bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024‒09‒08
forty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Electroacupuncture pretreatment maintains mitochondrial quality control via HO-1/MIC60 signaling pathway to alleviate endotoxin-induced acute lung injury.
  2. Correction to: Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy.
  3. Sesamol-mediated targeting of EPHA2 sensitises cervical cancer for cisplatin treatment by regulating mitochondrial dynamics, autophagy, and mitophagy.
  4. Molecular mechanism and potential role of mitophagy in acute pancreatitis.
  5. Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
  6. Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.
  7. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  8. Stearic acid alleviates aortic medial degeneration through maintaining mitochondrial dynamics homeostasis via inhibiting JNK/MAPK signaling.
  9. TR-107, An Agonist of Caseinolytic Peptidase Proteolytic Subunit, Disrupts Mitochondrial Metabolism and Inhibits the Growth of Human Colorectal Cancer Cells.
  10. Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.
  11. TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
  12. Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.
  13. TRAF3IP3 Blocks Mitophagy to Exacerbate Myocardial Injury Induced by Ischemia-Reperfusion.
  14. [Retracted] Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways.
  15. Dihydromyricetin suppresses endothelial NLRP3 inflammasome activation and attenuates atherogenesis by promoting mitophagy.
  16. SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
  17. The dysregulation of mitochondrial homeostasis-related genes could be involved in the decrease of mtDNA copy number in systemic lupus erythematosus patients.
  18. Mitophagy and cGAS-STING crosstalk in neuroinflammation.
  19. Lidamycin induces mitophagy in pancreatic cancer cells by regulating the expression of Mfn2.
  20. Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.
  21. Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
  22. Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
  23. How mitochondrial dynamics imbalance affects the progression of breast cancer:a mini review.
  24. GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus.
  25. Investigating the Interplay between Mitophagy and Diabetic Neuropathy: Uncovering the hidden secrets of the disease pathology.
  26. MEF2A, a gene associated with mitochondrial biogenesis, promotes drug resistance in gastric cancer.
  27. Patient mutations in DRP1 perturb synaptic maturation of cortical neurons.
  28. Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
  29. Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics.
  30. Mechanism of cigarette smoke in promoting small airway remodeling in mice via STAT 3 / PINK 1-Parkin / EMT.
  31. TUBB4A Inhibits Glioma Development by Regulating ROS-PINK1/Parkin-Mitophagy Pathway.
  32. AdipoRon exerts an antidepressant effect by inhibiting NLRP3 inflammasome activation in microglia via promoting mitophagy.
  33. Protection of Parkin over-expression on lung in rats with exertional heat stroke by activating mitophagy.
  34. Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
  35. Parkin deficiency exacerbates particulate matter-induced injury by enhancing airway epithelial necroptosis.
  36. Allicin Mitigates Diabetic Retinopathy in Rats by Activating Phosphatase and Tensin Homolog-induced Kinase 1/Parkin-mitophagy and Inhibiting Oxidative Stress-mediated NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome.
  37. Ligustilide alleviates oxidative stress during renal ischemia-reperfusion injury through maintaining Sirt3-dependent mitochondrial homeostasis.
  38. Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.
  39. Dysregulation of mitochondrial dynamics and mitophagy are involved in High-fat diet-induced steroidogenesis inhibition.
  40. Correction: Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress.
  41. Young small extracellular vesicles rejuvenate replicative senescence by remodeling Drp1 translocation-mediated mitochondrial dynamics.
  1. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 30. pii: S0925-4439(24)00474-5. [Epub ahead of print]1870(8): 167480
    Electroacupuncture pretreatment maintains mitochondrial quality control via HO-1/MIC60 signaling pathway to alleviate endotoxin-induced acute lung injury.
    Jia Shi, Meiling Piao, Chuanning Liu, Jing Yang, Xin Guan, Huayang Liu, Qiujia Li, Yuan Zhang, Jianbo Yu.
      Electroacupuncture has been demonstrated to mitigate endotoxin-induced acute lung injury by enhancing mitochondrial function. This study investigates whether electroacupuncture confers lung protection through the regulation of mitochondrial quality control mediated by heme oxygenase-1 (HO-1) and the mitochondrial inner membrane protein MIC60. HO-1, an inducible stress protein, is crucial for maintaining mitochondrial homeostasis and protecting against lung injury. MIC60, a key component of the mitochondrial contact site and cristae organizing system, supports mitochondrial integrity. We employed genetic knockout/silencing and cell transfection techniques to model lipopolysaccharide (LPS)-induced lung injury, assessing changes in mitochondrial structure, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and the expression of proteins essential for mitochondrial quality control. Our findings reveal that electroacupuncture alleviates endotoxin-induced acute lung injury and associated mitochondrial dysfunction, as evidenced by reductions in lung injury scores, decreased ROS production, and suppressed expression of proteins involved in mitochondrial fission and mitophagy. Additionally, electroacupuncture enhanced MMP and upregulated proteins that facilitate mitochondrial fusion and biogenesis. Importantly, the protective effects of electroacupuncture were reduced in models with Hmox1 knockout or Mic60 silencing, and in macrophages transfected with Hmox1-siRNA or Mic60-siRNA. Moreover, HO-1 was found to influence MIC60 expression during electroacupuncture preconditioning and LPS challenge, demonstrating that these proteins not only co-localize but also interact directly. In conclusion, electroacupuncture effectively modulates mitochondrial quality control through the HO-1/MIC60 signaling pathway, offering an adjunctive therapeutic strategy to ameliorate endotoxin-induced acute lung injury in both in vivo and in vitro settings.
