bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–10–20
fifty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Molecular mechanisms of mitochondrial dynamics.
  2. Mitophagy as a guardian against cellular aging.
  3. Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
  4. Polysiloxane-Based Fluorescent Probes for Visualizing pH and Thiocyanate during Mitochondrial Autophagy.
  5. Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy.
  6. A viable hypomorphic mutation in the mitochondrial ribosome subunit, MRPS-31, exhibits mitochondrial dysfunction in C. elegans.
  7. High-fat diet-induced L-saccharopine accumulation inhibits estradiol synthesis and damages oocyte quality by disturbing mitochondrial homeostasis.
  8. LETMD1 regulates mitochondrial protein synthesis and import to guard brown fat mitochondrial integrity and function.
  9. Tetrahydroxy stilbene glucoside promotes mitophagy and ameliorates neuronal injury after cerebral ischemia reperfusion via promoting USP10 mediated YBX1 stability.
  10. High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1-Nrf2-PHB2 pathway in diabetic encephalopathy.
  11. A mitochondrial unfolded protein response-independent role of DVE-1 in longevity regulation.
  12. Visualizing VDAC1 in live cells using a tetracysteine tag.
  13. PRKAA2-mediated mitophagy regulates oxygen consumption in yak renal tubular epithelial cells under chronic hypoxia.
  14. Enhancing CNS mitophagy: drug development and disease-relevant models.
  15. Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
  16. SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke.
  17. Peroxisomal import stress activates integrated stress response and inhibits ribosome biogenesis.
  18. GLS2 reduces the occurrence of epilepsy by affecting mitophagy function in mouse hippocampal neurons.
  19. Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4.
  20. Yap1 alleviates sepsis associated encephalopathy by inhibiting hippocampus ferroptosis via maintaining mitochondrial dynamic homeostasis.
  21. UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.
  22. Mitophagy-associated programmed neuronal death and neuroinflammation.
  23. Coronavirus M protein promotes mitophagy over virophagy by recruiting PDPK1 to phosphorylate SQSTM1 at T138.
  24. RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis.
  25. Deciphering the intracellular forces shaping mitochondrial motion.
  26. Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis.
  27. Regulation of the NLRP3 inflammasome by autophagy and mitophagy.
  28. RETRACTION: Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy.
  29. Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
  30. Yiqihuoxue decoction (GSC) inhibits mitochondrial fission through the AMPK pathway to ameliorate EPCs senescence and optimize vascular aging transplantation regimens.
  31. The PINK1/Parkin signaling pathway-mediated mitophagy: a forgotten protagonist in myocardial ischemia/reperfusion injury.
  32. Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
  33. Mitophagy Defects Exacerbate Inflammation and Aberrant Proliferation in Lymphocytic Thyroiditis.
  34. The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy.
  35. Progress in the regulatory mechanism of mitophagy in chronic cerebral ischemic neuronal injury.
  36. Irisin improves ROS‑induced mitohormesis imbalance in H9c2 cells.
  37. Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signalling pathway.
  38. The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death.
  39. Mitochondria-giant lipid droplet proximity and autophagy suppression in nitrogen-depleted oleaginous yeast Lipomyces starkeyi cells.
  40. Mitophagy related diagnostic biomarkers for coronary in-stent restenosis identified using machine learning and bioinformatics.
  41. Mitochondrial fission factor: a living way for mitochondria sensing food.
  42. Protective effects of licofelone on scopolamine-induced spatial learning and memory impairment by enhancing parkin-dependent mitophagy and promotion of neural regeneration and in adult mice.
  43. NLRP3 inflammasome-mediated disruption of mitochondrial homeostasis in alveolar macrophages contributes to ozone-induced acute lung inflammatory injury.
  44. Aβ -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases.
  45. [Retracted] Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway.
  46. Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer.
  47. Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.
  48. Nrf2 mitigates sepsis-associated encephalopathy-induced hippocampus ferroptosis via modulating mitochondrial dynamic homeostasis.
  49. Mitochondrial transfer in the progression and treatment of cardiac disease.
  50. Thyroid Hormone-Mediated Selective Autophagy and Its Implications in Countering Metabolic Dysfunction-Associated Steatotic Liver Disease.
  51. Comprehensive atlas of mitochondrial distribution and dynamics during oocyte maturation in mouse models.
  52. Selenium nanoparticles ameliorate lumbar disc degeneration by restoring GPX1-mediated redox homeostasis and mitochondrial function of nucleus pulposus cells.
  53. Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.
  54. LC-Orbitrap HRMS-Based Proteomics Reveals Novel Mitochondrial Dynamics Regulatory Proteins Associated with RasV12-Induced Glioblastoma (GBM) of Drosophila.
  55. SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy.
  56. The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.
  57. m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.
  58. Oxidative stress alters mitochondrial homeostasis in isolated brain capillaries.
  59. Near-Infrared Ratiometric Hemicyanine Fluorescent Probes for Monitoring Mitochondrial pH Dynamics in Live Cells during Oxidative Stress and Hypoxia.
  1. Nat Rev Mol Cell Biol. 2024 Oct 17.
    Molecular mechanisms of mitochondrial dynamics.
    Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.
      Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.
    DOI:  https://doi.org/10.1038/s41580-024-00785-1
  2. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  3. EMBO J. 2024 Oct 17.
    Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates.
    Zi Yang, Saori R Yoshii, Yuji Sakai, Jing Zhang, Haruka Chino, Roland L Knorr, Noboru Mizushima.
      During PINK1- and Parkin-mediated mitophagy, autophagy adaptors are recruited to damaged mitochondria to promote their selective degradation. Autophagy adaptors such as optineurin (OPTN) and NDP52 facilitate mitophagy by recruiting the autophagy-initiation machinery, and assisting engulfment of damaged mitochondria through binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like nature of OPTN condensates is important for mitophagy activity, because reducing the fluidity of OPTN-ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like, rather than a stoichiometric, model of autophagy adaptors to explain the interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid-liquid phase separation in facilitating membrane-membrane contacts, likely through the generation of capillary forces.
    Keywords:  Autophagy; Liquid–Liquid Phase Separation; Mitophagy; Optineurin; Wetting
    DOI:  https://doi.org/10.1038/s44318-024-00272-5
  4. Anal Chem. 2024 Oct 10.
    Polysiloxane-Based Fluorescent Probes for Visualizing pH and Thiocyanate during Mitochondrial Autophagy.
    Yujing Zuo, Ying Lan, Zhiming Gou, Yanfu Chai, Mei Yan.
      Mitochondrial autophagy, known as mitophagy, is a vital cellular process that involves the selective degradation of damaged or dysfunctional mitochondria through autophagy, which is critical to the functional integrity of the entire mitochondrial network and determines the survival and death of cells. An abnormal pH may lead to an imbalance in mitochondrial homeostasis and the occurrence of mitochondrial autophagic acidification and dysfunction. SCN- is also an important anion in cellular metabolism, and its abnormal concentration may lead to mitochondrial damage. However, so far, there are few reports on the simultaneous realization of pH and SCN- detection in mitochondria. Therefore, to complement the blank in this area, we developed the polysiloxane-based fluorescent probe P0-CMN that is capable of simultaneously visualizing pH and SCN- fluctuation levels in mitochondria. The probe P0-CMN has the desired mitochondrial-targeting properties and sensitivity to pH and SCN-. It is able to simultaneously monitor pH and SCN- changes in mitochondria in a dual-channel mode. In addition, probe P0-CMN can visualize pH changes during mitochondrial autophagy. This work provides an effective strategy for the design of dual-responsive fluorescent probes and further broadens the application of polysiloxane fluorescent materials.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03499
  5. Autophagy. 2024 Oct 16. 1-17
    Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy.
    Hanxiao Chang, Weiwei Zhang, Lei Xu, Zheng Li, Chao Lin, Yuqi Shen, Guangjian Zhang, Lei Mao, Chencheng Ma, Ning Liu, Hua Lu.
      Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.
    Keywords:  BNIP3; TRIM25; copper; mitophagy; traumatic brain injury
    DOI:  https://doi.org/10.1080/15548627.2024.2409613
  6. MicroPubl Biol. 2024 ;2024
    A viable hypomorphic mutation in the mitochondrial ribosome subunit, MRPS-31, exhibits mitochondrial dysfunction in C. elegans.
    Kylie M Jozwik, James P Held, Chloe A Hecht, Maulik R Patel.
      The mitochondrial ribosome (mitoribosome) translates mitochondrial genome encoded proteins essential for cellular energy production. Given this critical role, defects in the mitoribosome can cause mitochondrial stress and manifest as multisystemic diseases. In a screen for unique activators of the mitochondrial unfolded protein response (UPR mt ) in Caenorhabditis elegans , we recovered a strain harboring a missense mutation in the gene encoding mitochondrial ribosome protein S31 ( MRPS-31 )-a component of the mitoribosome small subunit. Herein, we confirm causality of the mrps-31 allele and characterize its induction of UPR mt and impact on organismal development, providing a valuable model for further study of the mitoribosome.
    DOI:  https://doi.org/10.17912/micropub.biology.001344
  7. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2412381
    High-fat diet-induced L-saccharopine accumulation inhibits estradiol synthesis and damages oocyte quality by disturbing mitochondrial homeostasis.
    Jingyi Wen, Yanzhi Feng, Liru Xue, Suzhen Yuan, Qian Chen, Aiyue Luo, Shixuan Wang, Jinjin Zhang.
      High-fat diet (HFD) has been linked to female infertility. However, the specific age at which HFD impacts ovarian function and the underlying mechanisms remain poorly understood. Here, we administered a HFD to female mice at various developmental stages: pre-puberty (4 weeks old), post-puberty (6 weeks old), young adult (9 weeks old), and middle age (32 weeks old). Our observations indicated that ovarian function was most significantly compromised when HFD was initiated at post-puberty. Consequently, post-puberty mice were chosen for further investigation. Through transplantation of fecal bacteria from the HFD mice to the mice on a normal diet, we confirmed that gut microbiota dysbiosis contributed to HFD-induced deteriorated fertility and disrupted estradiol synthesis. Utilizing untargeted and targeted metabolomics analyses, we identified L-saccharopine as a key metabolite, which was enriched in the feces, serum, and ovaries of HFD and HFD-FMT mice. Subsequent in vitro and in vivo experiments demonstrated that L-saccharopine disrupted mitochondrial homeostasis by impeding AMPKα/MFF-mediated mitochondrial fission. This disruption ultimately hindered estradiol synthesis and compromised oocyte quality. AICAR, an activator of AMPKα, ameliorated L-saccharopine induced mitochondrial damage in granulosa cells and oocytes, thereby enhancing E2 synthesis and improving oocyte quality. Collectively, our findings indicate that the accumulation of L-saccharopine may play a pivotal role in mediating HFD-induced ovarian dysfunction. This highlights the potential therapeutic benefits of targeting the gut microbiota-metabolite-ovary axis to address HFD-induced ovarian dysfunction.
