT-PCR results confirmed the differential expression of these genes between the KD patients and healthy controls.
    Conclusions: CKAP4 and SRPK1 emerged as promising diagnostic biomarkers for KD. These genes potentially influence the progression of KD through mitophagy regulation.
    Keywords:  Kawasaki disease (KD); bioinformatics analysis; immune cell infiltration; machine learning; mitophagy
    DOI:  https://doi.org/10.21037/tp-24-230
  49. Neural Regen Res. 2024 Sep 06.
    Mitophagy in acute central nervous system injuries: regulatory mechanisms and therapeutic potentials.
    Siyi Xu, Junqiu Jia, Rui Mao, Xiang Cao, Yun Xu.
      Acute central nervous system injuries, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury, are a major global health challenge. Identifying optimal therapies and improving the long-term neurological functions of patients with acute central nervous system injuries are urgent priorities. Mitochondria are susceptible to damage after acute central nervous system injury, and this leads to the release of toxic levels of reactive oxygen species, which induce cell death. Mitophagy, a selective form of autophagy, is crucial in eliminating redundant or damaged mitochondria during these events. Recent evidence has highlighted the significant role of mitophagy in acute central nervous system injuries. In this review, we provide a comprehensive overview of the process, classification, and related mechanisms of mitophagy. We also highlight the recent developments in research into the role of mitophagy in various acute central nervous system injuries and drug therapies that regulate mitophagy. In the final section of this review, we emphasize the potential for treating these disorders by focusing on mitophagy and suggest future research paths in this area.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00432
  50. Nucleic Acid Ther. 2024 Sep 12.
    Antisense Oligonucleotide STK-002 Increases OPA1 in Retina and Improves Mitochondrial Function in Autosomal Dominant Optic Atrophy Cells.
    Aditya Venkatesh, Taylor McKenty, Syed Ali, Donna Sonntag, Shobha Ravipaty, Yanyan Cui, Deirdre Slate, Qian Lin, Anne Christiansen, Sarah Jacobson, Jacob Kach, Kian Huat Lim, Vaishnavi Srinivasan, Boris Zinshteyn, Isabel Aznarez, Laryssa A Huryn, Zhiyu Li, Robert B Hufnagel, Gene Liau, Karen Anderson, Jeff Hoger.
      Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy most frequently associated with OPA1 mutations. Most variants result in haploinsufficiency, and patient cells express roughly half of the normal levels of OPA1 protein. OPA1 is a mitochondrial GTPase that is essential for normal mitochondrial function. We identified and characterized STK-002, an antisense oligonucleotide (ASO) designed to prevent the incorporation of a naturally occurring alternatively spliced nonproductive exon in OPA1. STK-002 dose dependently reduced the inclusion of this exon, and increased OPA1 protein in human cells, including ADOA patient-derived fibroblasts. ADOA patient cells manifest reduced mitochondrial respiration, and treatment with STK-002 improved the parameters of mitochondrial respiratory function in these cells. Since STK-002 increases OPA1 through the wild-type allele, we assessed retinal OPA1 in wild-type cynomolgus monkeys and rabbits after intravitreal administration of STK-002 or a rabbit-specific surrogate. Increased OPA1 protein was produced in retinal tissue in both species at 4 weeks after ASO injection and persisted in monkeys at 8 weeks. STK-002 and enhanced OPA1 immunofluorescence were visualized in retinal ganglion cells of cynomolgus monkeys treated with the ASO. Cumulatively, these data support the progression of STK-002 toward the clinic as the first potential disease-modifying treatment for ADOA.
    Keywords:  ADOA; ASO; OPA1; exon splicing; haploinsufficiency; mRNA
    DOI:  https://doi.org/10.1089/nat.2024.0022
  51. Mol Biol Rep. 2024 Sep 09. 51(1): 969
    Cardioprotective effect of Vitamin D on cardiac hypertrophy through improvement of mitophagy and apoptosis in an experimental rat model of levothyroxine -induced hyperthyroidism.