    Keywords:  Acute lung injury; Electroacupuncture; Endotoxemia; Heme oxygenase-1; MIC60/mitofilin; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167480
  2. J Mol Cell Biol. 2024 Sep 04. pii: mjae032. [Epub ahead of print]
    Correction to: Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy.
      
    DOI:  https://doi.org/10.1093/jmcb/mjae032
  3. Mol Biol Rep. 2024 Sep 02. 51(1): 949
    Sesamol-mediated targeting of EPHA2 sensitises cervical cancer for cisplatin treatment by regulating mitochondrial dynamics, autophagy, and mitophagy.
    P P Mubthasima, Sridevi Annapurna Singh, Anbarasu Kannan.
      BACKGROUND: Cervical cancer ranks as the fourth most prevalent cancer among women globally, presenting a significant therapeutic challenge due to its resistance to cisplatin. Ephrin type-A receptor 2 (EPHA2) is prominently overexpressed in cervical cancer and plays a vital role in cisplatin resistance, although the underlying mechanisms remain incompletely elucidated. Mitochondrial dynamics, autophagy, and mitophagy are critical in mediating cisplatin resistance. Sesamol, a phytochemical compound, has exhibited promising anticancer properties. This study aims to investigate the regulatory role of EPHA2 in these pathways underlying cisplatin resistance and to investigate the potential of sesamol in overcoming this resistance and inhibiting cervical cancer progression.METHODS AND RESULT: In this study, we knocked down EPHA2 in the SiHa cell line and evaluated the resulting changes in molecular markers associated with mitochondrial dynamics, mitophagy, and autophagy. Our results indicated that EPHA2 knockdown (EPHA2-KD) led to enhanced mitochondrial fusion and reduced mitochondrial fission, mitophagy, and autophagy. Furthermore, we investigated the effect of EPHA2-KD and sesamol treatment on sensitising cervical cancer to cisplatin treatment. Our data revealed that EPHA2-KD and sesamol treatment significantly increases cellular sensitivity to cisplatin-induced cytotoxicity. Additionally, we demonstrated that sesamol effectively targets EPHA2, as evidenced by decreased EPHA2 expression levels following sesamol treatment.
    CONCLUSION: In summary, targeting EPHA2 through knockdown or sesamol treatment enhances cisplatin sensitivity in cervical cancer by modulating mitochondrial dynamics, autophagy and mitophagy, suggesting promising therapeutic strategies to overcome chemoresistance.
    Keywords:  Autophagy; EPHA2; Mitochondrial dynamics; Mitophagy; Sesamol
    DOI:  https://doi.org/10.1007/s11033-024-09875-x
  4. Mol Med. 2024 Sep 03. 30(1): 136
    Molecular mechanism and potential role of mitophagy in acute pancreatitis.
    Lili Zhu, Yunfei Xu, Jian Lei.
      Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.
    Keywords:  Lysosome; Mitochondrial dysfunction; Mitophagosome; Mitophagy; Pancreatitis
    DOI:  https://doi.org/10.1186/s10020-024-00903-x
  5. J Biol Chem. 2024 Aug 28. pii: S0021-9258(24)02229-4. [Epub ahead of print] 107728
    Defective post-transcriptional modification of tRNA disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy.
    Juanjuan Zhang, Wenxu Li, Zhen Liu, Yingqi Chen, Xiaoyang Wei, Lu Peng, Man Xu, Yanchun Ji.
      Leber's Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G>A homoplasmic mutation damaged the highly conserved basepairing (28C-42G) in anticodon stem of tRNAThr, caused deficient t6A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G>A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including initiation phase, formation and maturation of autophagosome. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G>A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G>A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis.
    Keywords:  Leber’s hereditary optic neuropathy (LHON); apoptosis; autophagy; mitochondrial tRNA(Thr) mutation; mitophagy
    DOI:  https://doi.org/10.1016/j.jbc.2024.107728
  6. J Virol. 2024 Aug 30. e0104824
    Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.
    Yuan Zhao, Chan Ding, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Herman W Favoreel, Xiangdong Li.
      Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.
    Keywords:  MAVS; interferons production inhibition; mitochondria; mitophagy; pseudorabies virus (PRV)
    DOI:  https://doi.org/10.1128/jvi.01048-24
  7. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  8. iScience. 2024 Sep 20. 27(9): 110594
    Stearic acid alleviates aortic medial degeneration through maintaining mitochondrial dynamics homeostasis via inhibiting JNK/MAPK signaling.
    Kexin Wang, Xiaoping Xie, Xiaoping Hu, Zhiwei Wang, Jun Xia, Qi Wu.