    Keywords:  Infertility; L-saccharopine; gut microbiota; high-fat diet; mitochondrial homeostasis; oocyte quality; ovarian steroidogenesis
    DOI:  https://doi.org/10.1080/19490976.2024.2412381
  8. iScience. 2024 Oct 18. 27(10): 110944
    LETMD1 regulates mitochondrial protein synthesis and import to guard brown fat mitochondrial integrity and function.
    Madigan Snyder, Yi-Kai Liu, Renjie Shang, Haowei Xu, Charlie Thrift, Xiyue Chen, Jingjuan Chen, Kun Ho Kim, Jiamin Qiu, Pengpeng Bi, W Andy Tao, Shihuan Kuang.
      Thermogenic brown adipocytes (BAs) catabolize lipids to generate heat, representing powerful agents against the growing global obesity epidemic. We and others reported recently that LETMD1 is a BA-specific protein essential for mitochondrial structure and function, but the mechanisms of action remain unclear. We performed sequential digestion to demonstrate that LETMD1 is a trans-inner mitochondrial membrane protein. We then generated UCP1Cre-driven BA-specific Letmd1 knockout (Letmd1 UKO ) mice to show that Letmd1 UKO leads to protein aggregation, reactive oxidative stress, hyperpolarization, and mitophagy in BAs. We further employed TurboID proximity labeling to identify LETMD1-interacting proteins. Many candidate proteins are associated with mitochondrial ribosomes, protein import machinery, and electron transport chain complexes (ETC-I and ETC-IV). Using quantitative proteomics, we confirmed the elevated aggregations of ETC and mitochondrial ribosomal proteins, impairing mitochondrial protein synthesis in the Letmd1 UKO BAs. Therefore, LETMD1 may function to maintain mitochondrial proteostasis through regulating import of nuclear-encoded proteins and local protein translation in brown fat mitochondria.
    Keywords:  Cell; Cell biology; Cellular physiology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110944
  9. eNeuro. 2024 Oct 15. pii: ENEURO.0269-24.2024. [Epub ahead of print]
    Tetrahydroxy stilbene glucoside promotes mitophagy and ameliorates neuronal injury after cerebral ischemia reperfusion via promoting USP10 mediated YBX1 stability.
    Yuxian Li, Ke Hu, Jie Li, Xirong Yang, Xiuyu Wu, Qian Liu, Yuefu Chen, Yan Ding, Lingli Liu, Qiansheng Yang, Guangwei Wang.
      Tetrahydroxy stilbene glucoside (TSG) from polygonum multiflorum exerts neuroprotective effects after ischemic stroke. We explored whether TSG improved ischemic stroke injury via PINK1/Parkin-mediated mitophagy. Oxygen glucose deprivation/reoxygenation (OGD/R) in vitro model and middle cerebral artery occlusion (MCAO) rat model were established. Cerebral injury was assessed by neurological score, hematoxylin and eosin staining, TTC staining and brain water content. Apoptosis, cell viability and mitochondrial membrane potential were assessed by flow cytometry, CCK-8 and JC-1 staining, respectively. Co-localization of LC3-labeled autophagosomes with LAMP2-labeled lysosomes or Tomm20-labeled mitochondria was observed with fluorescence microscopy. Ubiquitination level was determined using ubiquitination assay. The interaction between molecules was validated by co-immunoprecipitation and GST pull-down. We found that TSG promoted mitophagy and improved cerebral I/R damage in MCAO rats. In OGD/R-subjected neurons, TSG promoted mitophagy, repressed neuronal apoptosis, upregulated Y-box binding protein-1 (YBX1) and activated PINK1/Parkin signaling. TSG upregulated ubiquitin-specific peptidase 10 (USP10) to elevate YBX1 protein. Furthermore, USP10 inhibited ubiquitination-dependent YBX1 degradation. USP10 overexpression activated PINK1/Parkin signaling and promoted mitophagy, which were reversed by YBX1 knockdown. Moreover, TSG upregulated USP10 to promote mitophagy and inhibited neuronal apoptosis. Collectively, TSG facilitated PINK1/Parkin pathway mediated mitophagy by upregulating USP10/YBX1 axis to ameliorate ischemic stroke.Significance Statement: Ischemic stroke is one of leading causes of disability and death worldwide. Previous studies have demonstrated a neuroprotective role of TSG in ischemic stroke, while the underlying mechanism is still not fully understood. Here, this study confirmed that TSG relieved cerebral I/R injury in vivo and in vitro via facilitated PINK1/Parkin-mediated mitophagy. In addition, we further identified the molecular mechanism by which TSG regulates mitochondrial autophagy. Our study provided new insights into the protective role TSG in ischemic stroke via regulating mitophagy.
    DOI:  https://doi.org/10.1523/ENEURO.0269-24.2024
  10. Sci Rep. 2024 10 14. 14(1): 24044
    High glucose- or AGE-induced oxidative stress inhibits hippocampal neuronal mitophagy through the Keap1-Nrf2-PHB2 pathway in diabetic encephalopathy.
    Shan Xu, Zhaoyu Gao, Lei Jiang, Jiazheng Li, Yushi Qin, Di Zhang, Pei Tian, Wanchang Wang, Nan Zhang, Rui Zhang, Shunjiang Xu.
      Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1-Nrf2-PHB2 pathway, thereby contributing to the cognitive decline in DE.
    Keywords:  Advanced glycosylation end products; Diabetic encephalopathy; High glucose; Mitophagy; Prohibitin 2
    DOI:  https://doi.org/10.1038/s41598-024-70584-3
  11. Cell Rep. 2024 Oct 16. pii: S2211-1247(24)01240-3. [Epub ahead of print]43(11): 114889
    A mitochondrial unfolded protein response-independent role of DVE-1 in longevity regulation.
    Yi Sheng, Adriana Abreu, Zachary Markovich, Pearl Ebea, Leah Davis, Eric Park, Peike Sheng, Mingyi Xie, Sung Min Han, Rui Xiao.
      The special AT-rich sequence-binding (SATB) protein DVE-1 is widely recognized for its pivotal involvement in orchestrating the retrograde mitochondrial unfolded protein response (mitoUPR) in C. elegans. In our study of downstream factors contributing to lifespan extension in sensory ciliary mutants, we find that DVE-1 is crucial for this longevity effect independent of its canonical mitoUPR function. Additionally, DVE-1 also influences lifespan under conditions of dietary restriction and germline loss, again distinct from its role in mitoUPR. Mechanistically, while mitochondrial stress typically prompts nuclear accumulation of DVE-1 to initiate the transcriptional mitoUPR program, these long-lived mutants reduce DVE-1 nuclear accumulation, likely by enhancing its cytosolic translocation. This observation suggests a cytosolic role for DVE-1 in lifespan extension. Overall, our study implies that, in contrast to the more narrowly defined role of the mitoUPR-related transcription factor ATFS-1, DVE-1 may possess broader functions than previously recognized in modulating longevity and defending against stress.
    Keywords:  ATFS-1; C. elegans; CP: Cell biology; CP: Molecular biology; DVE-1; cilia; dietary restriction; germline signaling; longevity; mitoUPR
    DOI:  https://doi.org/10.1016/j.celrep.2024.114889
  12. PLoS One. 2024 ;19(10): e0311107
    Visualizing VDAC1 in live cells using a tetracysteine tag.
    Johannes Pilic, Furkan E Oflaz, Benjamin Gottschalk, Yusuf C Erdogan, Wolfgang F Graier, Roland Malli.
      The voltage-dependent anion channel 1 (VDAC1) is a crucial gatekeeper in the outer mitochondrial membrane, controlling metabolic and energy homeostasis. The available methodological approaches fell short of accurate visualization of VDAC1 in living cells. To permit precise VDAC1 imaging, we utilized the tetracysteine (TC)-tag and visualized VDAC1 dynamics in living cells. TC-tagged VDAC1 had a cluster-like distribution on mitochondria. The labeling of TC-tagged VDAC1 was validated with immunofluorescence. The majority of VDAC1-TC-clusters were localized at endoplasmic reticulum (ER)-mitochondria contact sites. Notably, VDAC1 colocalized with BCL-2 Antagonist/Killer (BAK)-clusters upon apoptotic stimulation. Using this new tool, we were able to observe VDAC1-TC at mitochondrial fission sites. These findings highlight the suitability of the TC-tag for live-cell imaging of VDAC1, shedding light on the roles of VDAC1 in cellular processes.
    DOI:  https://doi.org/10.1371/journal.pone.0311107
  13. Cell Signal. 2024 Oct 11. pii: S0898-6568(24)00423-6. [Epub ahead of print]124 111450
    PRKAA2-mediated mitophagy regulates oxygen consumption in yak renal tubular epithelial cells under chronic hypoxia.
    Xuefeng Bai, Hongqin Lu, Yan Cui, Sijiu Yu, Rui Ma, Shanshan Yang, Junfeng He.
      Hypoxic environments are significant factors in the induction of various kidney diseases and are closely associated with high oxygen consumption in the kidneys. Yaks live at high altitude for a long time, exhibit a unique ability to regulate kidney oxygen consumption, protecting them from hypoxia-induced damage. However, the mechanisms underlying the regulation of oxygen consumption in yak kidneys under hypoxic conditions remain unclear. To explore this hypoxia adaptation mechanism in yak kidneys, this study analyzed the oxygen consumption rate (OCR) of renal tubular epithelial cells (RTECs) under hypoxia. We found that the OCR and apoptosis rates of RTECs under chronic hypoxia (> 24 h) were lower than those under acute hypoxia (≤ 24 h). However, when oxygen consumption was promoted under chronic hypoxia, the apoptosis rate increased, indicating that reducing the cellular OCR is crucial for maintaining RTECs activity under hypoxia. High-throughput sequencing results showed that the mitophagy pathway is likely a key mechanism for inhibiting OCR of yak RTECs, with protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) playing a significant role in this process. Further studies demonstrated that chronic hypoxia activates the mitophagy pathway, which inhibits oxidative phosphorylation (OXPHOS) while increasing glycolytic flux in yak RTECs. Conversely, when the mitophagy pathway was inhibited, there was an increase in the activity of OXPHOS enzymes and OCR. To further explore the role of PRKAA2 in the mitophagy pathway, we inhibited PRKAA2 expression under chronic hypoxia. Results showed that the downregulation of PRKAA2 decreased the expression of mitophagy-related proteins, such as p-FUNDC1/FUNDC1, LC3-II/LC3-I, BNIP3 and ULK1 while upregulating P62 expression. Additionally, there was an increase in the enzyme activities of Complex II, Complex IV, PDH, and SDH, which further promoted oxygen consumption in RTECs. These findings suggest that PRKAA2 mediated mitophagy under chronic hypoxia is crucial mechanism for reducing oxygen consumption in yak RTECs.
    Keywords:  Hypoxia; Mitophagy; OCR; PRKAA2; RTECs; Yak
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111450
  14. Trends Pharmacol Sci. 2024 Oct 16. pii: S0165-6147(24)00187-1. [Epub ahead of print]
    Enhancing CNS mitophagy: drug development and disease-relevant models.
