bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–11–03
forty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency.
  2. Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
  3. Apoptosis, Mitochondrial Autophagy, Fission, and Fusion Maintain Mitochondrial Homeostasis in Mouse Liver Under Tail Suspension Conditions.
  4. Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3 Mediated Mitophagy: Prevented by Enocyanin.
  5. The Large GTPase Guanylate-Binding Protein-1 (GBP-1) Promotes Mitochondrial Fission in Glioblastoma.
  6. Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
  7. Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1.
  8. AMPD3 promotes doxorubicin-induced cardiomyopathy through HSP90α-mediated ferroptosis.
  9. IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2.
  10. Pink1-Dependent Mitophagy in Vascular Smooth Muscle Cells: Implications for Arterial Constriction.
  11. Mitophagy in Cell Death Regulation: Insights into Mechanisms and Disease Implications.
  12. Brain mitophagy in space and time.
  13. Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway.
  14. Advances in Small-Molecule Fluorescent pH Probes for Monitoring Mitophagy.
  15. Assays to monitor mitochondrial translation.
  16. Astragaloside IV reduces mutant Ataxin-3 levels and supports mitochondrial function in Spinocerebellar Ataxia Type 3.
  17. m7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes.
  18. Mitophagy: insights into its signaling molecules, biological functions, and therapeutic potential in breast cancer.
  19. Identifying the prognostic significance of mitophagy-associated genes in multiple myeloma: a novel risk model construction.
  20. CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination.
  21. Nicotinamide N-oxide Inhibits Microglial Pyroptosis by Upregulating Mitophagy and Alleviates Neural Damage in Rats after TBI.
  22. Shaping cardiac destiny: the role of post-translational modifications on endoplasmic reticulum - mitochondria crosstalk in cardiac remodeling.
  23. Hesperitin prevents non-alcoholic steatohepatitis by modulating mitochondrial dynamics and mitophagy via the AMPKα-Drp1/PINK1-Parkin signaling pathway.
  24. Monitoring and analysis of mitochondrial precursor protein aggregates in the cytosol.
  25. Analysis of mitochondrial biogenesis and protein localization by genetic screens and automated imaging.
  26. AdipoRon Alleviates Liver Injury by Protecting Hepatocytes from Mitochondrial Damage Caused by Ionizing Radiation.
  27. Monitoring the in vitro import and assembly of mitochondrial precursor proteins into mammalian mitochondria.
  28. Ibrutinib Promotes Atrial Fibrillation by Disrupting A-Kinase Anchoring Protein 1-Mediated Mitochondrial Quality Surveillance in Cardiomyocytes.
  29. Molybdenum nanodots act as antioxidants for photothermal therapy osteoarthritis.
  30. Quercetin inhibits mitophagy-mediated apoptosis and inflammatory response by targeting the PPARγ/PGC-1α/NF-κB axis to improve acute liver failure.
  31. HSP90 N-terminal inhibition promotes mitochondria-derived vesicles related metastasis by reducing TFEB transcription via decreased HSP90AA1-HCFC1 interaction in liver cancer.
  32. Editorial: Role of mitochondrial stress response in metabolic health.
  33. TFAM as a sensor of UVC-induced mitochondrial DNA damage.
  34. Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy.
  35. The role of TRAP1 in regulating mitochondrial dynamics during acute hypoxia-induced brain injury.
  36. Targeting mitochondria: a novel approach for treating platinum-resistant ovarian cancer.
  37. The Role of Mitochondrial Homeostasis in Mesenchymal Stem Cell Therapy-Potential Implications in the Treatment of Osteogenesis Imperfecta.
  38. Glutamine and serum starvation alters the ATP production, oxidative stress, and abundance of mitochondrial RNAs in extracellular vesicles produced by cancer cells.
  39. Sex hormone-binding globulin promotes the osteogenic differentiation potential of equine adipose-derived stromal cells by activating the BMP signaling pathway.
  40. Resveratrol improved mitochondrial biogenesis by activating SIRT1/PGC-1α signal pathway in SAP.
  41. Apigenin Ameliorates H2O2-Induced Oxidative Damage in Melanocytes through Nuclear Factor-E2-Related Factor 2 (Nrf2) and Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt)/Mammalian Target of Rapamycin (mTOR) Pathways and Reducing the Generation of Reactive Oxygen Species (ROS) in Zebrafish.
  42. The Role of Non-Coding RNAs in Mitochondrial Dysfunction of Alzheimer's Disease.
  43. Retinal G-protein-coupled receptor deletion exacerbates AMD-like changes via the PINK1-parkin pathway under oxidative stress.
  44. The E3 ubiquitin ligase MARCH5 promotes mitochondrial fusion and cell cycle progression in acute myeloid leukemia.
  45. NPR1 promotes cisplatin resistance by inhibiting PARL-mediated mitophagy-dependent ferroptosis in gastric cancer.
  1. bioRxiv. 2024 Oct 17. pii: 2024.10.16.617214. [Epub ahead of print]
    The Integrated Stress Response Suppresses PINK1-dependent Mitophagy by Preserving Mitochondrial Import Efficiency.
    Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Xiaoyan Guo.
      Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of integrated stress response (ISR) in regulating mitophagy, a key mitochondrial stress pathway. Our findings show that the ISR suppresses mitophagy under non-depolarizing mitochondrial stress by positively regulating mitochondrial protein import, independent of ATF4 activation. Mitochondrial protein import is regulated by the rate of protein synthesis under both depolarizing and non-depolarizing stress. Without ISR, increased protein synthesis overwhelms the mitochondrial import machinery, reducing its efficiency. Under depolarizing stress, mitochondrial import is heavily impaired even with active ISR, leading to significant PINK1 accumulation. In contrast, non-depolarizing stress allows more efficient protein import in the presence of ISR, resulting in lower mitophagy. Without ISR, mitochondrial protein import becomes severely compromised, causing PINK1 accumulation to reach the threshold necessary to trigger mitophagy. These findings reveal a novel link between ISR-regulated protein synthesis, mitochondrial import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1101/2024.10.16.617214
  2. J Cell Sci. 2024 Oct 28. pii: jcs.263548. [Epub ahead of print]
    Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules.
    Marta Lopez-Nieto, Zhaozhi Sun, Emily Relton, Rahme Safakli, Brian D Freibaum, J Paul Taylor, Alessia Ruggieri, Ioannis Smyrnias, Nicolas Locker.
      To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2a phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that may contribute to restoring mitochondrial functions under stressful conditions.
    Keywords:  GADD34; Integrated stress response; Mitochondrial stress response; Stress granules; UPRmt
    DOI:  https://doi.org/10.1242/jcs.263548
  3. Int J Mol Sci. 2024 Oct 18. pii: 11196. [Epub ahead of print]25(20):
    Apoptosis, Mitochondrial Autophagy, Fission, and Fusion Maintain Mitochondrial Homeostasis in Mouse Liver Under Tail Suspension Conditions.
    Lu-Fan Li, Jiao Yu, Rui Li, Shan-Shan Li, Jun-Yao Huang, Ming-Di Wang, Li-Na Jiang, Jin-Hui Xu, Zhe Wang.
      Microgravity can induce alterations in liver morphology, structure, and function, with mitochondria playing an important role in these changes. Tail suspension (TS) is a well-established model for simulating the effects of microgravity on muscles and bones, but its impact on liver function remains unclear. In the current study, we explored the regulatory mechanisms of apoptosis, autophagy, fission, and fusion in maintaining liver mitochondrial homeostasis in mice subjected to TS for 2 or 4 weeks (TS2 and TS4). The results showed the following: (1) No significant differences were observed in nuclear ultrastructure or DNA fragmentation between the control and TS-treated groups. (2) No significant differences were detected in the mitochondrial area ratio among the three groups. (3) Cysteine aspartic acid-specific protease 3 (Caspase3) activity and the Bcl-2-associated X protein (bax)/B-cell lymphoma-2 (bcl2) ratio were not higher in the TS2 and TS4 groups compared to the control group. (4) dynamin-related protein 1 (DRP1) protein expression was increased, while mitochondrial fission factor (MFF) protein levels were decreased in the TS2 and TS4 groups compared to the control, suggesting stable mitochondrial fission. (5) No significant differences were observed in the optic atrophy 1 (OPA1), mitofusin 1 and 2 (MFN1 and MFN2) protein expression levels across the three groups. (6) Mitochondrial autophagy vesicles were present in the TS2 and TS4 groups, with a significant increase in Parkin phosphorylation corresponding to the duration of the TS treatment. (7) ATP synthase and citrate synthase activities were significantly elevated in the TS2 group compared to the control group but were significantly reduced in the TS4 group compared to the TS2 group. In summary, the coordinated regulation of apoptosis, mitochondrial fission and fusion, and particularly mitochondrial autophagy preserved mitochondrial morphology and contributed to the restoration of the activities of these two key mitochondrial enzymes, thereby maintaining liver mitochondrial homeostasis in mice under TS conditions.
    Keywords:  apoptosis; liver; mitochondria; tail suspension
    DOI:  https://doi.org/10.3390/ijms252011196
  4. Int J Mol Sci. 2024 Oct 16. pii: 11122. [Epub ahead of print]25(20):
    Immp2l Deficiency Induced Granulosa Cell Senescence Through STAT1/ATF4 Mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3 Mediated Mitophagy: Prevented by Enocyanin.
    Xiaoya Qu, Pengge Pan, Sinan Cao, Yan Ma, Jinyi Yang, Hui Gao, Xiuying Pei, Yanzhou Yang.