      Aortic dissection is characterized pathologically by aortic medial degeneration (AMD) where disturbance of mitochondrial dynamics may be involved. Stearic acid (SA) can promote mitochondrial fusion and improve mitochondrial function. Here, we established an AMD mouse model through oral administration of β-aminopropionitrile (BAPN) and a cellular model by treating primary vascular smooth muscle cells (VSMCs) with Angiotensin-II to explore the potential role of SA in AMD. Our results showed SA reduced AMD and prolonged survival of BAPN-treated mice. Excessive mitochondrial fission was observed during AMD both in vivo and in vitro, and SA reduced mitochondrial fission and increased fusion. Additionally, SA promoted expression of contractile phenotype markers of VSMCs. At the molecular level, SA reduced AMD by inhibiting JNK/MAPK signaling. Our study suggests SA can promote mitochondrial fusion and increase the contractile phenotype of VSMCs by inhibiting JNK/MAPK signaling, thereby reducing AMD formation and possibly the consequent risk of aortic dissection.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110594
  9. Mol Cancer Ther. 2024 Sep 05.
    TR-107, An Agonist of Caseinolytic Peptidase Proteolytic Subunit, Disrupts Mitochondrial Metabolism and Inhibits the Growth of Human Colorectal Cancer Cells.
    Michael Giarrizzo, Joseph F LaComb, Hetvi R Patel, Rohan G Reddy, John D Haley, Lee M Graves, Edwin J Iwanowicz, Agnieszka B Bialkowska.
      Oxidative phosphorylation (OXPHOS) is an essential metabolic process for cancer proliferation and therapy resistance. The ClpXP complex maintains mitochondrial proteostasis by degrading misfolded proteins. Madera Therapeutics has developed a class of highly potent and selective small-molecule activators (TR compounds) of the ClpXP component caseinolytic peptidase proteolytic subunit (ClpP). This approach to cancer therapy eliminates substrate recognition and activates non-specific protease function within mitochondria, which has shown encouraging preclinical efficacy in multiple malignancies. The class-leading compound, TR-107, has demonstrated significantly improved potency in ClpP affinity and activation and enhanced pharmacokinetic properties over the multi-targeting clinical agent ONC201. In this study, we investigate the in vitro efficacy of TR-107 against human colorectal cancer (CRC) cells. TR-107 inhibited CRC cell proliferation in a dose- and time-dependent manner and induced cell cycle arrest at low nanomolar concentrations. Mechanistically, TR-107 downregulated the expression of proteins involved in the mitochondrial unfolded protein response (UPRmt) and mtDNA transcription and translation. TR-107 attenuated oxygen consumption rate and glycolytic compensation, confirming inactivation of OXPHOS and a reduction in total cellular respiration. Multi-omics analysis of treated cells indicated a downregulation of respiratory chain complex subunits and an upregulation of mitophagy and ferroptosis pathways. Further evaluation of ferroptosis revealed a depletion of antioxidant and iron toxicity defenses that could potentiate sensitivity to combinatory chemotherapeutics. Together, this study provides evidence and insight into the subcellular mechanisms employed by CRC cells in response to potent ClpP agonism. Our findings demonstrate a productive approach to disrupting mitochondrial metabolism, supporting the translational potential of TR-107.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0170
  10. Research (Wash D C). 2024 ;7 0465
    Imbalanced Skeletal Muscle Mitochondrial Proteostasis Causes Bone Loss.
    Zhen Jin, Yan Mao, Qiqi Guo, Yujing Yin, Abdukahar Kiram, Danxia Zhou, Jing Yang, Zheng Zhou, Jiachen Xue, Zhenhua Feng, Zhen Liu, Yong Qiu, Tingting Fu, Zhenji Gan, Zezhang Zhu.
      Although microgravity has been implicated in osteoporosis, the precise molecular mechanism remains elusive. Here, we found that microgravity might induce mitochondrial protein buildup in skeletal muscle, alongside reduced levels of LONP1 protein. We revealed that disruptions in mitochondrial proteolysis, induced by the targeted skeletal muscle-specific deletion of the essential mitochondrial protease LONP1 or by the acute inducible deletion of muscle LONP1 in adult mice, cause reduced bone mass and compromised mechanical function. Moreover, the bone loss and weakness phenotypes were recapitulated in skeletal muscle-specific overexpressing ΔOTC mice, a known protein degraded by LONP1. Mechanistically, mitochondrial proteostasis imbalance triggered the mitochondrial unfolded protein response (UPRmt) in muscle, leading to an up-regulation of multiple myokines, including FGF21, which acts as a pro-osteoclastogenic factor. Surprisingly, this mitochondrial proteostasis stress influenced muscle-bone crosstalk independently of ATF4 in skeletal muscle. Furthermore, we established a marked association between serum FGF21 levels and bone health in humans. These findings emphasize the pivotal role of skeletal muscle mitochondrial proteostasis in responding to alterations in loading conditions and in coordinating UPRmt to modulate bone metabolism.
    DOI:  https://doi.org/10.34133/research.0465
  11. J Mol Med (Berl). 2024 Aug 29.
    TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells.
    Giuseppina Bruno, Michele Pietrafesa, Fabiana Crispo, Annamaria Piscazzi, Francesca Maddalena, Guido Giordano, Vincenza Conteduca, Marianna Garofoli, Almudena Porras, Franca Esposito, Matteo Landriscina.
      Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60-70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells. KEY MESSAGES: TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours. TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells. TRAP1 silencing favours mitochondrial biogenesis in CRC cells.