    Krishayant S Dhar, Brendan Townsend, Andrew P Montgomery, Jonathan J Danon, Julia K Pagan, Michael Kassiou.
      Mitophagy, the selective degradation of mitochondria, is impaired in many neurodegenerative diseases (NDs), resulting in an accumulation of dysfunctional mitochondria and neuronal damage. Although enhancing mitophagy shows promise as a therapeutic strategy, the clinical significance of mitophagy activators remains uncertain due to limited understanding and poor representation of mitophagy in the central nervous system (CNS). This review explores recent insights into which mitophagy pathways to target and the extent of modulation necessary to be therapeutic towards NDs. We also highlight the complexities of mitophagy in the CNS, highlighting the need for disease-relevant models. Last, we outline crucial aspects of in vitro models to consider during drug discovery, aiming to bridge the gap between preclinical research and clinical applications in treating NDs through mitophagy modulation.
    Keywords:  central nervous system; clinical relevance; disease models; drug development; mitochondrial dysfunction; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.tips.2024.09.002
  15. Adv Biol (Weinh). 2024 Oct 16. e2400235
    Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
    Xin Zhang, Suchan Liao, Lingling Huang, Jinhua Wang.
      Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.
    Keywords:  Aging; mechanism; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1002/adbi.202400235
  16. Brain Res Bull. 2024 Oct 11. pii: S0361-9230(24)00235-1. [Epub ahead of print]218 111101
    SIRT1 modulates microglia phenotypes via inhibiting drp1 phosphorylation reduces neuroinflammation in heatstroke.
    Jie Zhu, Panshi Jin, Tingting Zhou, Dingshun Zhang, Zixin Wang, Zhen Tang, Zhifeng Liu, Guangli Ren.
       BACKGROUND: Brain injury often results in high mortality rates and significant sequelae following severe heatstroke (HS). Neuroinflammation aggravates HS-induced brain injury, yet the involvement of microglia in heat-induced neuroinflammation deserves further investigation.
    METHODS: Our study investigated activation status, phenotype markers, production of pro-inflammatory cytokine and reactive oxygen species (ROS) of microglia both in vitro and in vivo under HS. Utilizing high-throughput sequencing, we identified SIRT1 as a potential modulator of microglia phenotype, and observed that SIRT1 alleviated severe heatstroke-induced brain injury following intraperitoneal administration of the SIRT1 agonist SRT-1720 and the inhibitor selisistat. Additionally, the effects of SRT-1720 and selisistat on mitochondrial dynamics and microglial phenotype transition were examined in BV2 cells in vitro.
    RESULTS: Heatstroke promotes microglia activation, as evidenced by the increased production of pro-inflammatory cytokine and reactive oxygen species. High-throughput sequencing revealed elevated expression of SIRT1 in BV2 cells under HS. Upon inhibition of SIRT1 expression, there was a corresponding increase in pro-inflammatory cytokine, iNOS, and ROS expression in BV2 cells. In vivo experiments with the SIRT1 agonist SRT-1720 showed a mitigation of neuron injury under HS, as assessed by Nissl and HE staining. Activation of SIRT1 was associated with a reduction in mitochondrial injury and a decrease in the phosphorylation of mitochondrial fission protein Drp1ser616. Furthermore, the heat-induced activation of microglia was reversed by the Drp1 inhibitor, Mdivi.
    CONCLUSIONS: Our findings provided evidence that SIRT1 played a crucial role in inhibiting heat stress-induced microglial activation. By suppressing the phosphorylation of mitochondrial fission protein Drp1, SIRT1 contributed to the reduction of neuroinflammation and severity of heatstroke-induced brain injury.
    Keywords:  Heatstroke; Microglia; Mitochondrial quality control; Neuroinflammation; SIRT1
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.111101
  17. PNAS Nexus. 2024 Oct;3(10): pgae429
    Peroxisomal import stress activates integrated stress response and inhibits ribosome biogenesis.
    Jinoh Kim, Kerui Huang, Pham Thuy Tien Vo, Ting Miao, Jacinta Correia, Ankur Kumar, Mirre J P Simons, Hua Bai.
      Impaired organelle-specific protein import triggers a variety of cellular stress responses, including adaptive pathways to balance protein homeostasis. Most of the previous studies focus on the cellular stress response triggered by misfolded proteins or defective protein import in the endoplasmic reticulum or mitochondria. However, little is known about the cellular stress response to impaired protein import in the peroxisome, an understudied organelle that has recently emerged as a key signaling hub for cellular and metabolic homeostasis. To uncover evolutionarily conserved cellular responses upon defective peroxisomal import, we carried out a comparative transcriptomic analysis on fruit flies with tissue-specific peroxin knockdown and human HEK293 cells expressing dominant-negative PEX5C11A. Our RNA-seq results reveal that defective peroxisomal import upregulates integrated stress response (ISR) and downregulates ribosome biogenesis in both flies and human cells. Functional analyses confirm that impaired peroxisomal import induces eIF2α phosphorylation and ATF4 expression. Loss of ATF4 exaggerates cellular damage upon peroxisomal import defects, suggesting that ATF4 activation serves as a cellular cytoprotective mechanism upon peroxisomal import stress. Intriguingly, we show that peroxisomal import stress decreases the expression of rRNA processing genes and inhibits early pre-rRNA processing, which leads to the accumulation of 47S precursor rRNA and reduction of downstream rRNA intermediates. Taken together, we identify ISR activation and ribosome biogenesis inhibition as conserved adaptive stress responses to defective peroxisomal import and uncover a novel link between peroxisomal dysfunction and rRNA processing.
    Keywords:  PEX5; early rRNA processing; integrated stress response; peroxisomal import stress; ribosome biogenesis
    DOI:  https://doi.org/10.1093/pnasnexus/pgae429
  18. CNS Neurosci Ther. 2024 Oct;30(10): e70036
    GLS2 reduces the occurrence of epilepsy by affecting mitophagy function in mouse hippocampal neurons.
    Yuan Gao, Limin Ma, Jinxian Yuan, Yunyi Huang, Yuenan Ban, Peng Zhang, Dandan Tan, Minxue Liang, Zhipeng Li, Chen Gong, Tao Xu, Xiaolan Yang, Yangmei Chen.
       BACKGROUND: Altered mitophagy has been observed in various neurological disorders, such as epilepsy. The role of mitophagy in causing neuronal damage during epileptic episodes is significant, and recent research has indicated that GLS2 plays a crucial role in regulating autophagy. However, exactly how GLS2 affects epilepsy is still unclear.
    AIMS: To investigate the expression and distribution characteristics of GLS2 in epilepsy, and then observed the changes in behavior and electrophysiology caused by overexpression of GLS2 in epileptic mice, and determined whether GLS2 regulated seizure-like changes in the mouse model through the protective mechanism of mitophagy.
    RESULTS: The expression of GLS2 in a kainic acid (KA)-induced epileptic mouse model and aglutamate-inducedneuronal excitatory damage in HT22 cells model was downregulation. In brief, overexpression of GLS2 can alleviate epileptic activity. Subsequently, we demonstrated that GLS2 interacts with mitophagy-related proteins in a KA-induced epilepsy mouse model. Mechanistically, overexpression of GLS2 inhibited mitophagy in epileptic mice, downregulating the expression of LC3 and reducing ROS production.
    CONCLUSIONS: This study proves the GLS2 expression pattern is abnormal in epileptic mice. The function of mitophagy in hippocampal neurons is affected by GLS2, and overexpression of GLS2 can reduce the occurrence of seizure-like events (SLEs) by altering mitophagy function. Thus, GLS2 might control seizures, and our findings provide a fresh avenue for antiepileptic treatment and offer novel insights into treating and preventing epilepsy.
    Keywords:  GLS2; epilepsy; mitophagy; neuron; reactive oxygen species (ROS); seizure
    DOI:  https://doi.org/10.1111/cns.70036
  19. J Appl Physiol (1985). 2024 Oct 17.
    Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4.
    Victoria C Sanfrancesco, David A Hood.
      Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress, however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5 and 1 tetanic contraction/per second for 9 mins, followed by a 1-hour recovery period. CAMKII and JNK2 were robustly activated 6-fold immediately following the protocol. ISR activation, denoted as the ratio of phosphorylated to total-eIF2a protein levels, was also elevated following recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust 2-fold increases in the mRNA expression of ATF4 and CHOP were also observed following the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed using an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post-contractile activity, as a result of enhanced stabilization by the RNA binding protein, HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise.
    Keywords:  Adaptations; Exercise; Mitochondrial Biogenesis; Skeletal Muscle; eIF2α
    DOI:  https://doi.org/10.1152/japplphysiol.00307.2024
  20. J Cell Mol Med. 2024 Oct;28(19): e70156
    Yap1 alleviates sepsis associated encephalopathy by inhibiting hippocampus ferroptosis via maintaining mitochondrial dynamic homeostasis.
    Xin Yang, Haifeng Duan, Sirui Li, Jing Zhang, Liang Dong, Jingli Ding, Xinyi Li.
      Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied by acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. As a key transcriptional coactivator in the Hippo signalling pathway, Yes-associated protein 1 (YAP1) could target ferroptosis-related genes. This study was aimed to determine whether Yap1 protects against SAE and inhibits ferroptosis via maintaining mitochondrial dynamic homeostasis. Caecal ligation puncture (CLP) was used to establish the SAE model, and LPS was applied in hippocampal cells to mimic the inflammatory model in vitro. The results showed that Yap1 conditional knockout in hippocampal caused lower survival in SAE mice and cognitive dysfunction, as proved by Morri's water maze (MWM) task, tail suspension test (TST), open field test (OFT) and elevated plus maze test (EPMT). After Yap1 knockout, the production of ROS, MDA and Fe2+ and proinflammatory cytokines in the hippocampus were increased, indicating that Yap1 deficiency exacerbates CLP-induced brain injury and hippocampus ferroptosis. Meanwhile, GPX4, SLC7A11, ferritin (FTH1) and GSH levels were decreased in the Yap1 knockout group. In vitro, Yap1 overexpression mitigated LPS-induced hippocampal cell ferroptosis and improved mitochondrial function by inhibiting mitochondrial fission, as evidenced by lower mitochondrial ROS, cell viability, Fe2+ and the expression of Fis1 and Drp1. Further, the present study suggested that Yap1 could inhibit ferritinophagy-mediated ferroptosis in the hippocampus via inhibiting mitochondrial fission, thus reducing cognitive dysfunction in SAE mice.
    Keywords:  Yap1; ferroptosis; mitochondrial homeostasis; sepsis; sepsis‐associated encephalopathy
    DOI:  https://doi.org/10.1111/jcmm.70156
  21. Pharmacology. 2024 Oct 16. 1-22
    UCF101 Rescues against Diabetes-Evoked Cardiac Remodeling and Contractile Anomalies through AMPK-Mediated Induction of Mitophagy.
    Zhiqiang Zhuang, Yuxi Zhu, Jun Tao, Yandong Liu, Jie Lin, Chunjie Yang, Chule Dong, Xing Qin, Qun Li, Russel J Reiter, Guizhen Wang, Zhaohui Pei, Jun Ren.