      Dysfunctional mitochondria producing excessive ROS are the main factors that cause ovarian aging. Immp2l deficiency causes mitochondrial dysfunction and excessive ROS production, leading to ovarian aging, which is attributed to granulosa cell senescence. The pathway controlling mitochondrial proteostasis and mitochondrial homeostasis of the UPRmt and mitophagy are closely related with the ROS and cell senescence. Our results suggest that Immp2l knockout led to granulosa cell senescence, and enocyanin treatment alleviated Immp2l deficiency-induced granulosa cell senescence, which was accompanied by improvements in mitochondrial function and reduced ROS levels. Interestingly, redox-related protein modifications, including S-glutathionylation and S-nitrosylation, were markedly increased in Immp2l-knockout granulosa cells, and were markedly reduced by enocyanin treatment. Furthermore, STAT1 was significantly increased in Immp2l-knockout granulosa cells and reduced by enocyanin treatment. The co-IP results suggest that the expression of STAT1 was controlled by S-glutathionylation and S-nitrosylation, but not phosphorylation. The UPRmt was impaired in Immp2l-deficient granulosa cells, and unfolded and misfolded proteins aggregated in mitochondria. Then, the HIF1α/BNIP3-mediated mitophagy pathway was activated, but mitophagy was impaired due to the reduced fusion of mitophagosomes and lysosomes. The excessive aggregation of mitochondria increased ROS production, leading to senescence. Hence, Enocyanin treatment alleviated granulosa cell senescence through STAT1/ATF4-mediated UPRmt and STAT1/(ATF4)/HIF1α/BNIP3-mediated mitophagy.
    Keywords:  HIF1α/BNIP3 pathway; STAT1; UPRmt; cell senescence; enocyanin; mitophagy
    DOI:  https://doi.org/10.3390/ijms252011122
  5. Int J Mol Sci. 2024 Oct 19. pii: 11236. [Epub ahead of print]25(20):
    The Large GTPase Guanylate-Binding Protein-1 (GBP-1) Promotes Mitochondrial Fission in Glioblastoma.
    Ryan C Kalb, Geoffrey O Nyabuto, Michael P Morran, Swagata Maity, Jacob S Justinger, Andrea L Nestor-Kalinoski, Deborah J Vestal.
      Glioblastomas (aka Glioblastoma multiformes (GBMs)) are the most deadly of the adult brain tumors. Even with aggressive treatment, the prognosis is extremely poor. The large GTPase Guanylate-Binding Protein-1 (GBP-1) contributes to the poor prognosis of GBM by promoting migration and invasion. GBP-1 is substantially localized to the cytosolic side of the outer membrane of mitochondria in GBM cells. Because mitochondrial dynamics, particularly mitochondrial fission, can drive cell migration and invasion, the potential interactions between GBP-1 and mitochondrial dynamin-related protein 1 (Drp1) were explored. Drp1 is the major driver of mitochondrial fission. While GBP-1 and Drp1 both had punctate distributions within the cytoplasm and localized to regions of the cytoplasmic side of the plasma membrane of GBM cells, the proteins were only molecularly co-localized at the mitochondria. Subcellular fractionation showed that the presence of elevated GBP-1 promoted the movement of Drp1 from the cytosol to the mitochondria. The migration of U251 cells treated with the Drp1 inhibitor, Mdivi-1, was less inhibited in the cells with elevated GBP-1. Elevated GBP-1 in GBM cells resulted in shorter and wider mitochondria, most likely from mitochondrial fission. Mitochondrial fission can drive several important cellular processes, including cell migration, invasion, and metastasis.
    Keywords:  Dynamin-like Proteins (DLPs); Epidermal Growth Factor Receptor (EGFR); Guanylate-Binding Protein-1 (GBP-1); Translocase of Outer Mitochondrial Membrane 40 (TOMM40); glioblastoma multiforme (GBM); immunofluorescence; mitochondrial dynamin-related protein 1 (Drp1)
    DOI:  https://doi.org/10.3390/ijms252011236
  6. bioRxiv. 2024 Oct 22. pii: 2024.10.22.619706. [Epub ahead of print]
    Mitochondrial fission controls astrocyte morphogenesis and organization in the cortex.
    Maria Pia Rodriguez Salazar, Sprihaa Kolanukuduru, Valentina Ramirez, Boyu Lyu, Gabrielle Sejourne, Hiromi Sesaki, Guoqiang Yu, Cagla Eroglu.
      Dysfunctional mitochondrial dynamics are a hallmark of devastating neurodevelopmental disorders such as childhood refractory epilepsy. However, the role of glial mitochondria in proper brain development is not well understood. We show that astrocyte mitochondria undergo extensive fission while populating astrocyte distal branches during postnatal cortical development. Loss of mitochondrial fission regulator, Dynamin-related protein 1 (Drp1), decreases mitochondrial localization to distal astrocyte processes, and this mitochondrial mislocalization reduces astrocyte morphological complexity. Functionally, astrocyte-specific conditional deletion of Drp1 induces astrocyte reactivity and disrupts astrocyte organization in the cortex. These morphological and organizational deficits are accompanied by loss of astrocytic gap junction protein Connexin 43. These findings uncover a crucial role for mitochondrial fission in coordinating astrocytic morphogenesis and organization, revealing the regulation of astrocytic mitochondria dynamics as a critical step in neurodevelopment.
    Summary: During cortical astrocyte morphogenesis, mitochondria decrease in size to populate distal astrocyte processes. Drp1-mediated mitochondrial fission is necessary for peripheral astrocyte process formation. Astrocyte-specific Drp1 loss induces astrocyte reactivity, disrupts cortical astrocyte organization, and dysregulates gap-junction protein Connexin 43 abundance.
    DOI:  https://doi.org/10.1101/2024.10.22.619706
  7. Sci Rep. 2024 10 30. 14(1): 26155
    Mitochondrial modulation treating postoperative cognitive dysfunction neuroprotection via DRP1 inhibition by Mdivi1.
    Jun Ying, Xiaobing Deng, Ruini Du, Qiyang Ding, Hao Tian, Yue Lin, Bin Zhou, Wei Gao.
      This study investigated the role of mitochondrial dynamics in postoperative cognitive dysfunction (POCD) and assessed the therapeutic potential of mitochondrial modulation, particularly through the inhibition of dynamin-related protein 1 (DRP1) with Mdivi-1. Our findings indicated that DRP1 inhibition substantially mitigated neuroinflammation mediated by microglial cells, contributing to improved cognitive function in POCD models. The administration of Mdivi-1 led to a notable decrease in mitochondrial fission, reduced reactive oxygen species (ROS) production, and stabilization of mitochondrial membrane potential, all of which correlate with diminished neuroinflammation, as evidenced by lower NOD-like receptor family pyrin domain containing 3 (NLRP3)/ interleukin-1β (IL-1β) expression in microglial cells. Importantly, Mdivi-1 treatment was also found to enhance synaptic plasticity, increasing synaptic spine density in the hippocampal region of POCD mice. This improvement in mitochondrial health and synaptic integrity was paralleled by enhanced cognitive performance, as demonstrated in Y-maze tests. These results underscored the critical role of mitochondrial dynamics in the pathophysiology of POCD and suggested that targeting mitochondrial dysfunction, specifically through DRP1 inhibition, could be an effective approach for POCD treatment.
    Keywords:  DRP1; NLRP3; Neuroinflammation; POCD
    DOI:  https://doi.org/10.1038/s41598-024-75548-1
  8. iScience. 2024 Oct 18. 27(10): 111005
    AMPD3 promotes doxorubicin-induced cardiomyopathy through HSP90α-mediated ferroptosis.
    Liting Cheng, Mingxiang Zhu, Xiang Xu, Xin Li, Yongming Yao, Chunlei Liu, Kunlun He.
      Doxorubicin (DOX), a widely used anticancer drug, can induce myocardial damage, and current treatments are limited. Our research identified AMPD3 upregulation in DOX-induced cardiotoxicity (DIC), and we hypothesized that AMPD3 may contribute to cardiac injury by regulating mitochondrial dynamics and ferroptosis. We generated AMPD3 knockout (KO) mice and AC16 cell models with AMPD3 knockdown/overexpression, using various methods to explore underlying mechanisms. AMPD3 KO mice showed improved ejection fractions and reduced myocardial injury compared to controls. Transcriptome sequencing revealed reduced HSP90AA1, HSP90B1, ACSL4, and dynamin-related protein 1 (DRP1) levels. We further demonstrated that AMPD3 interacts with HSP90α, activating DRP1, leading to mitochondrial fission, increased reactive oxygen species (ROS) release, and ACSL4-mediated ferroptosis. Our findings suggest inhibiting AMPD3 during DOX treatment may alleviate myocardial damage, highlighting mitochondrial function and ferroptosis as potential therapeutic targets for DIC.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111005
  9. Bone Res. 2024 Oct 28. 12(1): 63
    IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2.
    Zengfa Deng, Dianbo Long, Changzhao Li, Hailong Liu, Wei Li, Yanlin Zhong, Xiaolin Mo, Ruiyun Li, Zibo Yang, Yan Kang, Guping Mao.
      Osteoarthritis (OA) is an age-related cartilage-degenerating joint disease. Mitochondrial dysfunction has been reported to promote the development of OA. Poly (ADP-ribose) polymerase family member 12 (PARP12) is a key regulator of mitochondrial function, protein translation, and inflammation. However, the role of PARP12 in OA-based cartilage degradation and the underlying mechanisms are relatively unknown. Here, we first demonstrated that PARP12 inhibits mitophagy and promotes OA progression in human OA cartilage and a monosodium iodoacetate-induced rat OA model. Using mass spectrometry and co-immunoprecipitation assay, PARP12 was shown to interact with ISG15, upregulate mitofusin 1 and 2 (MFN1/2) ISGylation, which downregulated MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent chondrocyte mitophagy and promoting cartilage degradation. Moreover, inflammatory cytokine-induced interferon regulatory factor 1 (IRF1) activation was required for the upregulation of PARP12 expression, and it directly bound to the PARP12 promoter to activate transcription. XAV-939 inhibited PARP12 expression and suppressed OA pathogenesis in vitro and in vivo. Clinically, PARP12 can be used to predict the severity of OA; thus, it represents a new target for the study of mitophagy and OA progression. In brief, the IRF1-mediated upregulation of PARP12 promoted cartilage degradation by inhibiting PINK1/Parkin-dependent mitophagy via ISG15-based attenuation of MFN1/2 ubiquitylation and SUMOylation. Our data provide new insights into the molecular mechanisms underlying PARP12-based regulation of mitophagy and can facilitate the development of therapeutic strategies for the treatment of OA.