    Farid Shokri, Khadijeh Ramezani-Aliakbari, Mohammad Zarei, Alireza Komaki, Safoura Raoufi, Hanieh Naddaf, Fatemeh Ramezani-Aliakbari.
      BACKGROUND: Mitochondria are known to be involved in mediating the calorigenic effects of thyroid hormones. With an abundance of these hormones, alterations in energy metabolism and cellular respiration take place, leading to the development of cardiac hypertrophy. Vitamin D has recently gained attention due to its involvement in the regulation of mitochondrial function, demonstrating promising potential in preserving the integrity and functionality of the mitochondrial network. The present study aimed to investigate the therapeutic potential of Vitamin D on cardiac hypertrophy induced by hyperthyroidism, with a focus on the contributions of mitophagy and apoptosis as possible underlying molecular mechanisms.METHODS AND RESULTS: The rats were divided into three groups: control; hyperthyroid; hyperthyroid + Vitamin D. Hyperthyroidism was induced by Levothyroxine administration for four weeks. Serum thyroid hormones levels, myocardial damage markers, cardiac hypertrophy indices, and histological examination were assessed. The assessment of Malondialdehyde (MDA) levels and the expression of the related genes were conducted using heart tissue samples. Vitamin D pretreatment exhibited a significant improvement in the hyperthyroidism-induced decline in markers indicative of myocardial damage, oxidative stress, and indices of cardiac hypertrophy. Vitamin D pretreatment also improved the downregulation observed in myocardial expression levels of genes involved in the regulation of mitophagy and apoptosis, including PTEN putative kinase 1 (PINK1), Mitofusin-2 (MFN2), Dynamin-related Protein 1 (DRP1), and B cell lymphoma-2 (Bcl-2), induced by hyperthyroidism.
    CONCLUSIONS: These results suggest that supplementation with Vitamin D could be advantageous in preventing the progression of cardiac hypertrophy and myocardial damage.
    Keywords:  Apoptosis; Cardiac hypertrophy; Hyperthyroidism; Mitochondria; Mitophagy; Vitamin D
    DOI:  https://doi.org/10.1007/s11033-024-09897-5
  52. Light Sci Appl. 2024 Sep 09. 13(1): 244
    Visualizing mitochondrial dynamics at the nanoscale.
    Till Stephan, Peter Ilgen, Stefan Jakobs.
      The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.
    DOI:  https://doi.org/10.1038/s41377-024-01582-3
  53. Cell Death Discov. 2024 Sep 06. 10(1): 397
    Transcriptional activation of PINK1 by MyoD1 mediates mitochondrial homeostasis to induce renal calcification in pediatric nephrolithiasis.
    Kaiping Zhang, Xiang Fang, Ye Zhang, Yin Zhang, Min Chao.
      This study aims to uncover the molecular mechanisms underlying pediatric kidney stone formation induced by renal calcium deposition by utilizing high-throughput sequencing data to reveal the regulation of PINK1 by MyoD1. We performed transcriptome sequencing on peripheral blood samples from healthy children and children with kidney stones to obtain differentially expressed genes (DEGs). Genes related to mitochondrial oxidative stress were obtained from the Genecards website and intersected with DEGs to obtain candidate target genes. Additionally, we conducted protein-protein interaction (PPI) analysis using the STRING database to identify core genes involved in pediatric kidney stone disease (KSD) and predicted their transcription factors using the hTFtarget database. We assessed the impact of MyoD1 on the activity of the PINK1 promoter using dual-luciferase reporter assays and investigated the enrichment of MyoD1 on the PINK1 promoter through chromatin immunoprecipitation (ChIP) experiments. To validate our hypothesis, we selected HK-2 cells and established an in vitro kidney stone model induced by calcium oxalate monohydrate (COM). We evaluated the expression levels of various genes, cell viability, volume of adherent crystals in each group, as well as mitochondrial oxidative stress in cells by measuring mitochondrial membrane potential (Δψm), superoxide dismutase (SOD) activity, reactive oxygen species (ROS), and malondialdehyde (MDA) content. Mitochondrial autophagy was assessed using mtDNA fluorescence staining and Western