       BACKGROUND: Diabetes mellitus is known to provoke devastating anomalies in myocardial structure and function while effective therapeutic regimen is still lacking. The selective protease inhibitor UCF101 (5-[5-(2-nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid) has been shown to fend off ischemic heart injury although its impact on diabetic cardiomyopathy remains elusive.
    METHOD: Our present work was conducted to examine the effect of UCF101 on experimental diabetes-evoked cardiac geometric and functional abnormalities as well as mechanism involved. Adult mice were made diabetic using streptozotocin (STZ) while receiving UCF101 (7.15 mg/kg, i.p.) for 6 consecutive days.
    RESULT: STZ evidently evoked cardiac hypertrophy, interstitial fibrosis, mitochondrial ultrastructural damage, oxidative stress, dampened autophagy (LC3B, Beclin1, elevated p62), mitophagy (FUNDC1 and Parkin with elevated TOM20), increased left ventricular (LV) end systolic diameter, dampened fractional shortening, ejection fraction, cardiomyocyte shortening capacity, velocities of shortening/relengthening, and rise in intracellular Ca2+ in conjunction with elongated diastole and intracellular Ca2+ removal, the responses were overtly reconciled by UCF101 with little effect from UCF101 itself. Levels of cell injury markers Omi/HtrA2, TNFα, and stress signaling (JNK, ERK, p38) were overtly enhanced along with compromised phosphorylation of cellular fuel AMPK (Thr172) and cell survival molecule GSK3β, as well as downregulated SERCA2a and elevated phospholamban, the effect was reversed by UCF101 (except for SERCA2a). AMPK knockout, pharmacological inhibition, mitophagy inhibitor liensinine and parkin knockout nullified UCF101-offered cardioprotection in diabetes. UCF101 reversed STZ-induced upregulation in the AMPK degrading enzymes PP2A and PP2C.
    CONCLUSION: These findings denote that UCF101 rescues diabetes-instigated alterations in cardiac structure and contraction, likely through AMPK-mediated regulation of mitophagy.
    DOI:  https://doi.org/10.1159/000541569
  22. Front Immunol. 2024 ;15 1460286
    Mitophagy-associated programmed neuronal death and neuroinflammation.
    Yanlin Zhu, Jianning Zhang, Quanjun Deng, Xin Chen.
      Mitochondria are crucial organelles that play a central role in cellular metabolism and programmed cell death in eukaryotic cells. Mitochondrial autophagy (mitophagy) is a selective process where damaged mitochondria are encapsulated and degraded through autophagic mechanisms, ensuring the maintenance of both mitochondrial and cellular homeostasis. Excessive programmed cell death in neurons can result in functional impairments following cerebral ischemia and trauma, as well as in chronic neurodegenerative diseases, leading to irreversible declines in motor and cognitive functions. Neuroinflammation, an inflammatory response of the central nervous system to factors disrupting homeostasis, is a common feature across various neurological events, including ischemic, infectious, traumatic, and neurodegenerative conditions. Emerging research suggests that regulating autophagy may offer a promising therapeutic avenue for treating certain neurological diseases. Furthermore, existing literature indicates that various small molecule autophagy regulators have been tested in animal models and are linked to neurological disease outcomes. This review explores the role of mitophagy in programmed neuronal death and its connection to neuroinflammation.
    Keywords:  apoptosis; ferroptosis; mitophagy; necroptosis; neuroinflammation; pyroptosis
    DOI:  https://doi.org/10.3389/fimmu.2024.1460286
  23. Nat Commun. 2024 Oct 16. 15(1): 8927
    Coronavirus M protein promotes mitophagy over virophagy by recruiting PDPK1 to phosphorylate SQSTM1 at T138.
    Yahui Li, Chunyan Li, Chenchen Zhao, Jiayu Wu, Ya Zhu, Fei Wang, Jiepeng Zhong, Yan Yan, Yulan Jin, Weiren Dong, Jinyang Chen, Xianghong Yang, Jiyong Zhou, Boli Hu.
      Autophagy plays a dual role in coronavirus infection, facilitating the elimination of either proviral components (virophagy) or antiviral factors such as mitochondria (mitophagy), leading to complex mechanisms of immune evasion. Understanding the mechanisms that govern the switch between the autophagic degradation of deleterious or beneficial substrates in coronavirus infection is crucial for developing precise drug targets to treat virus-induced diseases. However, this switch remains largely unknown. Using a dual split-fluorescence assay, we identify PDPK1 as a negative regulator of innate immunity, directing the transition from virophagy to mitophagy through the phosphorylation of SQSTM1 at T138. Remarkably, a PDPK1-targeting peptide inhibits the replication of various RNA viruses by restoring innate immunity through enhanced virophagy and suppressed mitophagy, thereby protecting female mice from lethal infections. These findings underscore the detrimental role of PDPK1 in innate immunity by orchestrating the shift from virophagy to mitophagy, positioning PDPK1 as a promising pharmacological target for effectively combating a broad spectrum of virus infections.
    DOI:  https://doi.org/10.1038/s41467-024-53100-z
  24. Commun Biol. 2024 Oct 16. 7(1): 1333
    RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis.
    Ning Feng, Rui Zhang, Xin Wen, Wei Wang, Nie Zhang, Junnian Zheng, Longzhen Zhang, Nianli Liu.
      The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s42003-024-07028-1
  25. Sci Rep. 2024 10 13. 14(1): 23914
    Deciphering the intracellular forces shaping mitochondrial motion.
    Agustina Belén Fernández Casafuz, Azul Marí A Brigante, Marí A Cecilia De Rossi, Alejandro Gabriel Monastra, Luciana Bruno.
      We propose a novel quantitative method to explore the forces affecting mitochondria within living cells in an almost non-invasive fashion. This new tool enables the detection of localized mechanical impulses on these organelles that occur amidst the stationary fluctuations caused by the thermal jittering in the cytoplasm. Recent experimental evidence shows that the action of mechanical forces has important effects on the dynamics, morphology and distribution of mitochondria in cells. In particular, their crosstalk with the cytoskeleton has been found to alter these organelles function; however, the mechanisms underlying this phenomenon are largely unknown. Our results highlight the different functions that cytoskeletal networks play in shaping mitochondrial dynamics. This work presents a novel technique to extend our knowledge of how the impact of mechanical cues can be quantified at the single organelle level. Moreover, this approach can be expanded to the study of other organelles or biopolymers.
    DOI:  https://doi.org/10.1038/s41598-024-74734-5
  26. PLoS Pathog. 2024 Oct 15. 20(10): e1012638
    Host 5-HT affects Plasmodium transmission in mosquitoes via modulating mosquito mitochondrial homeostasis.
    Li Gao, Benguang Zhang, Yuebiao Feng, Wenxu Yang, Shibo Zhang, Jingwen Wang.
      Malaria parasites hijack the metabolism of their mammalian host during the blood-stage cycle. Anopheles mosquitoes depend on mammalian blood to lay eggs and to transmit malaria parasites. However, it remains understudied whether changes in host metabolism affect parasite transmission in mosquitoes. In this study, we discovered that Plasmodium infection significantly decreased the levels of the tryptophan metabolite, 5-hydroxytryptamine (5-HT), in both humans and mice. The reduction led to the decrease of 5-HT in mosquitoes. Oral supplementation of 5-HT to Anopheles stephensi enhanced its resistance to Plasmodium berghei infection by promoting the generation of mitochondrial reactive oxygen species. This effect was due to the accumulation of dysfunctional mitochondria caused by 5-HT-mediated inhibition of mitophagy. Elevating 5-HT levels in mouse serum significantly suppressed parasite infection in mosquitoes. In summary, our data highlight the critical role of metabolites in animal blood in determining the capacity of mosquitoes to control parasite infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012638
  27. Immunol Rev. 2024 Oct 17.
    Regulation of the NLRP3 inflammasome by autophagy and mitophagy.
    Suman Gupta, Suzanne L Cassel, Fayyaz S Sutterwala, Jargalsaikhan Dagvadorj.
      The NLRP3 inflammasome is a multiprotein complex that upon activation by the innate immune system drives a broad inflammatory response. The primary initial mediators of this response are pro-IL-1β and pro-IL-18, both of which are in an inactive form. Formation and activation of the NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1β and pro-IL-18 and triggers the formation of gasdermin D pores. Gasdermin D pores allow for the secretion of active IL-1β and IL-18 initiating the organism-wide inflammatory response. The NLRP3 inflammasome response can be beneficial to the host; however, if the NLRP3 inflammasome is inappropriately activated it can lead to significant pathology. While the primary components of the NLRP3 inflammasome are known, the precise details of assembly and activation are less well defined and conflicting. Here, we discuss several of the proposed pathways of activation of the NLRP3 inflammasome. We examine the role of subcellular localization and the reciprocal regulation of the NLRP3 inflammasome by autophagy. We focus on the roles of mitochondria and mitophagy in activating and regulating the NLRP3 inflammasome. Finally, we detail the impact of pathologic NLRP3 responses in the development and manifestations of pulmonary disease.
    Keywords:  NLRP3; caspase‐1; inflammasome; lung injury; mitochondria
    DOI:  https://doi.org/10.1111/imr.13410
  28. J Pineal Res. 2024 Oct;76(7): e70001
    RETRACTION: Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy.
       RETRACTION: H. Zhou, W. Du, Y. Li, C. Shi, N. Hu, S. Ma, W. Wang, and J. Ren, "Effects of Melatonin on Fatty Liver Disease: The Role of NR4A1/DNA-Pkcs/P53 Pathway, Mitochondrial Fission, and Mitophagy," Journal of Pineal Research 64, no. 1 (2018): e12450, https://doi.org/10.1111/jpi.12450. The above article, published online on 05 October 2017, in Wiley Online Library (wileyonlinelibrary.com) and its correction (https://doi.org/10.1111/jpi.12946) have been retracted by agreement between the journal Editor-in-Chief, Gianluca Tosini, and John Wiley and Sons Ltd. The retraction has been agreed upon following an investigation into additional concerns raised by a third party regarding the scientific integrity of the generation of DNA-PKcsfl/fl mouse model and the reliability of the data presented in Figure 4 A and J, Figure 5E-G and Figure 7A and E. The original raw data was not available upon request from the authors. The senior corresponding author's institute stated that the study was not conducted at their university. Given the extent of the identified issues, the editors have lost confidence in the data presented and the article's conclusions can no longer be considered reliable. The first author disagrees with the retraction, and all other authors remained unresponsive.
    DOI:  https://doi.org/10.1111/jpi.70001
  29. Cells. 2024 Oct 09. pii: 1671. [Epub ahead of print]13(19):
    Optogenetic Control of the Mitochondrial Protein Import in Mammalian Cells.
    Lukas F J Althoff, Markus M Kramer, Benjamin Bührer, Denise Gaspar, Gerald Radziwill.