    DOI:  https://doi.org/10.1038/s41413-024-00363-3
  10. Free Radic Biol Med. 2024 Oct 29. pii: S0891-5849(24)01014-1. [Epub ahead of print]
    Pink1-Dependent Mitophagy in Vascular Smooth Muscle Cells: Implications for Arterial Constriction.
    Dongliang Li, Shi Zhang, Jingqi Nie, Shengmiao Yu, Yang Li, Feifei Zheng, Shipeng Bo, Nan Wang, Yanqiu Zhang.
      Hypertension is a major global health issue, contributing to significant cardiovascular morbidity and mortality. Mitochondrial dysfunction, particularly through dysregulated mitophagy, has been implicated in the pathogenesis of hypertension. We wanted to find out the relationship between mitochondrial autophagy and changes in arterial smooth muscle cell tension and the molecular mechanism. Using RNA-seq analysis, we identified significant upregulation of autophagy-related genes, including Pink1, in the aortas of spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. Further in vivo and in vitro studies revealed enhanced mitophagy, characterized by increased expression of Pink1 protein. Our experiments showed that knockdown of Pink1 expression by shRNA attenuated KPSS-induced vascular smooth muscle cells (VSMCs) contraction, suggesting that excessive mitophagy contributes to vascular dysfunction in hypertension. These findings highlight Pink1-mediated mitophagy as a crucial player in hypertensive vascular remodeling and present a potential therapeutic target for managing hypertension.
    Keywords:  Mitophagy; Pink1; arterial constriction; hypertension; smooth muscle cell
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.306
  11. Biomolecules. 2024 Oct 09. pii: 1270. [Epub ahead of print]14(10):
    Mitophagy in Cell Death Regulation: Insights into Mechanisms and Disease Implications.
    Jiani Lin, Xinyao Chen, Yuyang Du, Jiapeng Li, Tingting Guo, Sai Luo.
      Mitophagy, a selective form of autophagy, plays a crucial role in maintaining optimal mitochondrial populations, normal function, and intracellular homeostasis by monitoring and removing damaged or excess mitochondria. Furthermore, mitophagy promotes mitochondrial degradation via the lysosomal pathway, and not only eliminates damaged mitochondria but also regulates programmed cell death-associated genes, thus preventing cell death. The interaction between mitophagy and various forms of cell death has recently gained increasing attention in relation to the pathogenesis of clinical diseases, such as cancers and osteoarthritis, neurodegenerative, cardiovascular, and renal diseases. However, despite the abundant literature on this subject, there is a lack of understanding regarding the interaction between mitophagy and cell death. In this review, we discuss the main pathways of mitophagy, those related to cell death mechanisms (including apoptosis, ferroptosis, and pyroptosis), and the relationship between mitophagy and cell death uncovered in recent years. Our study offers potential directions for therapeutic intervention and disease diagnosis, and contributes to understanding the molecular mechanism of mitophagy.
    Keywords:  cell death; intracellular homeostasis; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/biom14101270
  12. EMBO J. 2024 Oct 30.
    Brain mitophagy in space and time.
    Vassiliki Nikoletopoulou.
      
    DOI:  https://doi.org/10.1038/s44318-024-00275-2
  13. Life Sci. 2024 Oct 24. pii: S0024-3205(24)00763-X. [Epub ahead of print]358 123173
    Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway.
    Eddie Tam, Erfei Song, Nina Noskovicova, Boris Hinz, Aimin Xu, Gary Sweeney.
       AIMS: Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization.
    MATERIALS AND METHODS: Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied.
    KEY FINDINGS: We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses.
    SIGNIFICANCE: Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury.
    Keywords:  Atg7; Autophagy; Cell death; Heart; Hypoxia; Reoxygenation
    DOI:  https://doi.org/10.1016/j.lfs.2024.123173
  14. Chem Biomed Imaging. 2024 Feb 26. 2(2): 81-97
    Advances in Small-Molecule Fluorescent pH Probes for Monitoring Mitophagy.
    Yurui Liu, Duoteng Zhang, Yunwei Qu, Fang Tang, Hui Wang, Aixiang Ding, Lin Li.
      Mitochondria play a crucial role in regulating cellular energy homeostasis and cell death, making them essential organelles. Maintaining proper cellular functions relies on the removal of damaged mitochondria through a process called mitophagy. Mitophagy is associated with changes in the pH value and has implications for numerous diseases. To effectively monitor mitophagy, fluorescent probes that exhibit high selectivity and sensitivity based on pH detection have emerged as powerful tools. In this review, we present recent advancements in the monitoring of mitophagy using small-molecule fluorescence pH probes. We focus on various sensing mechanisms employed by these probes, including intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), through bond energy transfer (TBET), and photoelectron transfer (PET). Additionally, we discuss disease models used for studying mitophagy and summarize the design requirements for small-molecule fluorescent pH probes suitable for monitoring the mitophagy process. Lastly, we highlight the remaining challenges in this field and propose potential directions for the future development of mitophagy probes.
    DOI:  https://doi.org/10.1021/cbmi.3c00070
  15. Methods Enzymol. 2024 ;pii: S0076-6879(24)00385-9. [Epub ahead of print]706 519-532
    Assays to monitor mitochondrial translation.
    Sung-Jun Jung, Martin Ott.
      The complexes of the oxidative phosphorylation (OXPHOS) system found in the mitochondrial inner membrane comprises nuclear and mitochondrial-encoded proteins. The mitochondrial-encoded subunits of the OXPHOS complexes play vital catalytic roles for OXPHOS. These subunits are inserted co-translationally into the inner membrane, where they are matured and assembled with nuclear encoded subunits, requiring a set of OXPHOS assembly and quality control factors. Hence, monitoring the fate of newly synthesized mitochondrial-encoded polypeptides is a basic and essential approach for exploring OXPHOS biogenesis and the related protein quality control processes. Here, we describe a detailed protocol for labeling mitochondrial encoded proteins with 35S-methionine for pulse and pulse/chase experiments, both in vivo and in organello, using the yeast Saccharomyces cerevisiae as the model. These methods enable analyses of the early steps during the biogenesis and turnover of mitochondrial-encoded proteins.
    Keywords:  35S-methionine; Mitochondrial translation; isolated mitochondria; protein stability; protein synthesis; yeast
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.045
  16. Sci Rep. 2024 10 29. 14(1): 25979
    Astragaloside IV reduces mutant Ataxin-3 levels and supports mitochondrial function in Spinocerebellar Ataxia Type 3.
    Yongshiou Lin, Wenling Cheng, Juichih Chang, Yuling Wu, Mingli Hsieh, Chinsan Liu.
      This study investigated the therapeutic effects of astragaloside IV (AST) on spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), a neurodegenerative disorder. Human neuroblastoma SK-N-SH cells expressing mutant ataxin-3 protein with 78 CAG repeats (MJD78) were employed as an in vitro model. Protein expression analysis demonstrated that AST treatment reduced mutant ataxin-3 protein expression and aggregation by enhancing the autophagic process in MJD78 cells. Elevated oxidative stress levels in MJD78 cells were significantly reduced following AST treatment, which also enhanced antioxidant capacity, as evidenced by flow cytometry and antioxidant enzyme activity assays. Furthermore, AST treatment ameliorated mitochondrial dysfunction in MJD78 cells, including improvements in mitochondrial membrane potential, respiration, and mitochondrial dynamics. In conclusion, AST administration increased antioxidant capacity, reduced both cellular and mitochondrial oxidative stress, and improved mitochondrial quality control processes through fusion, fission, and autophagy. These mechanisms collectively reduced intracellular mutant ataxin-3 protein aggregation, thereby achieving therapeutic efficacy in the SCA3 model.
    Keywords:  Astragaloside IV; Autophagy; Mitochondrial dysfunction; Oxidative stress; Spinocerebellar ataxia type 3
    DOI:  https://doi.org/10.1038/s41598-024-77763-2
  17. Biomaterials. 2024 Oct 23. pii: S0142-9612(24)00437-X. [Epub ahead of print]314 122903
    m7G-modified mt-tRF3b-LeuTAA regulates mitophagy and metabolic reprogramming via SUMOylation of SIRT3 in chondrocytes.
    Dianbo Long, Zengfa Deng, Xiaoyi Zhao, Yiyang Xu, Wei Li, Xiaolin Mo, Yanlin Zhong, Ming Li, Aishan He, Ziji Zhang, Yan Kang, Guping Mao.
      N7-methylguanosine (m7G) modification is one of the most prevalent RNA modifications, and methyltransferase-like protein-1 (METTL1) is a key component of the m7G methyltransferase complex. METTL1-catalyzed m7G as a new RNA modification pathway that regulates RNA structure, biogenesis, and cell migration. Increasing evidence indicates that m7G modification has been implicated in the pathophysiological process of osteoarthritis (OA). However, the underlying molecular mechanisms of m7G modification remains incompletely elucidated during the progression of OA. Here we found that METTL1 and m7G levels were markedly increased in OA chondrocytes. In addition, METTL1-mediated m7G modification upregulated mt-tRF3b-LeuTAA expression to exacerbate chondrocyte degeneration. Mechanistically, mt-tRF3b-LeuTAA decreased the SUMO-specific protease 1 (SENP1) protein expression and upregulated the level of sirtuin 3 (SIRT3) SUMOylation to inhibit PTEN induced kinase 1 (PINK1)/Parkin-mediated mitochondrial mitophagy. Intra-articular injection of PMC-tRF3b-LeuTAA inhibitor (Polyamidoamine-polyethylene glycol surface-modified with Minimal self-peptides and Chondrocyte-affinity peptides, PMC) attenuated destabilization of the medial meniscus (DMM) mouse cartilage degeneration in vivo. Our study demonstrates that METTL1/m7G/mt-tRF3b-LeuTAA axis accelerate cartilage degradation by inhibiting mitophagy and promoting mitochondrial dysfunction through SIRT3 SUMOylation, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for OA treatment.