blot analysis of PINK1-related proteins. Apoptosis-related proteins were evaluated using Western blot analysis, and cell apoptosis was measured using flow cytometry. Furthermore, we developed a rat model of KSD and assessed the expression levels of various genes, as well as the pathologic changes in rat renal tissues using H&E and von Kossa staining, transmission electron microscopy (TEM), and the expression of creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) to evaluate the mitochondrial oxidative stress in vivo (through measurement of Δψm, SOD activity, ROS, and MDA content). Mitochondrial autophagy was evaluated by Western blot analysis of PINK1-associated proteins. Apoptosis-related proteins were detected using Western blot analysis, and cellular apoptosis was examined using cell flow cytometry and TUNEL staining. Bioinformatics analysis revealed that the PINK1 gene is upregulated and vital in pediatric kidney stone patients. Our in vitro and in vivo experiments demonstrated that silencing PINK1 could inhibit kidney stone formation by suppressing mitochondrial oxidative stress both in vitro and in vivo. We identified MyoD1 as an upstream transcription factor of PINK1 that contributes to the occurrence of pediatric kidney stones through the activation of PINK1. Our in vivo and in vitro experiments collectively confirmed that silencing MyoD1 could inhibit mitochondrial oxidative stress, mitochondrial autophagy, and cellular apoptosis in a rat model of kidney stones by downregulating PINK1 expression, consequently suppressing the formation of kidney stones. In this study, we discovered that MyoD1 may promote kidney stone formation and development in pediatric patients by transcriptionally activating PINK1 to induce mitochondrial oxidative stress.
    DOI:  https://doi.org/10.1038/s41420-024-02117-w
  54. Int J Mol Sci. 2024 Aug 23. pii: 9143. [Epub ahead of print]25(17):
    The Interplay between Autophagy and Mitochondria in Cancer.
    Aleksandra Zdanowicz, Emilia Grosicka-Maciąg.
      Besides producing cellular energy, mitochondria are crucial in controlling oxidative stress and modulating cellular metabolism, particularly under stressful conditions. A key aspect of this regulatory role involves the recycling process of autophagy, which helps to sustain energy homeostasis. Autophagy, a lysosome-dependent degradation pathway, plays a fundamental role in maintaining cellular homeostasis by degrading damaged organelles and misfolded proteins. In the context of tumor formation, autophagy significantly influences cancer metabolism and chemotherapy resistance, contributing to both tumor suppression and surveillance. This review focuses on the relationship between mitochondria and autophagy, specifically in the context of cancer progression. Investigating the interaction between autophagy and mitochondria reveals new possibilities for cancer treatments and may result in the development of more effective therapies targeting mitochondria, which could have significant implications for cancer treatment. Additionally, this review highlights the increasing understanding of autophagy's role in tumor development, with a focus on modulating mitochondrial function and autophagy in both pre-clinical and clinical cancer research. It also explores the potential for developing more-targeted and personalized therapies by investigating autophagy-related biomarkers.
    Keywords:  autophagy; autophagy-related biomarkers; cancer; mitochondria; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/ijms25179143
  55. Sci Rep. 2024 09 10. 14(1): 21154
    Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.
    Jialin Li, Sheng Zhang, Can Li, Xiaoxia Zhang, Yuhui Shan, Ziyi Zhang, Hai Bo, Yong Zhang.
      Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.
    Keywords:  AMPK; Endurance exercise; Histone methylation; Mitochondrial biogenesis; ROS; Skeletal muscle fiber type
    DOI:  https://doi.org/10.1038/s41598-024-72088-6
  56. Comp Biochem Physiol B Biochem Mol Biol. 2024 Sep 07. pii: S1096-4959(24)00097-6. [Epub ahead of print]275 111030
    Up-regulated mitochondrial biogenesis associated with GH/IGF axis in the ovaries of muskrats (Ondatra zibethicus).