      Mitochondria provide cells with energy and regulate the cellular metabolism. Almost all mitochondrial proteins are nuclear-encoded, translated on ribosomes in the cytoplasm, and subsequently transferred to the different subcellular compartments of mitochondria. Here, we developed OptoMitoImport, an optogenetic tool to control the import of proteins into the mitochondrial matrix via the presequence pathway on demand. OptoMitoImport is based on a two-step process: first, light-induced cleavage by a TEV protease cuts off a plasma membrane-anchored fusion construct in close proximity to a mitochondrial targeting sequence; second, the mitochondrial targeting sequence preceding the protein of interest recruits to the outer mitochondrial membrane and imports the protein fused to it into mitochondria. Upon reaching the mitochondrial matrix, the matrix processing peptidase cuts off the mitochondrial targeting sequence and releases the protein of interest. OptoMitoImport is available as a two-plasmid system as well as a P2A peptide or IRES sequence-based bicistronic system. Fluorescence studies demonstrate the release of the plasma membrane-anchored protein of interest through light-induced TEV protease cleavage and its localization to mitochondria. Cell fractionation experiments confirm the presence of the peptidase-cleaved protein of interest in the mitochondrial fraction. The processed product is protected from proteinase K treatment. Depletion of the membrane potential across the inner mitochondria membrane prevents the mitochondrial protein import, indicating an import of the protein of interest by the presequence pathway. These data demonstrate the functionality of OptoMitoImport as a generic system with which to control the post-translational mitochondrial import of proteins via the presequence pathway.
    Keywords:  CRY2; LOV domain; MTS; TEV; matrix peptidases; mitochondrial import; optogenetics
    DOI:  https://doi.org/10.3390/cells13191671
  30. Chin Med. 2024 Oct 14. 19(1): 143
    Yiqihuoxue decoction (GSC) inhibits mitochondrial fission through the AMPK pathway to ameliorate EPCs senescence and optimize vascular aging transplantation regimens.
    Yinan Liu, Zenghui Niu, Xue Wang, Chengkui Xiu, Yanhong Hu, Jiali Wang, Yan Lei, Jing Yang.
       BACKGROUND: During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms.
    METHODS: The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT-qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits.
    RESULTS: In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence.
    Keywords:  AMPK; GSC; Mitochondrial fission; Transplantation; Vascular aging
    DOI:  https://doi.org/10.1186/s13020-024-01008-7
  31. Pharmacol Res. 2024 Oct 15. pii: S1043-6618(24)00411-0. [Epub ahead of print] 107466
    The PINK1/Parkin signaling pathway-mediated mitophagy: a forgotten protagonist in myocardial ischemia/reperfusion injury.
    Xiaopeng Zhao, Zheng Wang, Lijie Wang, Tao Jiang, Dan Dong, Mingli Sun.
      Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential "culprit" of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI.
    Keywords:  Dapagliflozin (PubChem CID: 9887712); Dexmedetomidine (PubChem CID: 5311068); Dexpramipexole (PubChem CID: 59868); Dl-3-n-butylphthalide (PubChem CID: 61361); Gastrodin (PubChem CID: 115067); Honokiol (PubChem CID: 72303); Intervention protocols; MIRI; Melatonin (PubChem CID: 896); Mitophagy; Pathological mechanisms; Potential interventions; Resveratrol (PubChem CID: 445154); Simvastatin (PubChem CID: 54454); Sitagliptin (PubChem CID: 4369359); The PINK1/Parkin signaling pathway
    DOI:  https://doi.org/10.1016/j.phrs.2024.107466
  32. Nat Commun. 2024 Oct 18. 15(1): 9008
    Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.
    Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas Christian, Robert Y Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A Piccirilli, Meni Wanunu, Erin Seifert, Douglas C Wallace, Ya-Ming Hou.
      Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53318-x
  33. Thyroid. 2024 Oct 14.
    Mitophagy Defects Exacerbate Inflammation and Aberrant Proliferation in Lymphocytic Thyroiditis.
    Han Sai Lee, Jinju Lee, Hyun-Ju An, Min-Ji Sung, Jin-Hyung Heo, So-Young Lee, Young Shin Song.
      Background: Mitochondrial dysfunction in the thyroid due to defective mitophagy has been observed in lymphocytic thyroiditis (LT). However, the effect of impaired mitophagy on the pathogenesis of LT is not well understood. The aim of this study is to investigate the role of mitophagy dysregulation in the thyroid gland. Methods: We analyzed RNA sequencing data of human thyroid glands with/without LT from Genotype-Tissue Expression (GTEx; n = 653) and performed RNA sequencing in thyroid glands of phosphatase and tensin homolog-induced putative protein kinase 1 (Pink1) knock-out and wild-type mice. We evaluated the phenotypic and histopathologic characteristics of the human (n = 16) and mouse thyroids. Additionally, we assessed cell proliferation, reactive oxygen species (ROS) production, and cytokine secretion of human thyroid epithelial cells (HTori-3) treated with PINK1 siRNA or a mitophagy inhibitor. Results: We found that expression of PINK1, a key regulator of mitophagy, was compromised in human thyroids with LT. Thyroid glands of Pink1-deficient mice exhibited increased inflammatory responses and nodular hyperplasia. Furthermore, mitophagy defects led to the production of pro-inflammatory cytokines and ROS in thyroid cells, resulting in immune cell recruitment. Notably, these mitophagy defects upregulated both the RNA expression and protein secretion of amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, in thyroid cells, while decreasing the protein expression of cAMP response element-binding protein (CREB), a transcription factor that suppresses AREG transcription. Finally, we demonstrated that aberrant cell proliferation in thyroid cells, driven by mitophagy defects, was mitigated after treatment with cetuximab, an EGFR inhibitor. Conclusions: In this study, we observed that mitophagy defects in the thyroid not only intensify inflammation through the accumulation of ROS, cytokine production, and immune cell recruitment but also contribute to hyperplasia via the EGFR pathway, facilitated by increased secretion of AREG from thyroid cells.
    Keywords:  PINK1; RNA sequencing; hyperplasia; inflammation; lymphocytic thyroiditis; mitophagy
    DOI:  https://doi.org/10.1089/thy.2024.0125
  34. Free Radic Biol Med. 2024 Oct 12. pii: S0891-5849(24)00983-3. [Epub ahead of print]
    The tolerable upper intake level of manganese alleviates Parkinson-like motor performance and neuronal loss by activating mitophagy.
    Xiao Han, Bingge Zhang, Qichao Gong, Tiansu Liu, Chao Wang, Yuguo Sun, Hongyi Jia, Yinyan Pu, Qinghua Hou, Xifei Yang.
      Manganese (Mn2+) is among the indispensable trace elements required by the human body, but high-dose Mn2+ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn2+ has been established for normal individuals in different countries. However, whether the UL of Mn2+ is suitable for the patients of Parkinson's disease (PD) is unclear. Here, we found unexpectedly that the dietary UL of Mn2+ supplement enhanced mitophagy through the PINK1/parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn2+ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn2+ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or cyclosporine A), abolished the neuroprotective effects of Mn2+. These findings demonstrate that the dietary UL of Mn2+ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn2+ intake.
    Keywords:  Mitophagy; Mn; MnSOD; Oxidative Stress; PD; UL
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.281
  35. Exp Neurol. 2024 Oct 15. pii: S0014-4886(24)00329-7. [Epub ahead of print] 115003
    Progress in the regulatory mechanism of mitophagy in chronic cerebral ischemic neuronal injury.
    Lihong Li, Rui Yuan, Moxin Wu, Xiaoping Yin, Manqing Zhang, Zhiying Chen.
      Chronic cerebral ischemia (CCI) is a common clinical syndrome that can impact various cerebrovascular diseases. Its pathological mechanism of injury involves energy imbalance, oxidative stress, inflammatory response, and many other processes. Neuronal damage occurs in a complex and multifaceted manner. This article provides a detailed discussion of the activation and inhibition mechanisms of mitophagy under cerebral ischemia and considers the advantages and disadvantages of mitophagy in the recovery process of ischemic brain injury. Finally, we address the future direction of research on neuronal injury and the regulatory mechanisms of mitophagy in chronic cerebral ischemia. Future studies should focus on drug intervention at specific regulatory points and the cross-regulation of related signaling pathways to comprehensively deepen understanding of the mechanisms of neuronal injury in chronic cerebral ischemia. Promising interventions could potentially improve the treatment and outcomes of chronic cerebral ischemia.
    Keywords:  Chronic cerebral ischemia; Inflammatory response; Mitophagy; Neuronal damage; Oxidative stress
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115003
  36. Mol Med Rep. 2024 Dec;pii: 240. [Epub ahead of print]30(6):
    Irisin improves ROS‑induced mitohormesis imbalance in H9c2 cells.
    Baogui Wang, Haibo Xu, Shuai Shang, Longxiang Liu, Chunlong Sun, Wen Du.
      Abnormal mitohormesis is a key pathogenic mechanism that induces a variety of cardiac diseases, including cardiac hypertrophy and heart failure. Irisin as a muscle factor serves a cardioprotective role in response to cellular oxidative stress injury. Rat cardiomyocyte cells (H9c2) were treated with 40 µM exogenous H2O2 to establish an oxidative stress model, followed by addition of 75 nM exogenous irisin for experiments to determine mitochondrial membrane potential, reactive oxygen species, and Mitohormesis‑related factors by attrition cytometry. Subsequently, the expression of mitochondrial membrane potential, reactive oxygen species and Mitohormesis‑related factors were continued to be determined by establishing a peroxisome proliferator‑activated receptor γ coactivator‑1 alpha (PGC‑1α) siRNA interference model and continuing the treatment with the addition of 75 nM irisin 12 h before the end of interference. When H9c2 cells underwent oxidative stress, irisin partially improved mitochondrial membrane potential and reactive oxygen species levels and partially restored mitochondrial energy metabolism by upregulating fusion proteins optic atrophy 1 (OPA1) mitochondrial dynamin‑like GTPase and mitofusin 2 and downregulating fission protein dynamin‑related protein 1. Following interference with PGC‑1α, irisin promoted mitochondrial biosynthesis by increasing the mRNA levels of OPA1 and protein levels of cytochrome c oxidase subunit 4. These results suggested that irisin acted partially independently of the PGC‑1α signaling pathway to regulate mitohormesis imbalance due to oxidative stress and maintain energy metabolism by improving mitochondrial structure.
    Keywords:  H9c2; PGC‑1α; irisin; mitohormesis; reactive oxygen species
    DOI:  https://doi.org/10.3892/mmr.2024.13364
  37. Cell Prolif. 2024 Oct 16. e13764
    Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signalling pathway.
    Chenglei Zhang, Jiarui Li, Lijuan Wang, Jie Ma, Xin Li, Yuanyuan Wu, Yanru Ren, Yanhui Yang, Hui Song, Jianning Li, Yi Yang.