    Keywords:  Colorectal cancer; Metabolism; Mitochondrial biogenesis; Peroxisome proliferation-activated receptor gamma coactivator α1-alpha; TNF receptor-associated protein 1; Transcription factor A mitochondrial
    DOI:  https://doi.org/10.1007/s00109-024-02479-9
  12. bioRxiv. 2024 Aug 20. pii: 2024.08.19.608723. [Epub ahead of print]
    Dynamins combine mechano-constriction and membrane remodeling to enable two-step mitochondrial fission via a 'snap-through' instability.
    Haleh Alimohamadi, Elizabeth Wei-Chia Luo, Rena Yang, Shivam Gupta, Kelsey A Nolden, Taraknath Mandal, R Blake Hill, Gerard C L Wong.
      Mitochondrial fission is controlled by dynamin proteins, the dysregulation of which is correlated with diverse diseases. Fission dynamins are GTP hydrolysis-driven mechanoenzymes that self-oligomerize into helical structures that constrict membrane to achieve fission, but details are not well understood. However, dynamins can also remodel membranes by inducing negative Gaussian curvature, the type of curvature required for completion of fission. Here, we examine how these drastically different mechanisms synergistically exert their influences on a membrane, via a mechanical model calibrated with small-angle X-ray scattering structural data. We find that free dynamin can trigger a "snap-through instability" that enforces a shape transition from an oligomer-confined cylindrical membrane to a drastically narrower catenoid-shaped neck within the spontaneous hemi-fission regime, in a manner that depends critically on the length of the confined tube. These results indicate how the combination of dynamin assembly, and paradoxically disassembly, can lead to diverse pathways to scission.Teaser: Dynamin mechano-constriction by assembly and curvature-driven instability by free monomers synergistically drive mitochondrial fission.
    DOI:  https://doi.org/10.1101/2024.08.19.608723
  13. Cardiovasc Toxicol. 2024 Sep 06.
    TRAF3IP3 Blocks Mitophagy to Exacerbate Myocardial Injury Induced by Ischemia-Reperfusion.
    Zhongcheng Wei, Juan Liu, Hailang Liu, Aixia Jiang.
      To uncover the possible role of TRAF3IP3 in the progression of myocardial infarction (MI), clarify its role in mitophagy and mitochondrial function, and explore the underlying mechanism. GEO chip analysis, RT-qPCR, and LDH release assay were used to detect the expression of TRAF3IP3 in tissues and cells and its effects on cell damage. Immunostaining and ATP product assays were performed to examine the effects of TRAF3IP3 on mitochondrial function. Co-IP, CHX assays, Immunoblot and Immunostaining assays were conducted to determine the effects of TRAF3IP3 on mitophagy. TRAF3IP3 was highly expressed in IR rats and HR-induced H9C2 cells. TRAF3IP3 knockdown can alleviate H/R-induced H9C2 cell damage. In addition, TRAF3IP3 knockdown can induce mitophagy, thus enhancing mitochondrial function. We further revealed that TRAF3IP3 can promote the degradation of NEDD4 protein. Moreover, TRAF3IP3 knockdown suppressed myocardial injury in I/R rats. TRAF3IP3 blocks mitophagy to exacerbate myocardial injury induced by I/R via mediating NEDD4 expression.
    Keywords:  Mitochondrial function; Mitophagy; Myocardial infarction (MI); NEDD4; TRAF3IP3
    DOI:  https://doi.org/10.1007/s12012-024-09916-8
  14. Mol Med Rep. 2024 Nov;pii: 191. [Epub ahead of print]30(5):
    [Retracted] Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways.
    Lili He, Kebo Gu.
      Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the immunofluorescence assay data shown in Fig. 4A on p. 1698 were strikingly similar to data that had already been submitted for publication in different form in another article written by different authors at different research institutes. In addition, there was an instance of apparent duplication of western blot data comparing between Fig. 5A and 5G, and the reader also had concerns regarding the presentation of the flow‑cytometry cell‑count histograms in Fig. 2A. Owing to the fact that the contentious data in the above article had already been submitted for publication elsewhere prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 1692‑1703, 2018; DOI: 10.3892/mmr.2018.9087].
    Keywords:  Parkin; S-phase kinase associated protein 2; Tanshinone IIA; adenosine monophosphate-activated protein kinase; colorectal cancer; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2024.13315
  15. Lipids Health Dis. 2024 Sep 03. 23(1): 279
    Dihydromyricetin suppresses endothelial NLRP3 inflammasome activation and attenuates atherogenesis by promoting mitophagy.
    Qin Hu, Chengying Li, Ting Zhang, Long Yi, Yifan Shan, Xiangyu Ma, Tongjian Cai, Li Ran, Hui Shen, Yafei Li.