    Wenjing Lu, Yuan Chen, María Daniela Artigas Ramírez, Yuning Liu, Haolin Zhang, Zhengrong Yuan, Yingying Han, Qiang Weng.
      Mitochondria play a critical role in follicular development and ovulation, at least in part through the actions of growth hormone (GH)/insulin-like growth factor-1 (IGF-1) on mitochondrial biogenesis. This study aimed to identify seasonal alterations in the GH/IGF-1 system and mitochondrial biogenesis in muskrat (Ondatra zibethicus) ovaries. We utilized the muskrat, a typical seasonal breeder, to clarify the potential impact of the GH/IGF-1 system on mitochondrial biogenesis across different breeding seasons using immunohistochemistry, gene expression and high-throughput sequencing. Alterations in follicular development existed in muskrat ovaries between the breeding season (BS) and non-breeding season (NBS), accompanied by a striking decrease in circulating and ovarian GH and IGF-1 concentrations. GH, GHR, IGF-1, IGF-1R, and mitochondrial biogenesis markers were localized in the ovarian cells of muskrats during both seasons. In contrast, Gh, Ghr, Igf-1, Igf-1r, Ppargc1a, Ppargc1b, Tfam, and Nrf1/2 mRNA levels were higher in BS. The relative levels of GH and IGF-1 in circulation and ovaries were positively associated with mitochondrial biogenesis markers. Additionally, RNA-seq analysis demonstrated that differentially expressed genes might be associated with insulin and PI3K/Akt signaling pathways, as well as mitochondrial function-related pathways. These findings suggest that the intra-ovarian GH/IGF-1 system, which is associated with seasonal changes in mitochondrial biogenesis, is activated in muskrat ovaries in BS.
    Keywords:  Follicular development; Growth hormone; Insulin-like growth factor; Mitochondrial biogenesis; Muskrat
    DOI:  https://doi.org/10.1016/j.cbpb.2024.111030
  57. Mol Neurobiol. 2024 Sep 14.
    Inner Mitochondrial Membrane Peptidase 2-Like Deletion Aggravates Mitochondrial Apoptosis and Inhibits Autophagy After Hyperglycemia Stroke.
    Ning Ma, Xiaohong Luo, Jianan Wang, Shihui Sun, Ruimin Liang, Zijing Zhang, Zhengyi Cheng, Jinlian Wang, Yi Ma.
      This study investigated the effects of inner mitochondrial membrane peptidase 2-like (Immp2l) deletion on mitochondrial apoptosis and mitochondrial autophagy under hyperglycemic conditions. The middle cerebral artery occlusion (MCAO) model was established in wild-type (WT) mice and Immp2l+/- mice; animals were then exposed to hyperglycemic (induced using 1% streptozotocin) and normoglycemic conditions. Tissues were collected at various time points post-reperfusion. The production of reactive oxygen species (ROS) was assessed by fluorescent measurements, and mitochondrial membrane potential was evaluated using a JC-1 assay kit. Autophagy was analyzed by measuring LC3II/LC3I protein expression and Beclin 1 expression. Mitochondrial ultrastructure was examined through transmission electron microscopy (TEM); neuronal autophagosomes were also assessed. Immp2l mutation in a hyperglycemic environment exacerbated brain injury by increasing ROS production, compromising mitochondrial membrane potential, inducing apoptotic cascades, and impairing mitochondrial autophagy. These findings highlight the critical role of Immp2l in modulating the response to hyperglycemic cerebral ischemia-reperfusion (I/R) injury. Furthermore, the deficiency of Immp2l appears to contribute to increased oxidative stress, mitochondrial dysfunction, and cell death, thereby exacerbating brain injury. These data may provide new insights into therapeutic strategies for reducing the impact of diabetes on stroke outcomes.
    Keywords:   Immp2l +/− mice; Apoptosis; Autophagy; Hyperglycemic cerebral ischemia–reperfusion; Mitochondrial membrane potential
    DOI:  https://doi.org/10.1007/s12035-024-04479-9
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