      GPR119 agonists are being developed to safeguard the function of pancreatic β-cells, especially in the context of non-alcoholic fatty pancreas disease (NAFPD) that is closely associated with β-cell dysfunction. This study aims to employ a drug repurposing strategy to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β-cell function in the context of NAFPD. MIN6 cells were stimulated with palmitic acid (PA), and a NAFPD model was established in GPR119-/- mice fed with a high-fat diet (HFD). Terazosin, identified through screening, was utilized to assess its impact on enhancing β-cell function via the MST1-Foxo3a pathway and mitophagy. Terazosin selectively activated GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β-cell function in NAFPD mice. It inhibited the upregulation of MST1-Foxo3a expression in pancreatic tissue and enhanced damaged mitophagy clearance, restoring autophagic flux, and improving mitochondrial quantity and structure in β-cells. Nevertheless, GPR119 deficiency negated the positive impact of terazosin on pancreatic β-cell function in NAFPD mice and abolished its inhibitory effect on the MST1-Foxo3a pathway. Terazosin activates GPR119 on the surface of pancreatic β-cells, enhancing mitophagy and alleviating β-cell dysfunction in the context of NAFPD by suppressing the MST1-Foxo3a signalling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.
    DOI:  https://doi.org/10.1111/cpr.13764
  38. Int J Mol Sci. 2024 Oct 01. pii: 10577. [Epub ahead of print]25(19):
    The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death.
    Stanton Tam, Balasubrahmanyam Umashankar, Md Khalilur Rahman, Hassan Choucair, Tristan Rawling, Michael Murray.
      Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity.
    Keywords:  anticancer agent; aryl-ureido fatty acids; mitochondrial fission and fusion; mitochondrial membrane; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms251910577
  39. J Biochem. 2024 Oct 15. pii: mvae069. [Epub ahead of print]
    Mitochondria-giant lipid droplet proximity and autophagy suppression in nitrogen-depleted oleaginous yeast Lipomyces starkeyi cells.
    Lan Duan, Akinobu Togou, Keisuke Ohta, Koji Okamoto.
      Balancing energy production and storage is a fundamental process critical for cellular homeostasis in most eukaryotes that relies on the intimate interplay between mitochondria and lipid droplets. In the oleaginous yeast Lipomyces starkeyi under nitrogen starvation, lipid droplet forms a single giant spherical structure that is easily visible under a light microscope. Currently, how mitochondria behave in L. starkeyi cells undergoing giant lipid droplet formation remains unknown. Here we show that mitochondria transition from fragments to elongated tubules and sheet-like structures that are in close proximity to a giant lipid droplet in nitrogen-depleted L. starkeyi cells. Under the same conditions, mitochondrial degradation and autophagy are strongly suppressed, suggesting that these catabolic events are not required for giant lipid droplet formation. Conversely, carbon-depleted cells suppress mitochondrial elongation and lipid droplet expansion, whereas they promote mitochondrial degradation and autophagy. We propose a potential link of mitochondrial proximity and autophagic suppression to giant lipid droplet formation.
    Keywords:  autophagy; lipid droplet; mitochondria; oleaginous yeast
    DOI:  https://doi.org/10.1093/jb/mvae069
  40. Sci Rep. 2024 10 15. 14(1): 24137
    Mitophagy related diagnostic biomarkers for coronary in-stent restenosis identified using machine learning and bioinformatics.
    Ming Shen, Meixian Chen, Yu Chen, Yunhua Yu.
      Percutaneous coronary intervention (PCI) combined with stent implantation is currently one of the most effective treatments for coronary artery disease (CAD). However, in-stent restenosis (ISR) significantly compromises its long-term efficacy. Mitophagy plays a crucial role in vascular homeostasis, yet its role in ISR remains unclear. This study aims to identify mitophagy-related biomarkers for ISR and explore their underlying molecular mechanisms. Through differential gene expression analysis between ISR and Control samples in the combined dataset, 169 differentially expressed genes (DEGs) were identified. Twenty-three differentially expressed mitophagy-related genes (DEMRGs) were identified by intersecting with mitophagy-related genes (MRGs) from the GeneCards, and functional enrichment analysis indicated their significant involvement in mitophagy-related biological processes. Using Weighted Gene Co-expression Network Analysis (WGCNA) and three machine learning algorithms (Logistic-LASSO, RF, and SVM-RFE), LRRK2, and ANKRD13A were identified as mitophagy-related biomarkers for ISR. The nomogram based on these two genes also exhibited promising diagnostic performance for ISR. Gene Set Enrichment Analysis (GSEA) as well as immune infiltration analyses showed that these two genes were closely associated with immune and inflammatory responses in ISR. Furthermore, potential small molecule compounds with therapeutic implications for ISR were predicted using the connectivity Map (cMAP) database. This study systematically investigated mitophagy-related biomarkers for ISR and their potential biological functions, providing new insights into early diagnosis and precision treatment strategies for ISR.
    Keywords:  Biomarkers; Coronary artery disease; Immune infiltration; In-stent restenosis; Machine learning; Mitophagy
    DOI:  https://doi.org/10.1038/s41598-024-74862-y
  41. MedComm (2020). 2024 Oct;5(10): e770
    Mitochondrial fission factor: a living way for mitochondria sensing food.
    Mengmeng Zhi, Rong Cao, Xianghui Fu, Ling Li.
      
    DOI:  https://doi.org/10.1002/mco2.770
  42. Eur J Pharmacol. 2024 Oct 10. pii: S0014-2999(24)00715-5. [Epub ahead of print]984 177025
    Protective effects of licofelone on scopolamine-induced spatial learning and memory impairment by enhancing parkin-dependent mitophagy and promotion of neural regeneration and in adult mice.
    Sepideh Goudarzi, Razieh Mohammad Jafari, Nikou Farsiu, Behnam Amini, Mohammad Amin Manavi, Javad Fahanik-Babaei, Shahram Ejtemaei-Mehr, Ahmad Reza Dehpour.
      Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.
    Keywords:  LOX; Memory; Mitophagy; Neurogenesis; Parkin; Scopolamine
    DOI:  https://doi.org/10.1016/j.ejphar.2024.177025
  43. Acta Biochim Biophys Sin (Shanghai). 2024 Oct 17.
    NLRP3 inflammasome-mediated disruption of mitochondrial homeostasis in alveolar macrophages contributes to ozone-induced acute lung inflammatory injury.
    Xinyi Miao, Xinling Li, Pengwei Ma, Mengyuan Li, Yuting Jiang, Pengpeng Wang, Xiaolei Zhou, Ling Wang, Pingping Shang, Qiao Zhang, Feifei Feng.
      Ozone (O 3), a prevalent atmospheric pollutant, can induce lung injury. However, the molecular mechanisms of O 3-induced acute lung inflammatory injury remain unclear. In this study, we investigate the abnormal changes in and molecular mechanism of mitochondrial homeostasis in alveolar macrophages (AMs) in O 3-induced acute lung inflammatory injury mice. Mitochondria and mitochondrial reactive oxygen species (mtROS) are labeled with Mito-Tracker® Deep Red and MitoSOX Red, respectively. Mitochondrial DNA (mtDNA) in AMs from the bronchoalveolar lavage fluid (BALF) is detected via real-time PCR, and the expressions of mitochondrial fusion/fission-related and biogenesis-related proteins in AMs are determined via immunofluorescence staining. Our data show that in O 3-induced acute lung inflammatory injury mice, the number of AMs and the protein expression of the NLRP3 inflammasome complex in the lung tissue are increased. In AMs from O 3-exposed mice, the number of mitochondria, mtROS, and fission-related protein DRP1 are increased, but the levels of Na +-K +-ATPase, fusion-related protein OPA1, biogenesis-related protein NRF1 and mtDNA are significantly decreased. Compared with that in O 3-exposed WT mice, lung inflammation is attenuated, especially the indicators of mitochondrial homeostatic imbalance in AMs, which are alleviated in NLRP3 ‒/‒ and Caspase-1 ‒/‒ mice after O 3 exposure. These findings indicate that the NLRP3 inflammasome-mediated imbalance in mitochondrial homeostasis in AMs contributes to O 3-induced acute lung inflammatory injury. This study may provide a new target for the prevention of lung inflammation induced by O 3.
    Keywords:  NLRP3 inflammasome; acute lung inflammatory injury; alveolar macrophages; mitochondrial homeostasis.; ozone
    DOI:  https://doi.org/10.3724/abbs.2024171
  44. Aging Cell. 2024 Oct 16. e14374
    Aβ -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases.
    Weidong Zhang, Fan Ding, Xing Rong, Qinghua Ren, Tomoka Hasegawa, Hongrui Liu, Minqi Li.
      Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD-related bone loss. In this study, APP/PS1 mice (4- and 8-month-old) and age-matched wild-type mice were used to assess the bone vascular alteration and its role in AD-related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi-1) and GSK-3β inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta-amyloid (Aβ) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aβ-induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK-3β was identified as a key regulatory target of Aβ-induced excessive mitochondrial fission and bone loss. The findings delineated that Aβ-induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK-3β inhibitor emerges as a potential therapeutic strategy.
    Keywords:  Alzheimer's disease; GSK‐3β; bone loss; mitochondrial fission; type H blood vessels
    DOI:  https://doi.org/10.1111/acel.14374
  45. Mol Med Rep. 2024 Dec;pii: 239. [Epub ahead of print]30(6):
    [Retracted] Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway.
    Huixiang Wang, Xiaoli Zhao, Chengxiang Ni, Yuyang Dai, Yan Guo.
      Following the publication of this article, a concerned reader drew to the Editor's attention that the experimental design of the western blot assay experiments portrayed in Fig. 5A on p. 7804, and the overall organization of this figure, may have been flawed, as mitochondrial and cytosolic proteins were featured in the figure with only one set of supporting control western blot data; in this scenario, the proteins would necessarily have needed to have been obtained from two separate cell samples in different experiments, and blotted on to separate gels. Moreover, there was also a concern that certain of the gels featured possible breaks in their continuity/splicing events, such that the protein bands in the figure were not shown consecutively, as they would have appeared, in the affected slices. After having conducted an internal investigation, the Editor of Molecular Medicine Reports agrees with the reader that there were anomalies associated with the presentation of Fig. 5. Therefore, on the grounds of a lack of confidence in the presented data, the Editor has decided that the article should be retracted from the publication. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused, and we also thank the reader for bringing this matter to our attention. [Molecular Medicine Reports 17: 7797‑7806, 2018; DOI: 10.3892/mmr.2018.8823].
    Keywords:  apoptosis; c-Jun N-terminal kinase; dynamin-related protein 1; endometrial stromal cells; migration; mitochondrial fission; zearalenone
    DOI:  https://doi.org/10.3892/mmr.2024.13363
  46. Mater Today Bio. 2024 Dec;29 101273
    Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer.
    Yang Wang, Yao Liu, Xiaomin Su, Lili Niu, Nannan Li, Ce Xu, Zanya Sun, Huishu Guo, Shun Shen, Minghua Yu.