    Keywords:  Metabolic reprogramming; Mitophagy; N7-methylguanosine; Nanoparticle; tRNA-derived fragments
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122903
  18. Cell Death Discov. 2024 Oct 29. 10(1): 457
    Mitophagy: insights into its signaling molecules, biological functions, and therapeutic potential in breast cancer.
    Cong Chen, Aizhai Xiang, Xia Lin, Jufeng Guo, Jian Liu, Shufang Hu, Tao Rui, Qianwei Ye.
      Mitophagy, a form of selective autophagy that removes damaged or dysfunctional mitochondria, plays a crucial role in maintaining mitochondrial and cellular homeostasis. Recent findings suggest that defective mitophagy is closely associated with various diseases, including breast cancer. Moreover, a better understanding of the multifaceted roles of mitophagy in breast cancer progression is crucial for the treatment of this disease. Here, we will summarize the molecular mechanisms of mitophagy process. In addition, we highlight the expression patterns and roles of mitophagy-related signaling molecules in breast cancer progression and the potential implications of mitophagy for the development of breast cancer, aiming to provide better therapeutic strategies for breast cancer treatment.
    DOI:  https://doi.org/10.1038/s41420-024-02226-6
  19. Clin Exp Med. 2024 Oct 29. 24(1): 249
    Identifying the prognostic significance of mitophagy-associated genes in multiple myeloma: a novel risk model construction.
    Rui Min, Zeyu Hu, Yulan Zhou.
      Multiple myeloma (MM) is a highly heterogeneous hematological malignancy that is currently incurable. Individualized therapeutic approaches based on accurate risk assessment are essential for improving the prognosis of MM patients. Nevertheless, current prognostic models for MM exhibit certain limitations and prognosis heterogeneity still an unresolved issue. Recent studies have highlighted the pivotal involvement of mitochondrial autophagy in the development and drug sensitivity of MM. This study seeks to conduct an integrative analysis of the prognostic significance and immune microenvironment of mitophagy-related signature in MM, with the aim of constructing a novel predictive risk model. GSE4581 and GSE47552 datasets were acquired from the Gene Expression Omnibus database. MM-differentially expressed genes (DEGs) were identified by limma between MM samples and normal samples in GSE47552. Mitophagy key module genes were obtained by weighted gene co-expression network analysis in the Cancer Genome Atlas (TCGA)-MM dataset. Mitophagy DEGs were identified by the overlap genes between MM-DEGs and mitophagy key module genes. Prognostic genes were selected through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, and a risk model was subsequently constructed based on these prognostic genes. Subsequently, the MM samples were stratified into high- and low-risk groups based on their median risk scores. The validity of the risk model was further evaluated using the GSE4581 dataset. Moreover, a nomogram was developed using the independent prognostic factors identified from the risk score and various clinical indicators. Additionally, analyses were conducted on immune infiltration, immune scores, immune checkpoint, and chemotherapy drug sensitivity. The 17 mitophagy DEGs were obtained by intersection of 803 MM-DEGs and 1084 mitophagy key module genes. Five prognostic genes (CDC6, PRIM1, SNRPB, TOP2A, and ZNF486) were selected via LASSO and univariate cox regression analyses. The predictive performance of the risk model, which was constructed based on the five prognostic genes, demonstrated favorable results in both TCGA-MM and GSE4581 datasets as indicated by the receiver operating characteristic (ROC) curves. In addition, calibration curve, ROC curve, and decision curve analysis curve corroborated that the nomogram exhibited superior predictive accuracy for MM. Furthermore, immune analysis results indicated a significant difference in stromal scores of two risk groups categorized on median risk scores. And four immune checkpoints (CD274, CTLA4, LAG3, and PDCD1LG2) showed significant differences in different risk groups. The analysis of chemotherapy drug sensitivity revealed that etoposide and doxorubicin, which target TOP2A, exhibited superior treatment outcomes in the high-risk group. A novel prognostic model for MM was developed and validated, demonstrating significant potential in predicting patient outcomes and providing valuable guidance for personalized immunotherapy counseling.
    Keywords:  Immune; Mitophagy; Multiple myeloma; Prognostic model; Risk score
    DOI:  https://doi.org/10.1007/s10238-024-01499-6
  20. Metabolism. 2024 Oct 23. pii: S0026-0495(24)00276-2. [Epub ahead of print] 156048
    CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination.
    Tong-Tong Yang, Liu-Hua Zhou, Ling-Feng Gu, Ling-Ling Qian, Yu-Lin Bao, Peng Jing, Jia-Teng Sun, Chong Du, Tian-Kai Shan, Si-Bo Wang, Wen-Jing Wang, Jia-Yi Chen, Ze-Mu Wang, Hao Wang, Qi-Ming Wang, Ru-Xing Wang, Lian-Sheng Wang.
       BACKGROUND: Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation, however, its role on mitochondrial function in I/R injury remains unknown.
    METHODS: To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/overexpression mouse models were generated. Adult mouse cardiomyocytes (AMCMs) were isolated for in vitro study. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism.
    RESULTS: CHK1 was downregulated in myocardium post I/R and AMCMs post oxygen-glucose deprivation/re‑oxygenation (OGD/R). In vivo, CHK1 overexpression protected against I/R induced cardiac dysfunction, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. The role of CHK1 in maintaining mitochondrial dynamics control and myocardial protection is abolished by SIRT1 inhibition, while inactivated mutation of SIRT1 Thr530 fails to reverse the impaired mitochondrial dynamics following CHK1 knockdown. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown attenuated the protective role of CHK1 in I/R injury.
    CONCLUSIONS: Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.
    Keywords:  CHK1; Cardiac dysfunction; Mitochondrial quality control; SIRT1; Ubiquitination
    DOI:  https://doi.org/10.1016/j.metabol.2024.156048
  21. Inflammation. 2024 Oct 30.
    Nicotinamide N-oxide Inhibits Microglial Pyroptosis by Upregulating Mitophagy and Alleviates Neural Damage in Rats after TBI.
    Xiaoyan Li, Lan Luo, Pengyu Duan, Yonghong Bi, Yao Meng, Xiaoqian Zhang, Weiyu Feng, Zhehao Jin, Kun Zuo, Xiangcheng Zhao, Bing Zhang.
      Traumatic brain injury (TBI) is a severe injury characterized by neuroinflammation and oxidative stress. NAMO (Nicotinamide n-oxide) has anti-inflammatory and inhibits microglial overactivation in neurological disorders. However, the role and mechanism of NAMO in microglial pyroptosis after TBI are unknown. The aim of this study was to investigate the effects of NAMO on TBI and its potential mechanisms through in vivo and in vitro models. In this study, western blot assays were performed by extracting brain tissue mitochondria, and the results showed that NAMO promoted the expression of mitophagy-associated proteins (p62, LC3B, and TOMM20), reduced ROS levels, and inhibited pyroptosis-associated proteins (NLRP3, GSDMD, GSDMD-N, and Caspase-1) and inflammatory cytokines (IL-1β and IL-18). We followed up with immunofluorescence co-localization of GSDMD and IBA 1, which showed that NAMO inhibited microglial pyroptosis. In addition, NAMO promoted neurological recovery after TBI. In vitro experiments showed that NAMO upregulated mitophagy, improved mitochondrial dysfunction, and reduced ROS levels in microglia following lipopolysaccharide (LPS) + adenosine triphosphate (ATP) stimulation in HMC3 cells. We also found that NAMO inhibited pyroptosis-related proteins. To further illustrate whether NAMO affects pyroptosis through mitophagy, we applied the mitophagy inhibitor Mdivi-1 in both in vivo and in vitro models. The results showed that Mdivi-1 reversed NAMO's inhibitory effect on microglial pyroptosis. Taken together, our findings demonstrate that NAMO improves neurological recovery by inhibiting microglial pyroptosis through upregulation of mitophagy, suggesting that NAMO could be a potential therapeutic agent for TBI.
    Keywords:  Microglia; Mitophagy; Nicotinamide n-oxide; Pyroptosis; Traumatic brain injury
    DOI:  https://doi.org/10.1007/s10753-024-02171-7
  22. Front Pharmacol. 2024 ;15 1423356
    Shaping cardiac destiny: the role of post-translational modifications on endoplasmic reticulum - mitochondria crosstalk in cardiac remodeling.
    Xiaohan Zhang, Shuqing Shi, Yihang Du, Ruoning Chai, Zezhen Guo, Chenglin Duan, Huan Wang, Yuanhui Hu, Xing Chang, Bai Du.
      Cardiac remodeling is a shared pathological change in most cardiovascular diseases. Encompassing both adaptive physiological responses and decompensated pathological changes. Anatomically, atrial remodeling is primarily caused by atrial fibrillation, whereas ventricular remodeling is typically induced by myocardial infarction, hypertension, or cardiomyopathy. Mitochondria, the powerhouse of cardiomyocytes, collaborate with other organelles such as the endoplasmic reticulum to control a variety of pathophysiological processes such as calcium signaling, lipid transfer, mitochondrial dynamics, biogenesis, and mitophagy. This mechanism is proven to be essential for cardiac remodeling. Post-translational modifications can regulate intracellular signaling pathways, gene expression, and cellular stress responses in cardiac cells by modulating protein function, stability, and interactions, consequently shaping the myocardial response to injury and stress. These modifications, in particular phosphorylation, acetylation, and ubiquitination, are essential for the regulation of the complex molecular pathways that underlie cardiac remodeling. This review provides a comprehensive overview of the crosstalk between the endoplasmic reticulum and mitochondria during cardiac remodeling, focusing on the regulatory effects of various post-translational modifications on these interactions.
    Keywords:  atrial fibrillation keywords; cardiac remodeling; chronic heart failure; endoplasmic reticulum -mitochondria crosstalk; post-translational modifications
    DOI:  https://doi.org/10.3389/fphar.2024.1423356
  23. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Oct 23. pii: S1388-1981(24)00120-3. [Epub ahead of print]1870(1): 159570
    Hesperitin prevents non-alcoholic steatohepatitis by modulating mitochondrial dynamics and mitophagy via the AMPKα-Drp1/PINK1-Parkin signaling pathway.