      BACKGROUND: NOD-like receptor protein 3 (NLRP3) inflammasome activation is indispensable for atherogenesis. Mitophagy has emerged as a potential strategy to counteract NLRP3 inflammasome activation triggered by impaired mitochondria. Our previous research has indicated that dihydromyricetin, a natural flavonoid, can mitigate NLRP3-mediated endothelial inflammation, suggesting its potential to treat atherosclerosis. However, the precise underlying mechanisms remain elusive. This study sought to investigate whether dihydromyricetin modulates endothelial mitophagy and inhibits NLRP3 inflammasome activation to alleviate atherogenesis, along with the specific mechanisms involved.METHODS: Apolipoprotein E-deficient mice on a high-fat diet were administered daily oral gavages of dihydromyricetin for 14 weeks. Blood samples were procured to determine the serum lipid profiles and quantify proinflammatory cytokine concentrations. Aortas were harvested to evaluate atherosclerotic plaque formation and NLRP3 inflammasome activation. Concurrently, in human umbilical vein endothelial cells, Western blotting, flow cytometry, and quantitative real-time PCR were employed to elucidate the mechanistic role of mitophagy in the modulation of NLRP3 inflammasome activation by dihydromyricetin.
    RESULTS: Dihydromyricetin administration significantly attenuated NLRP3 inflammasome activation and vascular inflammation in mice on a high-fat diet, thereby exerting a pronounced inhibitory effect on atherogenesis. Both in vivo and in vitro, dihydromyricetin treatment markedly enhanced mitophagy. This enhancement in mitophagy ameliorated the mitochondrial damage instigated by saturated fatty acids, thereby inhibiting the activation and nuclear translocation of NF-κB. Consequently, concomitant reductions in the transcript levels of NLRP3 and interleukin-1β (IL-1β), alongside decreased activation of NLRP3 inflammasome and IL-1β secretion, were discerned. Notably, the inhibitory effects of dihydromyricetin on the activation of NF-κB and subsequently the NLRP3 inflammasome were determined to be, at least in part, contingent upon its capacity to promote mitophagy.
    CONCLUSION: This study suggested that dihydromyricetin may function as a modulator to promote mitophagy, which in turn mitigates NF-κB activity and subsequent NLRP3 inflammasome activation, thereby conferring protection against atherosclerosis.
    Keywords:  Atherosclerosis; Dihydromyricetin; Mitophagy; NLRP3 inflammasome; Vascular endothelium
    DOI:  https://doi.org/10.1186/s12944-024-02263-1
  16. Mitochondrion. 2024 Sep 03. pii: S1567-7249(24)00110-7. [Epub ahead of print]79 101952
    SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies.
    Chang-Lin Chen, Takaya Ishihara, Soumyadip Pal, Wei-Ling Huang, Emi Ogasawara, Chuang-Rung Chang, Naotada Ishihara.
      Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.
    Keywords:  Cytochrome c oxidase; Oxidative phosphorylation; Succinate dehydrogenase assembly factor 2 (SDHAF2)
    DOI:  https://doi.org/10.1016/j.mito.2024.101952
  17. Immunol Res. 2024 Sep 04.
    The dysregulation of mitochondrial homeostasis-related genes could be involved in the decrease of mtDNA copy number in systemic lupus erythematosus patients.
    Giada De Benedittis, Andrea Latini, Chiara Morgante, Carlo Perricone, Fulvia Ceccarelli, Giuseppe Novelli, Lucia Novelli, Cinzia Ciccacci, Paola Borgiani.
      Systemic lupus erythematosus (SLE) is a chronic multifactorial autoimmune disease. It is now widely demonstrated that oxidative stress (OS) plays an important role in the modulation of the pathogenesis of this disease. Mitochondrial DNA (mtDNA) is highly vulnerable to OS and it is known a decrease of mtDNA copy number in SLE patients. However, to date, it has not been investigated if this decrease is associated with a dysregulation of mitochondrial homeostasis genes. Our aim is to evaluate the amount of mtDNA copy number and the expression of the genes more involved in the mitochondrial homeostasis pathways, in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. We analysed the amount of mtDNA in PBMCs of 72 SLE patients and 61 healthy controls by qPCR. Then, we investigated the expression variability of TFAM and SIRT1 (biogenesis), MFN1 and MFF (fusion/fission) and PRKN2 (mitophagy) genes in a subgroup of SLE patients and healthy controls. Interestingly, we have observed a highly significant decrease in mtDNA copies in SLE patients compared to healthy controls (P < 0.0001). In addition, we have shown that the expression levels of SIRT1, MFN1 and PRKN2 genes were significantly decreased in SLE patients with respect to healthy controls (P = 0.00001 for SIRT1, P = 0.0150 for MFN1 and P = 0.0009 for PRKN2). Lastly, we have reported a positive correlation between PRKN2 expression level and mtDNA copy number (P = 0.019, r = 0.475). In conclusion, our data confirm the impairment of mtDNA copy number in the disease and show for the first time a dysregulation of the mitochondrial homeostasis genes. These results could provide additional support to the important role of mitochondria in SLE development.
    Keywords:  Mitochondrial homeostasis genes; MtDNA copy number; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s12026-024-09535-z
  18. Acta Pharm Sin B. 2024 Aug;14(8): 3327-3361
    Mitophagy and cGAS-STING crosstalk in neuroinflammation.
    Xiaogang Zhou, Jing Wang, Lu Yu, Gan Qiao, Dalian Qin, Betty Yuen-Kwan Law, Fang Ren, Jianming Wu, Anguo Wu.