      Bacteria-mediated antitumor therapy has gained widespread attention for its innate tumor-targeting capability and excellent immune activation properties. Nevertheless, the clinical approval of bacterial therapies remains elusive primarily due to the formidable challenge of balancing safety with enhancing in vivo efficacy. In this study, leveraging the probiotic Escherichia coli Nissle1917 (EcN) emerges as a promising approach for colon cancer therapy, offering a high level of safety attributed to its lack of virulence factors and its tumor-targeting potential owing to its obligate anaerobic nature. Specifically, we delineate the erythrocyte (RBC) membrane-camouflaged EcN, termed as Trojan horse EcN@RBC, which triggers apoptosis in tumor cells by mitigating mitochondrial membrane potential (MMP) and subsequently activating the PINK1/Parkin pathway associated with mitophagy. Concurrently, the decline in MMP induced by mitophagy disrupts the mitochondrial permeability transition pore (MPTP), leading to the release of Cytochrome C and subsequent apoptosis induction. Moreover, synergistic effects were observed through the combination of the autophagy activator rapamycin, bolstering the antitumor efficacy in vivo. These findings offer novel insights into probiotic-mediated antitumor mechanisms and underscore the therapeutic potential of EcN@RBC for colon cancer patients.
    Keywords:  Apoptosis; EcN@RBC; Mitophagy; RBC membrane
    DOI:  https://doi.org/10.1016/j.mtbio.2024.101273
  47. Front Pharmacol. 2024 ;15 1409625
    Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.
    Chunxin Jiang, Menglei Tan, Lunmeng Lai, Yanping Wang, Zijun Chen, Qing Xie, Yunsen Li.
       Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear.
    Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model.
    Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that.
    Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy.
    Keywords:  cardiac hypertrophy; glycosphingolipid; lactosylceramide; mitochondrial autophagy; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2024.1409625
  48. Int Immunopharmacol. 2024 Oct 12. pii: S1567-5769(24)01853-8. [Epub ahead of print]143(Pt 1): 113331
    Nrf2 mitigates sepsis-associated encephalopathy-induced hippocampus ferroptosis via modulating mitochondrial dynamic homeostasis.
    Haifeng Duan, Xin Yang, Shuhan Cai, Lei Zhang, Zebao Qiu, Jin Wang, Shun Wang, Zhi Li, Xinyi Li.
      Sepsis-associated encephalopathy (SAE) is a serious neurological complication accompanied with acute and long-term cognitive dysfunction. Ferroptosis is a newly discovered type of cell death that is produced by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis is involved in SAE. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a mitochondria related gene involved in ferroptosis. However, the role of Nrf2 in SAE and the mechanisms remains elusive. In this study, we found that Nrf2 knockout aggravated cognitive and emotional dysfunction and promoted caecal ligation and puncture (CLP)-induced brain injury and hippocampus ferroptosis as indicated by the increase of ROS, Fe2+ and the levels of proinflammatory cytokines. Meanwhile, the levels of glutathione peroxidase 4 (GPX4), SLC7A11 and glutathionewere downregulatedin Nrf2 knockout group. In vitro experiments showed that mitochondrial ROS, Fe2+ and the expression of Fis1 and Drp1 decreased, and the level of Mfn1 and Opa-1 increased after Nrf2 overexpression. The silence of Nrf2 increased the expression of ROS, MDA and Fe2+, while decreased glutathione, mitochondrial membrane potential (MMP) and cell viability in vitro, indicating Nrf2 improved LPS-induced mitochondrial dysfunction and mitigated hippocampal cells ferroptosis. These results suggest that Nrf2 could inhibit ferroptosis and neuroinflammation in hippocampus and reduce cognitive dysfunction in SAE mice, making it a potential therapeutic target in the treatment of SAE. The protective effects of Nrf2 on the brain may be mediated by maintaining mitochondrial dynamic homeostasis.
    Keywords:  Ferroptosis; Mitochondrial homeostasis; Neuroinflammation; Nrf2; Sepsis-associated encephalopathy
    DOI:  https://doi.org/10.1016/j.intimp.2024.113331
  49. Life Sci. 2024 Oct 10. pii: S0024-3205(24)00709-4. [Epub ahead of print]358 123119
    Mitochondrial transfer in the progression and treatment of cardiac disease.
    Yaqing Huang, Wanling Li, Hongyu Sun, Xin Guo, Yue Zhou, Jun Liu, Feila Liu, Yonghong Fan.
      Mitochondria are the primary site for energy production and play a crucial role in supporting normal physiological functions of the human body. In cardiomyocytes (CMs), mitochondria can occupy up to 30 % of the cell volume, providing sufficient energy for CMs contraction and relaxation. However, some pathological conditions such as ischemia, hypoxia, infection, and the side effect of drugs, can cause mitochondrial dysfunction in CMs, leading to various myocardial injury-related diseases including myocardial infarction (MI), myocardial hypertrophy, and heart failure. Self-control of mitochondria quality and conversion of metabolism pathway in energy production can serve as the self-rescue measure to avoid autologous mitochondrial damage. Particularly, mitochondrial transfer from the neighboring or extraneous cells enables to mitigate mitochondrial dysfunction and restore their biological functions in CMs. Here, we described the homeostatic control strategies and related mechanisms of mitochondria in injured CMs, including autologous mitochondrial quality control, mitochondrial energy conversion, and especially the exogenetic mitochondrial donation. Additionally, this review emphasizes on the therapeutic effects and potential application of utilizing mitochondrial transfer in reducing myocardial injury. We hope that this review can provide theoretical clues for the developing of advanced therapeutics to treat cardiac diseases.
    Keywords:  Cardiac diseases; Cardiomyocyte; Mitochondrial quality control; Mitochondrial therapy; Mitochondrial transfer
    DOI:  https://doi.org/10.1016/j.lfs.2024.123119
  50. Endocrinol Metab (Seoul). 2024 Oct 14.
    Thyroid Hormone-Mediated Selective Autophagy and Its Implications in Countering Metabolic Dysfunction-Associated Steatotic Liver Disease.
    Rohit A Sinha.
      The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.
    Keywords:  3,5-Diiodothyronine; Autophagy; Metabolic dysfunction-associated steatohepatitis; Metabolic dysfunction-associated steatotic liver disease; Mitophagy; Resmetirom; Thyroid hormones
    DOI:  https://doi.org/10.3803/EnM.2024.2068
  51. Biomark Res. 2024 Oct 16. 12(1): 125
    Comprehensive atlas of mitochondrial distribution and dynamics during oocyte maturation in mouse models.
    Xia Hao, Jian Zhao, Kenny A Rodriguez-Wallberg.
       BACKGROUND: Oocytes, the largest cells in mammals, harbor numerous mitochondria within their cytoplasm. These highly dynamic organelles are crucial for providing energy resources and serving as central regulators during oogenesis. Mitochondrial dynamics ensure proper energy distribution for various cellular processes involved in oocyte maturation. Previous studies have used alterations in mitochondrial distribution as a biomarker to assess the oocyte health. However, there are discrepancies between studies regarding mitochondrial distribution profiles in healthy oocytes. Consequently, a comprehensive mitochondrial distribution profile in oocytes during maturation has not been fully characterized. Additionally, there is a lack of objective, quantitative methods to evaluate alterations in mitochondrial distribution profiles in oocytes.
    METHODS: This study aims to provide an in-depth overview of mitochondrial distribution profiles in mouse oocytes at different maturation stages: germinal vesicle (GV) stage, metaphase I (MI), and mature metaphase II (MII). Freshly collected mouse GV, MI and MII oocytes were stained with MitoTracker Red. Confocal microscopy was used to obtain images of mitochondrial distribution profiles in these oocytes. Using the Imaris software, we reconstructed three-dimensional (3D) surface renderings of each oocyte and quantitatively illustrated the mitochondrial distribution profiles.
    RESULTS: At the GV stage, mitochondria in oocytes were evenly distributed throughout the ooplasm. As oocytes progressed to MI and MII stages, mitochondria aggregated and formed clusters, the mean size of mitochondrial clusters and the proportions of clustered mitochondria increased along with the maturation of oocytes.
    CONCLUSIONS: Our findings reveal that mitochondria in mouse oocytes are highly dynamic, undergoing significant reorganizations during oocyte maturation. We for the first time provided comprehensive mitochondrial distribution profiles in mouse oocytes at the GV, MI and MII stages. These mitochondrial distribution profiles were further quantitatively evaluated. Our methods provide an objective and standardized approach for evaluating alterations in mitochondrial dynamics, which can be used as biomarkers to monitor oocyte conditions during maturation.
    Keywords:  Mitochondria; Mitochondrial distribution; Oocyte; Oocyte maturation
    DOI:  https://doi.org/10.1186/s40364-024-00672-z
  52. J Nanobiotechnology. 2024 Oct 18. 22(1): 634
    Selenium nanoparticles ameliorate lumbar disc degeneration by restoring GPX1-mediated redox homeostasis and mitochondrial function of nucleus pulposus cells.
    Wei He, Xin Tian, Quan Zhou, Jiaheng Lv, Yangfeng Li, Chenyang Jin, Hao Liu, Huiling Yang, Yong Xu, Fan He, Tao Liu.
      Intervertebral disc degeneration (IVDD) is a prevalent musculoskeletal disorder that involves the excessive accumulation of reactive oxygen species (ROS), resulting in mitochondrial dysfunction and matrix metabolism imbalance in nucleus pulposus cells (NPCs). Selenium, an indispensable trace element, plays a crucial role in maintaining mitochondrial redox homeostasis by being incorporated into antioxidant selenoproteins as selenocysteine. In this study, we employed a straightforward synthesis method to produce selenium nanoparticles (SeNPs) with consistent size and distribution, and evaluated their potential protective effects in ameliorating IVDD. In a simulated inflammatory environment induced by interleukin-1beta (IL-1β) in vitro, SeNPs demonstrated a protective effect on the matrix synthesis capacity of NPCs through the up-regulation of aggrecan and type II collagen, while concurrently suppressing the expression of matrix degradation enzymes including MMP13 and ADAMTS5. Additionally, SeNPs preserved mitochondrial integrity and restored impaired mitochondrial energy metabolism by activating glutathione peroxidase1 (GPX1) to rebalance redox homeostasis. In a rat lumbar disc model induced by puncture, the local administration of SeNPs preserved the hydration of nucleus pulposus tissue, promoted matrix deposition, and effectively mitigated the progression of IVDD. Our results indicate that the enhancement of GPX1 by SeNPs may offer a promising therapeutic approach for IVDD by restoring mitochondrial function and redox homeostasis.
    Keywords:  Extracellular matrix; GPX1; Intervertebral disc degeneration; Mitochondrial homeostasis; Nucleus pulposus; Selenium nanoparticles
    DOI:  https://doi.org/10.1186/s12951-024-02890-x
  53. J Physiol Biochem. 2024 Oct 18.
    Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.
    Shohei Dobashi, Toshinori Yoshihara, Yuji Ogura, Hisashi Naito.
      High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O2) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O2) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.
    Keywords:  Autophagy; Hind limb muscle; Mitochondrial fusion and fission; Mitochondrial synthesis; Moderate hypoxia; Treadmill running
    DOI:  https://doi.org/10.1007/s13105-024-01052-9
  54. J Proteome Res. 2024 Oct 16.
    LC-Orbitrap HRMS-Based Proteomics Reveals Novel Mitochondrial Dynamics Regulatory Proteins Associated with RasV12-Induced Glioblastoma (GBM) of Drosophila.