    Suwen Chen, Haifei Lu, Guoliang Yin, Xin Zhang, Decheng Meng, Wenfei Yu, Linya Wang, Hongshuai Liu, Fengxia Zhang.
      Non-alcoholic fatty liver disease (NAFLD) is becoming a global public health burden, yet effective therapeutic strategies are notably lacking. NAFLD development may be mediated by mitochondrial dysfunction, according to new research. Producing mitochondrial regulators from plant-based substances to treat mitochondrial dysfunction is an appealing approach to treating NAFLD. Hesperetin (HES) is a flavonoid that is found naturally and is a member of the flavanone family. This study aims to clarify the mechanism of HES in preventing NAFLD which is caused by a high-fat diet (HFD). Serum and liver biochemical parameters, liver histology, lipid profiles, and mitochondrial function were evaluated in HFD-induced NAFLD Sprague-Dawley (SD) rats. HES treatment significantly reduced body weight gain, liver weight, and the liver index, while also improving hepatic steatosis, lipid metabolism disorders, and mitochondrial dysfunction in rats with NAFLD. The mechanism was investigated and confirmed using western blot and real-time quantitative polymerase chain reaction (RT-qPCR). We showed that in the liver of NAFLD rats, HES decreased the expression of dynamic-related protein 1 (Drp1), phosphorylated Drp1 at serine-616 (Drp1-pS616) and induced phosphorylated Drp1 at serine-637 (Drp1-pS637), PTEN-induced kinase 1 (PINK1), and E3 Ubiquitin-Protein Ligase Parkin (Parkin) via an AMP-activated protein kinase alpha (AMPKα)-dependent mechanism. Moreover, HES increased the expression of the mitochondrial fusion proteins mitofusin-2 (Mfn2) and optic atrophy 1 (Opa1) while suppressing the expression of fission protein 1 (Fis1). In this work, we identify a unique mechanism by which HES prevents NAFLD from developing. HES may be an attractive potential therapeutic agent to cure NAFLD.
    Keywords:  AMP-activated protein kinase alpha (AMPKα); Hesperitin (HES); Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Non-alcoholic fatty liver disease (NAFLD)
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159570
  24. Methods Enzymol. 2024 ;pii: S0076-6879(24)00356-2. [Epub ahead of print]706 287-311
    Monitoring and analysis of mitochondrial precursor protein aggregates in the cytosol.
    Klaudia K Maruszczak, Agnieszka Chacinska.
      The vast majority of mitochondrial precursor proteins is synthesized in the cytosol and subsequently imported into the organelle with the help of targeting signals that are present within these proteins. Disruptions in mitochondrial import will result in the accumulation of the organellar precursors in the cytosol of the cell. If mislocalized proteins exceed their critical concentrations, they become prone to aggregation. Under certain circumstances, protein aggregation becomes an irreversible process, which eventually endangers cellular health. Impairment in mitochondrial biogenesis and its effect on cellular protein homeostasis were recently linked to neurodegeneration, therefore placing this process in the center of attention. In this chapter, we are presenting a set of techniques that allows to monitor and study mitochondrial precursor protein aggregates upon mitochondrial dysfunction in the cytosol of both yeast and human cells.
    Keywords:  Mitochondria; Mitochondrial dysfunction; Mitochondrial import; Protein aggregates
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.020
  25. Methods Enzymol. 2024 ;pii: S0076-6879(24)00358-6. [Epub ahead of print]706 97-123
    Analysis of mitochondrial biogenesis and protein localization by genetic screens and automated imaging.
    Yury S Bykov, Maya Schuldiner.
      Budding yeast is a laboratory model of a simple eukaryotic cell. Its compact genome is very easy to edit. This allowed to create systematic collections (libraries) of yeast strains where every gene is either perturbed or tagged. Here we review how such collections were used to study mitochondrial biology by doing genetic screens. First, we introduce the principles of yeast genome editing and the basics of its life cycle that are useful for genetic experiments. Then we overview what yeast strain collections were created over the past years. We also describe the creation and the usage of the new generation of SWAP-Tag (SWAT) collections that allow to create custom libraries. We outline the principles of changing the genetic background of whole collections in parallel, and the basics of synthetic genetic array (SGA) approach. Then we review the discoveries that were made using different types of genetic screens focusing on general mitochondrial functions, proteome, and protein targeting pathways. The development of new collections and screening techniques will continue to bring valuable insight into the function of mitochondria and other organelles.
    Keywords:  High-throughput genetics; Mitochondria; Protein targeting; Proteome; Swap-Tag (SWAT); Synthetic genetic array; Yeast; Yeast collections
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.022
  26. Int J Mol Sci. 2024 Oct 20. pii: 11277. [Epub ahead of print]25(20):
    AdipoRon Alleviates Liver Injury by Protecting Hepatocytes from Mitochondrial Damage Caused by Ionizing Radiation.
    Yi Liu, Yinfen Xu, Huilin Ji, Fenfen Gao, Ruoting Ge, Dan Zhou, Hengyi Fu, Xiaodong Liu, Shumei Ma.
      Radiation liver injury is a common complication of hepatocellular carcinoma radiotherapy. It is mainly caused by irreversible damage to the DNA of hepatocellular cells directly by radiation, which seriously interferes with metabolism and causes cell death. AdipoRon can maintain lipid metabolism and stabilize blood sugar by activating adiponectin receptor 1 (AdipoR1). However, the role of AdipoRon/AdipoR1 in the regulation of ionizing radiation (IR)-induced mitochondrial damage remains unclear. In this study, we aimed to elucidate the roles of AdipoRon/AdipoR1 in IR-induced mitochondrial damage in normal hepatocyte cells. We found that AdipoRon treatment rescued IR-induced liver damage in mice and mitochondrial damage in normal hepatocytes in vivo and in vitro. AdipoR1 deficiency exacerbated IR-induced oxidative stress, mitochondrial dynamics, and biogenesis disorder. Mechanistically, the absence of AdipoR1 inhibits the activity of adenosine monophosphate-activated protein kinase α (AMPKα), subsequently leading to disrupted mitochondrial dynamics by decreasing mitofusin (MFN) and increasing dynamin-related protein 1 (DRP1) protein expression. It also controls mitochondrial biogenesis by suppressing the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) and transcription factor A (TFAM) signaling pathway, ultimately resulting in impaired mitochondrial function. To sum up, AdipoRon/AdipoR1 maintain mitochondrial function by regulating mitochondrial dynamics and biogenesis through the AdipoR1-AMPKα signaling pathway. This study reveals the significant role of AdipoR1 in regulating IR-induced mitochondrial damage in hepatocytes and offers a novel approach to protecting against damage caused by IR.
    Keywords:  AMPKα; AdipoR1; AdipoRon; ionizing radiation; liver injury; mitochondrial damage; radiation protection
    DOI:  https://doi.org/10.3390/ijms252011277
  27. Methods Enzymol. 2024 ;pii: S0076-6879(24)00370-7. [Epub ahead of print]706 365-390
    Monitoring the in vitro import and assembly of mitochondrial precursor proteins into mammalian mitochondria.
    Jordan J Crameri, Diana Stojanovski.
      Mitochondrial protein import is a complex process governing the delivery of the organelle's proteome. This process, in turn, is essential for maintaining mitochondrial function and cellular homeostasis. Initiated by protein synthesis in the cytoplasm, precursor proteins destined for the mitochondria possess targeting signals that guide them to the mitochondrial surface. At mitochondria, the translocation of proteins across the mitochondrial membranes involves an intricate interplay between translocases, chaperones, and receptors. The mitochondrial import assay offers researchers the opportunity to recapitulate the process of protein import in vitro. The assay has served as an indispensable tool in helping decipher the intricacies of protein translocation into mitochondria, first in fungal models, and subsequently in higher eukaryotic models. In this chapter, we will describe how protein import can be assayed using mammalian mitochondria and provide insight into the types of questions that can be addressed in mammalian mitochondrial biology using this experimental approach.
    Keywords:  in vitro; mitochondria; protein import; translocase
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.034
  28. Research (Wash D C). 2024 ;7 0509
    Ibrutinib Promotes Atrial Fibrillation by Disrupting A-Kinase Anchoring Protein 1-Mediated Mitochondrial Quality Surveillance in Cardiomyocytes.
    Yukun Li, Xinmeng Liu, Rong Lin, Xiaodong Peng, Xuesi Wang, Fanchao Meng, Shuqi Jin, Wenhe Lv, Xiaoying Liu, Zhuohang Du, Songnan Wen, Rong Bai, Yanfei Ruan, Hao Zhou, Rongjun Zou, Ribo Tang, Nian Liu.
      Background: Ibrutinib, a potent Bruton's tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed in vivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both in vivo and ex vivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.
    DOI:  https://doi.org/10.34133/research.0509
  29. Biomaterials. 2024 Oct 22. pii: S0142-9612(24)00443-5. [Epub ahead of print]315 122909
    Molybdenum nanodots act as antioxidants for photothermal therapy osteoarthritis.
    Guang Shi, Shenghui Lan, Qi Zhang, Junwu Wang, Feihong Shu, Zhuowen Hao, Tianhong Chen, Mengyue Zhu, Renxin Chen, Jiayao Chen, Zijian Wu, Bo Wu, Zhenwei Zou, Jingfeng Li.