      Mitophagy, essential for mitochondrial health, selectively degrades damaged mitochondria. It is intricately linked to the cGAS-STING pathway, which is crucial for innate immunity. This pathway responds to mitochondrial DNA and is associated with cellular stress response. Our review explores the molecular details and regulatory mechanisms of mitophagy and the cGAS-STING pathway. We critically evaluate the literature demonstrating how dysfunctional mitophagy leads to neuroinflammatory conditions, primarily through the accumulation of damaged mitochondria, which activates the cGAS-STING pathway. This activation prompts the production of pro-inflammatory cytokines, exacerbating neuroinflammation. This review emphasizes the interaction between mitophagy and the cGAS-STING pathways. Effective mitophagy may suppress the cGAS-STING pathway, offering protection against neuroinflammation. Conversely, impaired mitophagy may activate the cGAS-STING pathway, leading to chronic neuroinflammation. Additionally, we explored how this interaction influences neurodegenerative disorders, suggesting a common mechanism underlying these diseases. In conclusion, there is a need for additional targeted research to unravel the complexities of mitophagy-cGAS-STING interactions and their role in neurodegeneration. This review highlights potential therapies targeting these pathways, potentially leading to new treatments for neuroinflammatory and neurodegenerative conditions. This synthesis enhances our understanding of the cellular and molecular foundations of neuroinflammation and opens new therapeutic avenues for neurodegenerative disease research.
    Keywords:  Crosstalk; Innate immunity; Mitochondrial DNA; Mitophagy; Neurodegenerative diseases; Neuroinflammation; Therapeutic avenues; cGAS–STING
    DOI:  https://doi.org/10.1016/j.apsb.2024.05.012
  19. Sci Rep. 2024 Sep 05. 14(1): 20713
    Lidamycin induces mitophagy in pancreatic cancer cells by regulating the expression of Mfn2.
    Boya Wu, Bing Qi, Liumeng Duan, Jing Chen.
      Lidamycin (LDM) has been confirmed to have a strong anti-pancreatic cancer effect and can affect the mitochondrial function of pancreatic cancer cells. Mitofusin-2 (Mfn2) is located in the outer membrane of mitochondria, and Mfn2 is currently believed to play a role in cancer inhibition in pancreatic cancer. In order to explore whether the anti-pancreatic cancer effect of LDM is related to Mfn2-mediated mitophagy, Bioinformatics and in vitro cell experiments are used for experimental research. The experimental results demonstrated that Mfn2 is correlated with mitochondrial autophagy in pancreatic cancer. Lidamycin can increase the expression of Mfn2 in pancreatic cancer and affect the process of EMT, affect the level of reactive oxygen species and mitochondrial membrane potential, and increase the expression of mitochondrial autophagy marker proteins BNIP3L and Beclin1. These results demonstrate that Mfn2 affects mitophagy in pancreatic cancer cells by regulating the expression of Mfn2.
    Keywords:  Lidamycin; Mitofusin-2; Mitophagy; Pancreatic cancer
    DOI:  https://doi.org/10.1038/s41598-024-71377-4
  20. J Physiol. 2024 Sep 02.
    Muscle-specific mitophagy: insights into hindlimb and diaphragm responses during health and sepsis.
    Jordan D Fuqua, Paulo H C Mesquita, Michael E Taylor, Agnieszka K Borowik.
      
    Keywords:  autophagy; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287151
  21. Antioxid Redox Signal. 2024 Sep 03.
    Regulation of mitochondrial quality control of intestinal stem cells in homeostasis and diseases.
    Xudan Lei, Zhenni Xu, Yujun Huang, Lingxiao Huang, Jinyi Lang, Mingyue Qu, Dengqun Liu.
      SIGNIFICANCE: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases.RECENT ADVANCES: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating of ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological condition and protects against intestinal injury remains to be comprehensively reviewed.
    CRITICAL ISSUES: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy and proteostasis impact ISC proliferation, differentiation and regeneration, respectively.
    FUTURE DIRECTIONS: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases.
    DOI:  https://doi.org/10.1089/ars.2023.0489
  22. Front Genet. 2024 ;15 1437959
    Severe mitochondrial encephalomyopathy caused by de novo variants in OPA1 gene.
    Michela Di Nottia, Teresa Rizza, Enrico Baruffini, Claudia Nesti, Alessandra Torraco, Daria Diodato, Diego Martinelli, Flavio Dal Canto, Alexandru Ionut Gilea, Martina Zoccola, Barbara Siri, Carlo Dionisi-Vici, Enrico Bertini, Filippo Maria Santorelli, Paola Goffrini, Rosalba Carrozzo.
      Background: Mitochondria adjust their shape in response to the different energetic and metabolic requirements of the cell, through extremely dynamic fusion and fission events. Several highly conserved dynamin-like GTPases are involved in these processes and, among those, the OPA1 protein is a key player in the fusion of inner mitochondrial membranes. Hundreds of monoallelic or biallelic pathogenic gene variants have been described in OPA1, all associated with a plethora of clinical phenotypes without a straightforward genotype-phenotype correlation.Methods: Here we report two patients harboring novel de novo variants in OPA1. DNA of two patients was analyzed using NGS technology and the pathogenicity has been evaluated through biochemical and morphological studies in patient's derived fibroblasts and in yeast model.