    Pradeep Kumar, Rohit Kumar, Prabhat Kumar, Sunaina Kushwaha, Sandhya Kumari, Neha Yadav, Saripella Srikrishna.
      Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor found in adult humans with a poor prognosis and average survival of 14-15 months. In order to have a comprehensive understanding of proteome and identify novel therapeutic targets, this study focused mainly on the differentially abundant proteins (DAPs) of RasV12-induced GBM. RasV12 is a constitutively active Ras mutant form essential for tumor progression by continuously activating signaling pathways leading to uncontrolled tumor growth. This study used a transgenic Drosophila model with RasV12 overexpression using the repo-GAL4 driver line, specifically in glial cells, to study GBM. The high-resolution mass spectrometry (HRMS)-based proteomic analysis of the GBM larval central nervous system identified three novel DAPs specific to mitochondria. These DAPs, probable maleylacetoacetate isomerase 2 (Q9VHD2), bifunctional methylene tetrahydrofolate dehydrogenase (Q04448), and glutamine synthetase1 (P20477), identified through HRMS were further validated by qRT-PCR. The protein-protein interaction analysis revealed interactions between RasV12 and DAPs, with functional links to mitochondrial dynamics regulators such as Drp1, Marf, Parkin, and HtrA2. Notably, altered expressions of Q9VHD2, P20477, and Q04448 were observed during GBM progression, which offers new insights into the involvement of mitochondrial dynamic regulators in RasV12-induced GBM pathophysiology.
    Keywords:  CNS; Drosophila; RasV12; brain tumor; glioblastoma; mass spectrometry; mitochondrial dynamics; proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00502
  55. Cell Biochem Biophys. 2024 Oct 17.
    SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy.
    Xiaojing Hua, Qing Lu, Li Zeng.
      Sestrin 2 (SESN2) has been reported to participate in the regulation of granulosa cell function in ovarian tissues. However, the role of SESN2 in polycystic ovarian syndrome (PCOS) is still incompletely understood. Here, we investigated the functional role and mechanism of SESN2 in dihydrotestosterone (DHT)-induced granulosa cells. In this study, DHT was utilized to induce PCOS cell model and the AMP-activated protein kinase (AMPK) inhibitor Compound C (CC) was utilized to inhibit the AMPK pathway. qRT-PCR was performed to detect the expression of SESN2 in HGLS cells. Cell apoptosis was evaluated by flow cytometry. Oxidative stress was detected by DCFH-DA staining, superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) kits. The expression of SESN2, cell apoptosis, oxidative stress, mitophagy and AMPK/ULK1 signaling-related proteins were measured by western blot. The results showed that SESN2 was downregulated in DHT-induced granulosa cells. Overexpression of SESN2 inhibited the DHT-induced apoptosis and oxidative stress of HGLS cells. DHT induction aggravated HGLS cell apoptosis and oxidative stress. SESN2 overexpression inhibited the DHT-induced apoptosis and oxidative stress of HGLS cells. In addition, overexpression of SESN2 activated the AMPK/ULK1 signaling pathway and promoted mitophagy. Treatment of CC reversed the regulatory effect of SESN2 on mitophagy. CC also reversed the influences of SESN2 overexpression on apoptosis and oxidative stress in DHT-induced HGLS cells. Overall, SESN2 suppressed DHT-induced apoptosis and oxidative stress in PCOS through AMPK/ULK1-mediated mitophagy.
    Keywords:  AMPK/ULK1; Polycystic ovarian syndrome; Sestrin 2; granulosa cell; mitophagy
    DOI:  https://doi.org/10.1007/s12013-024-01589-y
  56. EMBO J. 2024 Oct 18.
    The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.
    Wandi Xiong, Kaiyu Xu, Jacquelyne Ka-Li Sun, Siling Liu, Baizhen Zhao, Jie Shi, Karl Herrup, Hei-Man Chow, Lin Lu, Jiali Li.
      Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.
    Keywords:   lncMtDloop ; Alzheimer’s Disease; Mitochondrial Homeostasis; TFAM; mtDNA
    DOI:  https://doi.org/10.1038/s44318-024-00270-7
  57. Adv Sci (Weinh). 2024 Oct 18. e2404033
    m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression.
    Wenqin Luo, Zhehao Xu, Fan Li, Lifeng Ding, Ruyue Wang, Yudong Lin, Xudong Mao, Xianjiong Chen, Yang Li, Zeyi Lu, Haiyun Xie, Huan Wang, Ziwei Zhu, Yi Lu, Luying Guo, Xiaojing Yu, Liqun Xia, Housheng Hansen He, Gonghui Li.
      N6-methyl-2'-O-methyladenosine (m6Am), occurring adjacent to the 7-methylguanosine (m7G) cap structure and catalyzed by the newly identified writer PCIF1 (phosphorylated CTD interacting factor 1), has been implicated in the pathogenesis of various diseases. However, its involvement in renal cell carcinoma (RCC) remains unexplored. Here, significant upregulation of PCIF1 and m6Am levels in RCC tissues are identified, unveiling their oncogenic roles both in vitro and in vivo. Mechanically, employing m6Am-Exo-Seq, LPP3 (phospholipid phosphatase 3) mRNA is identified as a key downstream target whose translation is enhanced by m6Am modification. Furthermore, LPP3 is revealed as a key regulator of phosphatidic acid metabolism, critical for preventing its accumulation in mitochondria and facilitating mitochondrial fission. Consequently, Inhibition of the PCIF1/LPP3 axis significantly altered mitochondrial morphology and reduced RCC tumor progression. In addition, depletion of PCIF1 sensitizes RCC to sunitinib treatment. This study highlights the intricate interplay between m6Am modification, phosphatidic acid metabolism, and mitochondrial dynamics, offering a promising therapeutic avenue for RCC.
    Keywords:  N6,2′‐O‐dimethyladenosine; PCIF1; mitochondrial dynamics; phosphatidic acid metabolism; renal cell carcinoma
    DOI:  https://doi.org/10.1002/advs.202404033
  58. Fluids Barriers CNS. 2024 Oct 15. 21(1): 81
    Oxidative stress alters mitochondrial homeostasis in isolated brain capillaries.
    Gopal V Velmurugan, Hemendra J Vekaria, Anika M S Hartz, Björn Bauer, W Brad Hubbard.
       BACKGROUND: Neurovascular deficits and blood-brain barrier (BBB) dysfunction are major hallmarks of brain trauma and neurodegenerative diseases. Oxidative stress is a prominent contributor to neurovascular unit (NVU) dysfunction and can propagate BBB disruption. Oxidative damage results in an imbalance of mitochondrial homeostasis, which can further drive functional impairment of brain capillaries. To this end, we developed a method to track mitochondrial-related changes after oxidative stress in the context of neurovascular pathophysiology as a critical endophenotype of neurodegenerative diseases.
    METHODS: To study brain capillary-specific mitochondrial function and dynamics in response to oxidative stress, we developed an ex vivo model in which we used isolated brain capillaries from transgenic mice that express dendra2 green specifically in mitochondria (mtD2g). Isolated brain capillaries were incubated with 2,2'-azobis-2-methyl-propanimidamide dihydrochloride (AAPH) or hydrogen peroxide (H2O2) to induce oxidative stress through lipid peroxidation. Following the oxidative insult, mitochondrial bioenergetics were measured using the Seahorse XFe96 flux analyzer, and mitochondrial dynamics were measured using confocal microscopy with Imaris software.
    RESULTS: We optimized brain capillary isolation with intact endothelial cell tight-junction and pericyte integrity. Further, we demonstrate consistency of the capillary isolation process and cellular enrichment of the isolated capillaries. Mitochondrial bioenergetics and morphology assessments were optimized in isolated brain capillaries. Finally, we found that oxidative stress significantly decreased mitochondrial respiration and altered mitochondrial morphology in brain capillaries, including mitochondrial volume and count.
    CONCLUSIONS: Following ex vivo isolation of brain capillaries, we confirmed the stability of mitochondrial parameters, demonstrating the feasibility of this newly developed platform. We also demonstrated that oxidative stress has profound effects on mitochondrial homeostasis in isolated brain capillaries. This novel method can be used to evaluate pharmacological interventions to target oxidative stress or mitochondrial dysfunction in cerebral small vessel disease and neurovascular pathophysiology as major players in neurodegenerative disease.
    Keywords:  Blood vessel; Endothelial cells; Fission; Microvessels; Mitochondria; Oxygen-glucose deprivation; Small vessel disease
    DOI:  https://doi.org/10.1186/s12987-024-00579-9
  59. ACS Omega. 2024 Oct 08. 9(40): 42049-42060
    Near-Infrared Ratiometric Hemicyanine Fluorescent Probes for Monitoring Mitochondrial pH Dynamics in Live Cells during Oxidative Stress and Hypoxia.
    Sushil K Dwivedi, Dilka Liyana Arachchige, Adenike Mary Olowolagba, Mohamed Mahmoud, Subash Pandey, Tara Vohs, Haiying Liu, Rudy L Luck.
      Novel near-infrared ratiometric molecules (probes A and B) produced by linking formyl-functionalized xanthene and methoxybenzene moieties, respectively, onto a xanthene-hemicyanine framework are detailed. Probe A exhibited a primary absorption peak at 780 nm and a shoulder peak at 730 nm and exhibited fluorescence at 740 nm↓ (signifies a downward shift in intensity upon acidification) in a pH 9.3 buffer and 780 nm↑ at pH 2.8 under excitation at 700 nm. Probe B featured absorptions at 618 and 668 nm at pH 3.2 and at 717 nm at pH 8.6, and fluorescence at 693 nm↑ at pH 3.2 and at 739 nm↓ at pH 8.6, in mostly the red to near-IR region. The ratiometric changes in the intensity of the fluorescent absorptions were reversed between A and B upon acidification as indicated by the arrows. Theoretical calculations confirmed that there were slight changes in conformation between probes and the protonated molecules, suggesting that the changes in emission spectra were due mostly to conjugation effects. Calculations at the APFD/6-311+g(d,p) level with a solvent described by the polarizable continuum model resulted in pK a values for A at 6.33 and B at 6.41, in good agreement with the experimentally determined value of 6.97 and an average of 6.40, respectively. The versatilities of the probes were demonstrated in various experimental contexts, including the effective detection of mitochondrial pH fluctuations. Live cell experiments involving exposure to different pH buffers in the presence of H+ ionophores, monitoring mitophagy processes during cell starvation, studying hypoxia induced by CoCl2 treatment, and investigating responses to various oxidative stresses are detailed. Our findings highlight the potential of attaching xanthene and methoxybenzaldehyde groups onto xanthene-hemicyanine structures as versatile tools for monitoring pH changes in a variety of cellular environments and processes.
    DOI:  https://doi.org/10.1021/acsomega.4c07303
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒20 at 10:03.