      Osteoarthritis (OA) manifests as the degradation of cartilage and remodeling of subchondral bone. Restoring homeostasis within the joint is imperative for alleviating OA symptoms. Current interventions primarily target singular aspects, such as anti-aging, inflammation inhibition, free radical scavenging, and regeneration of cartilage and subchondral bone. Herein, we developed molybdenum nanodots (MNDs) as bionic photothermal nanomaterials to mimic the antioxidant synthase to concurrently protected cartilage and facilitate subchondral bone regeneration. With near-infrared (NIR) irradiation, MNDs effectively eliminate reactive oxygen and nitrogen species (ROS/RNS) from OA chondrocytes, thereby reversed mitochondrial dysfunction, mitigating chondrocyte senescence, and simultaneously suppresses inflammation, hence preserving the inherent homeostasis between cartilage matrix synthesis and degradation while circumventing safety concerns. RNA sequencing of OA chondrocytes treated with MNDs-NIR revealed the reinstatement of chondrocyte functionality, activation of antioxidant enzymes, anti-aging properties, and regulation of inflammation. NIR irradiation induces thermogenesis and synergistically promotes subchondral bone regeneration via MNDs, as validated through histological assessments and microcomputed tomography (Micro-CT) scans. MNDs-NIR effectively attenuate cellular senescence and inhibit inflammation in vivo, while also remodeling mitochondrial dynamics by upregulating fusion proteins and inhibiting fission proteins, thereby regulating the oxidative stress microenvironment. Additionally, MNDs-NIR exhibited remarkable therapeutic effects in alleviating articular cartilage degeneration in an OA mouse model, evidenced by a 1.67-fold reduction in subchondral bone plate thickness, an 88.57 % decrease in OARSI score, a 5.52-fold reduction in MMP13 expression, and a 6.80-fold increase in Col II expression. This novel disease-modifying approach for OA utilizing MNDs-NIR offers insight and a paradigm for improving mitochondrial dysfunction by regulating the accumulation of mitochondrial ROS and ultimately alleviating cellular senescence. Moreover, the dual-pronged therapeutic approach of MNDs-NIR, which addresses both cartilage erosion and subchondral bone lesions in OA, represents a highly promising strategy for managing OA.
    Keywords:  Articular cartilage; Mitochondrial homeostasis; Molybdenum nanodots; Osteoarthritis; Photothermal therapy; Reactive oxygen species; Subchondral bone
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122909
  30. Int Immunopharmacol. 2024 Oct 24. pii: S1567-5769(24)01966-0. [Epub ahead of print]143(Pt 2): 113444
    Quercetin inhibits mitophagy-mediated apoptosis and inflammatory response by targeting the PPARγ/PGC-1α/NF-κB axis to improve acute liver failure.
    Huan Wu, Long Wu, Li Luo, Ye-Ting Wu, Qing-Xiu Zhang, Hai-Yang Li, Bao-Fang Zhang.
       BACKGROUND: Reactive oxygen species (ROS) from mitochondrial dysfunction are critical in triggering apoptosis and inflammation in acute liver failure (ALF). Quercetin (QUE), an antioxidant, is renowned for its therapeutic effects onliverdiseases. There are no studies on whether QUE regulates mitophagy level in hepatocytes to inhibit ALF.
    OBJECTIVE: This study investigates QUE's protective effects on ALF and elucidates the mechanisms involved.
    METHODS: The ALF and hepatocyte inflammatory injury model was established using LPS and D-Galn. To predict potential targets and mechanisms of QUE in ALF treatment, transcriptomics, network pharmacology, molecular docking techniques, and ChIP were employed. The expression level related to mitophagy, apoptosis, and signaling pathways were detected by CCK8, IHC, IF staining, TUNEL, RT-qPCR, TEM, Western blotting, ELISA, and flow cytometry.
    RESULTS: Network pharmacology and transcriptomics revealed common targets between QUE and ALF. Enrichment analysis showed that the anti-ALF targets of QUE were significantly associated with mitochondria and NF-κB-related pathways. Subsequent experiments showed that QUE pretreatment significantly alleviated the loss of hepatocyte viability, enhanced mitochondrial membrane potential, activated mitophagy, and promoted the clearance of damaged mitochondria, thereby reducing ROS accumulation, significantly reducing cell apoptosis and inflammatory responses, reducing ALT and AST levels, and improving liver tissue pathology. Mechanistically, molecular docking, DARTS, and CETSA analyses confirmed that QUE directly binds to the PPARγ molecule, which reduced binding to IκB and significantly inhibit the NF-κB pathway to exert its protective effects.
    CONCLUSION: In short, our results provide the first evidence that QUE improves acute liver failure by promoting mitophagy through regulating the PPARγ/PGC-1α/NF-κB axis and inhibiting apoptosis and inflammatory responses mediated by mitochondrial dysfunction, which provides evidence for the potential of QUE in the treatment of ALF.
    Keywords:  ALF; Mitophagy; PPARγ; Quercetin
    DOI:  https://doi.org/10.1016/j.intimp.2024.113444
  31. Autophagy. 2024 Oct 26.
    HSP90 N-terminal inhibition promotes mitochondria-derived vesicles related metastasis by reducing TFEB transcription via decreased HSP90AA1-HCFC1 interaction in liver cancer.
    Lixia Liu, Zhenming Zheng, Yaling Huang, Hairou Su, Guibing Wu, Zihao Deng, Yan Li, Guantai Xie, Jieyou Li, Fei Zou, Xuemei Chen.
      Cancer cells compensate with increasing mitochondria-derived vesicles (MDVs) to maintain mitochondrial homeostasis, when canonical MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta)-mediated mitophagy is lacking. MDVs promote the transport of mitochondrial components into extracellular vesicles (EVs) and induce tumor metastasis. Although HSP90 (heat shock protein 90) chaperones hundreds of client proteins and its inhibitors suppress tumors, HSP90 inhibitors-related chemotherapy is associated with unexpected metastasis. Herein, we find that HSP90 inhibitor causes mitochondrial damage but stimulates the low LC3-induced MDVs and the release of MDVs-derived EVs. However, why LC3 decreases and what is the transcriptional regulatory mechanism of MDVs formation under HSP90 inhibition remain unknown. Because TFEB (transcription factor EB) is the most important mitophagy transcription factor, and the HSP90 client HCFC1 (host cell factor C1) regulates TFEB transcription, there should be a hidden connection between TFEB, HCFC1 and HSP90 in MDVs formation. Our results support the idea that HSP90 N-terminal inhibition reduces TFEB transcription via decreased HSP90AA1-HCFC1 interaction, which prevents HCFC1 from binding to the TFEB proximal promoter region. Decreased TFEB transcription and consequently reduced LC3, ultimately promoted MDVs formation. Blocking MDVs formation with the microtubule inhibitor nocodazole (NOC) activates the HCFC1-TFEB-LC3 axis, weakens HSP90 inhibitors-induced MDVs and the release of MDVs-derived EVs, inhibits the growth of tumor cell spheres and primary liver tumors, and reduces the extravasation of cancer cells to secondary metastatic sites. Taken together, these data suggest that combination therapy should be used to reduce the metastatic risk of low TFEB-triggered-MDVs formation caused by HSP90 inhibitors.
    Keywords:  HCFC1/host cell factor C1; HSP90/heat shock protein 90; Mdvs/mitochondria-derived vesicles; Tfeb/transcription factor EB; metastasis; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2024.2421703
  32. Front Endocrinol (Lausanne). 2024 ;15 1504718
    Editorial: Role of mitochondrial stress response in metabolic health.
    Renata O Pereira, Susanne Keipert.
      
    Keywords:  FGF21; GDF15; MOTS-c; integrated stress response (ISR); metabolic health; mitochondria; mitohormesis; mitokine
    DOI:  https://doi.org/10.3389/fendo.2024.1504718
  33. bioRxiv. 2024 Oct 24. pii: 2024.10.24.620005. [Epub ahead of print]
    TFAM as a sensor of UVC-induced mitochondrial DNA damage.
    Dillon E King, Emily E Beard, Matthew J Satusky, Ian Ryde, Alex George, Caitlin Johnson, Emma L Dolan, Yuning Zhang, Wei Zhu, Hunter Wilkins, Evan Corden, Susan K Murphy, Dorothy Erie, Raluca Gordân, Joel N Meyer.
      Mitochondria lack nucleotide excision DNA repair; however, mitochondrial DNA (mtDNA) is resistant to mutation accumulation following DNA damage. These observations suggest additional damage sensing or protection mechanisms. Transcription Factor A, Mitochondrial (TFAM) compacts mtDNA into nucleoids. As such, TFAM has emerged as a candidate for protecting DNA or sensing damage. To examine these possibilities, we used live-cell imaging, cell-based assays, atomic force microscopy, and high-throughput protein-DNA binding assays to characterize the binding properties of TFAM to UVC-irradiated DNA and cellular consequences of UVC irradiation. Our data indicate an increase in mtDNA degradation and turnover, without a loss in mitochondrial membrane potential that might trigger mitophagy. We identified a reduction in sequence specificity of TFAM associated with UVC irradiation and a redistribution of TFAM binding throughout the mitochondrial genome. Our AFM data show increased compaction of DNA by TFAM in the presence of damage. Despite the TFAM-mediated compaction of mtDNA, we do not observe any protective effect on DNA damage accumulation in cells or in vitro . Taken together, these studies indicate that UVC-induced DNA damage promotes compaction by TFAM, suggesting that TFAM may act as a damage sensor, sequestering damaged genomes to prevent mutagenesis by direct removal or suppression of replication.
    DOI:  https://doi.org/10.1101/2024.10.24.620005
  34. Mol Cell Endocrinol. 2024 Oct 23. pii: S0303-7207(24)00248-X. [Epub ahead of print]595 112392
    Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy.
    Bin Zhao, Wen-Liang Tan, Bing-Bo Yu, Jun Fan, Chang Liu, Jian Liu, Zhen Liu.
      Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for in vivo and in vitro studies. Results reveal that hyperglycemia significantly downregulates SELENOM expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of SELENOM in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, SELENOM overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, SELENOM overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. SELENOM overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.
    Keywords:  Endothelial cells; Hyperglycemia; Mitophagy; Parkin; SELENOM
    DOI:  https://doi.org/10.1016/j.mce.2024.112392
  35. J Transl Med. 2024 Oct 28. 22(1): 974
    The role of TRAP1 in regulating mitochondrial dynamics during acute hypoxia-induced brain injury.
    Fengying Liu, Xueyang Lin, Xiaodong Wu, Xi Sui, Wenwen Ren, Qian Wang, Yongan Wang, Yuan Luo, Jiangbei Cao.
      Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.
    Keywords:  Acute hypoxia-induced brain injury; Mechanism; Mitochondrial dynamics; Tumor necrosis factor receptor-associated protein 1 (TRAP1)
    DOI:  https://doi.org/10.1186/s12967-024-05780-w
  36. J Transl Med. 2024 Oct 25. 22(1): 968
    Targeting mitochondria: a novel approach for treating platinum-resistant ovarian cancer.
    Xin Cui, Juan Xu, Xuemei Jia.
      Ovarian cancer is a prevalent gynecologic malignancy with the second-highest mortality rate among gynecologic malignancies. Platinum-based chemotherapy is the first-line treatment for ovarian cancer; however, a majority of patients with ovarian cancer experience relapse and develop platinum resistance following initial treatment. Despite extensive research on the mechanisms of platinum resistance at the nuclear level, the issue of platinum resistance in ovarian cancer remains largely unresolved. It is noteworthy that mitochondrial DNA (mtDNA) exhibits higher affinity for platinum compared to nuclear DNA (nDNA). Mutations in mtDNA can modulate tumor chemosensitivity through various mechanisms, including DNA damage responses, shifts in energy metabolism, maintenance of Reactive Oxygen Species (ROS) homeostasis, and alterations in mitochondrial dynamics. Concurrently, retrograde signals produced by mtDNA mutations and their subsequent cascades establish communication with the nucleus, leading to the reorganization of the nuclear transcriptome and governing the transcription of genes and signaling pathways associated with chemoresistance. Furthermore, mitochondrial translocation among cells emerges as a crucial factor influencing the effectiveness of chemotherapy in ovarian cancer. This review aims to explore the role and mechanism of mitochondria in platinum resistance, with a specific focus on mtDNA mutations and the resulting metabolic reprogramming, ROS regulation, changes in mitochondrial dynamics, mitochondria-nucleus communication, and mitochondrial transfer.
    Keywords:  Metabolic reprogramming; Mitochondria; Mitochondria DNA (mtDNA); Mitochondria transfer; Mitochondria-nucleus communication; Mitochondrial dynamics; Platinum resistance
    DOI:  https://doi.org/10.1186/s12967-024-05770-y
  37. Pharmaceuticals (Basel). 2024 Sep 29. pii: 1297. [Epub ahead of print]17(10):
    The Role of Mitochondrial Homeostasis in Mesenchymal Stem Cell Therapy-Potential Implications in the Treatment of Osteogenesis Imperfecta.
    Qingling Guo, Qiming Zhai, Ping Ji.
      Osteogenesis imperfecta (OI) is a hereditary disorder characterized by bones that are fragile and prone to breaking. The efficacy of existing therapies for OI is limited, and they are associated with potentially harmful side effects. OI is primarily due to a mutation of collagen type I and hence impairs bone regeneration. Mesenchymal stem cell (MSC) therapy is an attractive strategy to take advantage of the potential benefits of these multipotent stem cells to address the underlying molecular defects of OI by differentiating osteoblasts, paracrine effects, or immunomodulation. The maintenance of mitochondrial homeostasis is an essential component for improving the curative efficacy of MSCs in OI by affecting the differentiation, signaling, and immunomodulatory functions of MSCs. In this review, we highlight the MSC-based therapy pathway in OI and introduce the MSC regulation mechanism by mitochondrial homeostasis. Strategies aiming to modulate the metabolism and reduce the oxidative stress, as well as innovative strategies based on the use of compounds (resveratrol, NAD+, α-KG), antioxidants, and nanomaterials, are analyzed. These findings may enable the development of new strategies for the treatment of OI, ultimately resulting in improved patient outcomes.
    Keywords:  antioxidants; mesenchymal stem cells; mitochondrial homeostasis; mitochondrial metabolism; mitochondrial quality control; osteogenesis imperfecta
    DOI:  https://doi.org/10.3390/ph17101297
  38. Sci Rep. 2024 10 28. 14(1): 25815
    Glutamine and serum starvation alters the ATP production, oxidative stress, and abundance of mitochondrial RNAs in extracellular vesicles produced by cancer cells.
    Maria Bugajova, Martina Raudenska, Klara Hanelova, Jiri Navratil, Jaromir Gumulec, Frantisek Petrlak, Tomas Vicar, Sarka Hrachovinova, Michal Masarik, David Kalfert, Marek Grega, Jan Plzak, Jan Betka, Jan Balvan.
      Induction of autophagy represents an effective survival strategy for nutrient-deprived or stressed cancer cells. Autophagy contributes to the modulation of communication within the tumor microenvironment. Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu. We compared the effect of these different types of autophagy induction on ATP production, lipid peroxidation, mitophagy, RNA cargo of extracellular vesicles (EVs), and EVs-associated cytokine secretome of cancer cells. Both BEZ and starvation resulted in a decline in ATP production. Simultaneously, Gln starvation enhanced oxidative damage of cancer cells by lipid peroxidation. In starved cells, there was a discernible fragmentation of the mitochondrial network coupled with an increase in the presence of tumor susceptibility gene 101 (TSG101) on the mitochondrial membrane, indicative of the sorting of mitochondrial cargo into EVs. Consequently, the abundance of mitochondrial RNAs (mtRNAs) in EVs released by FaDu cells was enhanced. Notably, mtRNAs were also detectable in EVs isolated from the serum of both HNSCC patients and healthy controls. Starvation and BEZ reduced the production of EVs by cancer cells, yet the characteristic molecular profile of these EVs remained unchanged. We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.
    DOI:  https://doi.org/10.1038/s41598-024-73943-2
  39. Front Endocrinol (Lausanne). 2024 ;15 1424873
    Sex hormone-binding globulin promotes the osteogenic differentiation potential of equine adipose-derived stromal cells by activating the BMP signaling pathway.
    Jennifer M Irwin-Huston, Lynda Bourebaba, Nabila Bourebaba, Artur Tomal, Krzysztof Marycz.
       Background: Musculoskeletal injuries and chronic degenerative diseases pose significant challenges in equine health, impacting performance and overall well-being. Sex Hormone-Binding Globulin (SHBG) is a glycoprotein determining the bioavailability of sex hormones in the bloodstream, and exerting critical metabolic functions, thus impacting the homeostasis of many tissues including the bone.
    Methods: In this study, we investigated the potential role of SHBG in promoting osteogenesis and its underlying mechanisms in a model of equine adipose-derived stromal cells (ASCs). An SHBG-knocked down model has been established using predesigned siRNA, and cells subjected to osteogenic induction medium in the presence of exogenous SHBG protein. Changes in differentiation events where then screened using various analytical methods.
    Results: We demonstrated that SHBG treatment enhances the expression of key osteoconductive regulators in equine ASCs CD34+ cells, suggesting its therapeutic potential for bone regeneration. Specifically, SHBG increased the cellular expression of BMP2/4, osteocalcin (OCL), alkaline phosphatase (ALP), and osteopontin (OPN), crucial factors in early osteogenesis. Furthermore, SHBG treatment maintained adequate apoptosis and enhanced autophagy during osteogenic differentiation, contributing to bone formation and remodeling. SHBG further targeted mitochondrial dynamics, and promoted the reorganization of the mitochondrial network, as well as the expression of dynamics mediators including PINK, PARKIN and MFN1, suggesting its role in adapting cells to the osteogenic milieu, with implications for osteoblast maturation and differentiation.
    Conclusion: Overall, our findings provide novel insights into SHBG's role in bone formation and suggest its potential therapeutic utility for bone regeneration in equine medicine.
    Keywords:  ASCs; BMP; SHBG; autophagy; mitochondrial dynamics; osteogenesis
    DOI:  https://doi.org/10.3389/fendo.2024.1424873
  40. Sci Rep. 2024 Oct 31. 14(1): 26216
    Resveratrol improved mitochondrial biogenesis by activating SIRT1/PGC-1α signal pathway in SAP.
    Shu-Kun Wu, Le Wang, Fang Wang, Jiong Zhang.
      NLRP3 inflammasomes- pyroptosis axis is activated by microcirculation dysfunction and touched off severe acute pancreatitis (SAP). Activation of PGC-1α can improve microcirculation dysfunction by promoting mitochondrial biogenesis. Resveratrol (RSV), one typical SIRT1 agonist, possesses the ability of alleviating SAP and activing PGC-1α. Therefore, the study was designated to explore whether the protective effect of RSV in SAP was though suppressing NLRP3 inflammasomes- pyroptosis axis via advancing SIRT1/PGC-1α-dependent mitochondrial biogenesis. The models of SAP were induced by treating with sodium taurodeoxycholate in rats and AR42J cells. The pathological injury, water content (dry/wet ratio) and microcirculation function of pancreas, activity of lipase and amylase were used to evaluate pancreatic damage. The expression of inflammatory cytokine was measured by ELISA and RT-PCR. The damage of mitochondrial was evaluated by measuring the changes in Mitochondrial Membrane Potential (ΔΨm), mitochondrial ROS, ATP content and MDA as well as relocation of mtDNA and the activity of SOD and GSH. The expressions of NLRP3 inflammasomes- pyroptosis axis proteins were detected by Western blotting as well as SIRT1/PGC-1α/NRF1/TFAM pathway protein. Moreover, the modification of PGC-1α was measured by co-immunoprecipitation. The results displayed that RSV can significantly improve the damage of pancreas and mitochondrial, decrease the expression of pro-inflammatory factor and the activation of NLRP3 inflammasomes- pyroptosis axis, promote the expression of an-inflammatory factor and the deacetylation of PGC-1α together with facilitating SIRT1/PGC-1α-mediating mitochondrial biogenesis. Therefore, the protective effect of RSV in SAP is though inactivation of NLRP3 inflammasomes- pyroptosis axis via promoting mitochondrial biogenesis in a SIRT1/PGC-1α-dependent manner.