    Results: The two patients here reported manifest with neurological signs resembling Leigh syndrome, thus further expanding the clinical spectrum associated with variants in OPA1. In cultured skin fibroblasts we observed a reduced amount of mitochondrial DNA (mtDNA) and altered mitochondrial network characterized by more fragmented mitochondria. Modeling in yeast allowed to define the deleterious mechanism and the pathogenicity of the identified gene mutations.
    Conclusion: We have described two novel-single OPA1 mutations in two patients characterized by early-onset neurological signs, never documented, thus expanding the clinical spectrum of this complex syndrome. Moreover, both yeast model and patients derived fibroblasts showed mitochondrial defects, including decreased mtDNA maintenance, correlating with patients' clinical phenotypes.
    Keywords:  OPA1; encephalomyopathy; mitochondrial diseases; mitochondrial dynamics; optic atrophy
    DOI:  https://doi.org/10.3389/fgene.2024.1437959
  23. Med Oncol. 2024 Sep 01. 41(10): 238
    How mitochondrial dynamics imbalance affects the progression of breast cancer:a mini review.
    Jingwen Kuang, Hao Liu, Linlin Feng, Yuan Xue, Huiyi Tang, Pengcheng Xu.
      Despite the high incidence of breast cancer in women worldwide, there are still great challenges in the treatment process. Mitochondria are highly dynamic organelles, and their dynamics involve cellular energy conversion, signal conduction and other processes. In recent years, an increasing number of studies have affirmed the dynamics of mitochondria as the basis for cancer progression and metastasis; that is, an imbalance between mitochondrial fission and fusion may lead to the progression and metastasis of breast cancer. Here, we review the latest insights into mitochondrial dynamics in the progression of breast cancer and emphasize the clinical value of mitochondrial dynamics in diagnosis and prognosis, as well as important advances in clinical research.
    Keywords:  Breast cancer; Mitochondria; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion
    DOI:  https://doi.org/10.1007/s12032-024-02479-2
  24. Neuropharmacology. 2024 Aug 29. pii: S0028-3908(24)00304-6. [Epub ahead of print]260 110135
    GPx1-ERK1/2-CREB pathway regulates the distinct vulnerability of hippocampal neurons to oxidative stress via modulating mitochondrial dynamics following status epilepticus.
    Ji-Eun Kim, Duk-Shin Lee, Su Hyeon Wang, Tae-Hyun Kim, Tae-Cheon Kang.
      Glutathione peroxidase-1 (GPx1) and cAMP/Ca2+ responsive element (CRE)-binding protein (CREB) regulate neuronal viability by maintaining the redox homeostasis. Since GPx1 and CREB reciprocally regulate each other, it is likely that GPx1-CREB interaction may play a neuroprotective role against oxidative stress, which are largely unknown. Thus, we investigated the underlying mechanisms of the reciprocal regulation between GPx1 and CREB in the male rat hippocampus. Under physiological condition, L-buthionine sulfoximine (BSO)-induced oxidative stress increased GPx1 expression, extracellular signal-regulated kinase 1/2 (ERK1/2) activity and CREB serine (S) 133 phosphorylation in CA1 neurons, but not dentate granule cells (DGC), which were diminished by GPx1 siRNA, U0126 or CREB knockdown. GPx1 knockdown inhibited ERK1/2 and CREB activations induced by BSO. CREB knockdown also decreased the efficacy of BSO on ERK1/2 activation. BSO facilitated dynamin-related protein 1 (DRP1)-mediated mitochondrial fission in CA1 neurons, which abrogated by GPx1 knockdown and U0126. CREB knockdown blunted BSO-induced DRP1 upregulation without affecting DRP1 S616 phosphorylation ratio. Following status epilepticus (SE), GPx1 expression was reduced in CA1 neurons and DGC. SE also decreased CREB activity CA1 neurons, but not DGC. SE degenerated CA1 neurons, but not DGC, accompanied by mitochondrial elongation. These post-SE events were ameliorated by N-acetylcysteine (NAC, an antioxidant), but deteriorated by GPx1 knockdown. These findings indicate that a transient GPx1-ERK1/2-CREB activation may be a defense mechanism to protect hippocampal neurons against oxidative stress via maintenance of proper mitochondrial dynamics.
    Keywords:  BSO; DRP1; Epilepsy; Mitochondria; NAC; ROS; Seizure; U0126
    DOI:  https://doi.org/10.1016/j.neuropharm.2024.110135
  25. Pharmacol Res. 2024 Sep 02. pii: S1043-6618(24)00339-6. [Epub ahead of print] 107394
    Investigating the Interplay between Mitophagy and Diabetic Neuropathy: Uncovering the hidden secrets of the disease pathology.
    Kiavash Hushmandi, Behzad Einollahi, Rachel Aow, Suhana Binte Suhairi, Daniel J Klionsky, Amir Reza Aref, Russel J Reiter, Pooyan Makvandi, Navid Rabiee, Yi Xu, Noushin Nabavi, Seyed Hassan Saadat, Najma Farahani, Alan Prem Kumar.
      Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease.