    Keywords:  Mitochondrial biogenesis; NLRP3 inflammasomes- pyroptosis axis; Resveratrol; SIRT1/PGC-1α; Severe acute pancreatitis
    DOI:  https://doi.org/10.1038/s41598-024-76825-9
  41. Pharmaceuticals (Basel). 2024 Sep 30. pii: 1302. [Epub ahead of print]17(10):
    Apigenin Ameliorates H2O2-Induced Oxidative Damage in Melanocytes through Nuclear Factor-E2-Related Factor 2 (Nrf2) and Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (Akt)/Mammalian Target of Rapamycin (mTOR) Pathways and Reducing the Generation of Reactive Oxygen Species (ROS) in Zebrafish.
    Qing-Qing Tang, Zu-Ding Wang, Xiao-Hong An, Xin-Yuan Zhou, Rong-Zhan Zhang, Xiao Zhan, Wei Zhang, Jia Zhou.
      Background: Apigenin is one of the natural flavonoids found mainly in natural plants, as well as some fruits and vegetables, with celery in particular being the most abundant. Apigenin has antioxidant, anti-tumor, anti-inflammatory, and anticancer effects. In this research, we attempted to further investigate the effects of apigenin on the mechanism of repairing oxidative cell damage. The present study hopes to provide a potential candidate for abnormal skin pigmentation disorders. Methods: We used 0.4 mM H2O2 to treat B16F10 cells for 12 h to establish a model of oxidative stress in melanocytes, and then we gave apigenin (0.1~5 μM) to B16F10 cells for 48 h, and detected the expression levels of melanin synthesis-related proteins, dendritic regulation-related proteins, antioxidant signaling pathway- and Nrf2 signaling pathway-related proteins, autophagy, and autophagy-regulated pathways by immunoblotting using Western blotting. The expression levels of PI3K/Akt/mTOR proteins were measured by β-galactosidase staining and Western blotting for cellular decay, JC-1 staining for mitochondrial membrane potential, and Western blotting for mitochondrial fusion- and mitochondrial autophagy-related proteins. Results: Apigenin exerts antioxidant effects by activating the Nrf2 pathway, and apigenin up-regulates the expression of melanin synthesis-related proteins Tyr, TRP1, TRP2, and gp100, which are reduced in melanocytes under oxidative stress. By inhibiting the expression of senescence-related proteins p53 and p21, and delaying cellular senescence, we detected the mitochondrial membrane potential using JC-1, and found that apigenin improved the reduction in mitochondrial membrane potential in melanocytes under oxidative stress, and maintained the normal function of mitochondria. In addition, we further detected the key regulatory proteins of mitochondrial fusion and division, MFF, p-DRP1 (S637), and p-DRP1 (S616), and found that apigenin inhibited the down-regulation of fusion-associated protein, p-DRP1 (S637), and the up-regulation of division-associated proteins, MFF and p-DRP1 (S616), due to oxidative stress in melanocytes, and promoted the mitochondrial fusion and ameliorated the imbalance between mitochondrial division and fusion. We further detected the expression of fusion-related proteins OPA1 and Mitofusion-1, and found that apigenin restored the expression of the above fusion proteins under oxidative stress, which further indicated that apigenin promoted mitochondrial fusion, improved the imbalance between mitochondrial division and fusion, and delayed the loss of mitochondrial membrane potential. Apigenin promotes the expression of melanocyte autophagy-related proteins and the key mitochondrial autophagy proteins BNIP3L/Nix under oxidative stress, and activates the PINK1/Parkin signaling pathway by up-regulating the expression of autophagy-related proteins, as well as the expression of PINK1 and Parkin proteins, to promote melanocyte autophagy and mitochondrial autophagy. Conclusions: Apigenin exerts anti-melanocyte premature aging and detachment effects by promoting melanin synthesis, autophagy, and mitochondrial autophagy in melanocytes, and inhibiting oxidative cell damage and senescence.
    Keywords:  PI3K/Akt/mTOR signal pathway; PINK1/Parkin signal pathway; apigenin; melanocyte dendricity; melanogenesis
    DOI:  https://doi.org/10.3390/ph17101302
  42. J Mol Neurosci. 2024 Oct 28. 74(4): 100
    The Role of Non-Coding RNAs in Mitochondrial Dysfunction of Alzheimer's Disease.
    Samin Abed, Amir Ebrahimi, Fatemeh Fattahi, Ghazal Kouchakali, Mahmoud Shekari-Khaniani, Sima Mansoori-Derakhshan.
      Although brain amyloid-β (Aβ) peptide buildup is the main cause of Alzheimer's disease (AD), mitochondrial abnormalities can also contribute to the illness's development, as either a primary or secondary factor, as programmed cell death and efficient energy generation depend on the proper operation of mitochondria. As a result, non-coding RNAs (ncRNAs) may play a crucial role in ensuring that nuclear genes related to mitochondria and mitochondrial genes function normally. Interestingly, a significant number of recent studies have focused on the impact of ncRNAs on the expression of nucleus and mitochondrial genes. Additionally, researchers have proposed some intriguing therapeutic approaches to treat and reduce the severity of AD by adjusting the levels of these ncRNAs. The goal of this work was to consolidate the existing knowledge in this field of study by systematically investigating ncRNAs, with a particular emphasis on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs). Therefore, the impact and processes by which ncRNAs govern mitochondrial activity in the onset and progression of AD are thoroughly reviewed in this article. Collectively, the effects of ncRNAs on physiological and molecular mechanisms associated with mitochondrial abnormalities that exacerbate AD are thoroughly reviewed in the current research, while also emphasizing the relationship between disturbed mitophagy in AD and ncRNAs.
    Keywords:  Alzheimer’s disease; Mitochondrial dysfunction; Mitophagy; Non-coding RNAs
    DOI:  https://doi.org/10.1007/s12031-024-02262-y
  43. FASEB J. 2024 Oct;38(20): e70135
    Retinal G-protein-coupled receptor deletion exacerbates AMD-like changes via the PINK1-parkin pathway under oxidative stress.
    Yue Guo, Sitong Chen, Wenxue Guan, Ningda Xu, Li Zhu, Wei Du, Zhiming Liu, Henry K W Fong, Lvzhen Huang, Mingwei Zhao.
      The intake of high dietary fat has been correlated with the progression of age-related macular degeneration (AMD), affecting the function of the retinal pigment epithelium through oxidative stress. A high-fat diet (HFD) can lead to lipid metabolism disorders, excessive production of circulating free fatty acids, and systemic inflammation by aggravating the degree of oxidative stress. Deletion of the retinal G-protein-coupled receptor (RGR-d) has been identified in drusen. In this study, we investigated how the RGR-d exacerbates AMD-like changes under oxidative stress, both in vivo and in vitro. Fundus atrophy became evident, at 12 months old, particularly in the RGR-d + HFD group, and fluorescence angiography revealed narrower retinal vessels and a reduced perfusion area in the peripheral retina. Although rod electroretinography revealed decreasing trends in the a- and b-wave amplitudes in the RGR-d + HFD group at 12 months, the changes were not statistically significant. Mice in the RGR-d + HFD group showed a significantly thinner and more fragile retinal morphology than those in the WT + HFD group, with disordered and discontinuous pigment distribution in the RGR-d + HFD mice. Transmission electron microscopy revealed a thickened Bruch's membrane along the choriocapillaris endothelial cell wall in the RGR-d + HFD mice, and the outer nuclear layer structure appeared disorganized, with reduced nuclear density. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated significantly lower levels of 25(OH)-vitamin D3 metabolites in the RGR-d + HFD group. Under oxidative stress, RGR-d localized to the mitochondria and reduced the levels of the PINK1-parkin pathway. RGR-d mice fed an HFD were used as a new animal model of dry AMD. Under high-fat-induced oxidative stress, RGR-d accumulated in the mitochondria, disrupting normal mitophagy and causing cellular damage, thus exacerbating AMD-like changes both in vivo and in vitro.
    Keywords:  AMD; RGR‐d; metabolomic; mitochondria; mitophagy
    DOI:  https://doi.org/10.1096/fj.202401160RR
  44. Blood Adv. 2024 Oct 29. pii: bloodadvances.2024013890. [Epub ahead of print]
    The E3 ubiquitin ligase MARCH5 promotes mitochondrial fusion and cell cycle progression in acute myeloid leukemia.
    Clement Larrue, Sarah Mouche, Jérôme Tamburini.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013890
  45. Cell Biol Toxicol. 2024 Oct 30. 40(1): 93
    NPR1 promotes cisplatin resistance by inhibiting PARL-mediated mitophagy-dependent ferroptosis in gastric cancer.
    Chengwei Wu, Song Wang, Tao Huang, Xinran Xi, Lishuai Xu, Jiawei Wang, Yinfen Hou, Yabin Xia, Li Xu, Luman Wang, Xiaoxu Huang.
      Cisplatin-based chemotherapy serves as the standard of care for individuals with advanced stages of gastric cancer. Nevertheless, the emergence of chemoresistance in GC has detrimental impacts on prognosis, yet the underlying mechanisms governing this phenomenon remain elusive. Level of mitophagy and ferroptosis of GC cells were detected by fluorescence, flow cytometry, GSH, MDA, Fe2+ assays, and to explore the specific molecular mechanisms between NPR1 and cisplatin resistance by performing western blot and coimmunoprecipitation (co-IP) assays. These results indicates that NPR1 positively correlated with cisplatin-resistance and played a crucial part in conferring resistance to cisplatin in gastric cancer cells. Mechanistically, NPR1 affected levels of mitophagy and ferroptosis in human cisplatin-resistance GC cells with cisplatin treatment. Specifically, NPR1 inhibited mitophagy-dependent ferroptosis by reducing the ubiquitination-mediated degradation of PARL; moreover, NPR1 promoted PARL stabilization by disrupting the PARL-MARCH8 complex, which ultimately led to the development of chemoresistance in GC cells. Considering our findings, NPR1 appears to play an important role in chemotherapy for GC. NPR1 could potentially be used to overcome chemotherapy resistance.
    Keywords:  Chemoresistance; Ferroptosis; Gastric Cancer; Mitophagy; NPR1; PARL; Ubiquitination
    DOI:  https://doi.org/10.1007/s10565-024-09931-z
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