    Keywords:  Diabetic neuropathies; mitochondria; mitophagy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.phrs.2024.107394
  26. Biochim Biophys Acta Mol Basis Dis. 2024 Sep 03. pii: S0925-4439(24)00491-5. [Epub ahead of print] 167497
    MEF2A, a gene associated with mitochondrial biogenesis, promotes drug resistance in gastric cancer.
    Yao Shen, Tong Zhang, Xueyuan Jia, Fei Xi, Wanting Jing, Yusi Wang, Min Huang, Ruisi Na, Lidan Xu, Wei Ji, Yuandong Qiao, Xuelong Zhang, Wenjing Sun, Shuijie Li, Jie Wu.
      Chemotherapeutic resistance is a major obstacle to the effectiveness of cisplatin-based chemotherapy for gastric cancer (GC), leading to treatment failure and poor survival rates. However, the underlying mechanisms are not fully understood. Our study demonstrated that the transcription factor myocyte enhancer factor 2A (MEF2A) plays a role in chemotherapeutic drug resistance by regulating the transcription of PGC1α and KEAP1, promoting mitochondrial biogenesis. It was found that increased MEF2A expression is linked with poor prognosis, cisplatin insensitivity, and mitochondrial function in GC. MEF2A overexpression significantly decreases GC cell sensitivity in vitro and in vivo, while MEF2A knockdown enhances the sensitivity to cisplatin. Mechanistically, MEF2A activates the transcription of PGC1α, leading to increased mitochondrial biogenesis. In addition, MEF2A inhibits KEAP1 transcription, reduces NRF2 ubiquitination degradation, and activates the KEAP1/NRF2 signaling pathway, which modulates the reactive oxygen species level. The present study identifies a new critical oncogene involved in GC chemoresistance, suggesting a novel therapeutic target for GC.
    Keywords:  Drug resistance; GC; MEF2A; Mitochondria; PGC1α
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167497
  27. bioRxiv. 2024 Aug 26. pii: 2024.08.23.609462. [Epub ahead of print]
    Patient mutations in DRP1 perturb synaptic maturation of cortical neurons.
    T B Baum, C Bodnya, J Costanzo, V Gama.
      With the advent of exome sequencing, a growing number of children are being identified with de novo loss of function mutations in the dynamin 1 like ( DNM1L) gene encoding the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1); these mutations result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro . High-resolution time-lapse imaging of axonal transport in mutant DRP1 cortical neurons reveals mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicates mutation dependent alterations in synaptic development and calcium regulation gene expression. Disruptions in calcium dynamics were confirmed using live functional recordings of 100 DIV (days in vitro) mutant DRP1 cortical neurons. These findings and deficits in pre- and post-synaptic marker colocalization using super resolution microscopy, strongly suggest that altered mitochondrial morphology of DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
    DOI:  https://doi.org/10.1101/2024.08.23.609462
  28. Biochemistry (Mosc). 2024 Jul;89(7): 1336-1348
    Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
    Veronika V Nesterova, Polina I Babenkova, Anna A Brezgunova, Natalia A Samoylova, Irina S Sadovnikova, Dmitry S Semenovich, Nadezda V Andrianova, Artem P Gureev, Egor Y Plotnikov.
      One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.
    Keywords:  aging; beta-hydroxybutyrate; ketogenic diet; mitochondria; mitochondrial DNA; oxidative stress
    DOI:  https://doi.org/10.1134/S0006297924070149
  29. Pharmacol Res. 2024 Aug 28. pii: S1043-6618(24)00328-1. [Epub ahead of print] 107383
    Cell life-or-death events in osteoporosis: All roads lead to mitochondrial dynamics.
    Zhichao Li, Songlin Liang, Liqing Ke, Mengjie Wang, Kuanhui Gao, Dandan Li, Zhanwang Xu, Nianhu Li, Peng Zhang, Wenxiang Cheng.
      Mitochondria exhibit heterogeneous shapes and networks within and among cell types and tissues, also in normal or osteoporotic bone tissues with complex cell types. This dynamic characteristic is determined by the high plasticity provided by mitochondrial dynamics and is stemmed from responding to the survival and functional requirements of various bone cells in a specific microenvironments. In contrast, mitochondrial dysfunction, induced by dysregulation of mitochondrial dynamics, may act as a trigger of cell death signals, including common apoptosis and other forms of programmed cell death (PCD). These PCD processes consisting of tightly structured cascade gene expression events, can further influence the bone remodeling by facilitating the death of various bone cells. Mitochondrial dynamics, therefore, drive the bone cells to stand at the crossroads of life and death by integrating external signals and altering metabolism, shape, and signal-response properties of mitochondria. This implies that targeting mitochondrial dynamics displays significant potential in treatment of osteoporosis. Considerable effort has been made in osteoporosis to emphasize the parallel roles of mitochondria in regulating energy metabolism, calcium signal transduction, oxidative stress, inflammation, and cell death. However, the emerging field of mitochondrial dynamics-related PCD is not well understood. Herein, to bridge the gap, we outline the latest knowledge on mitochondrial dynamics regulating bone cell life or death during normal bone remodeling and osteoporosis.
    Keywords:  Apoptosis; Ferroptosis; Mitochondrial dynamics; Necroptosis; Osteoporosis; Programmed cell death; Pyroptosis
    DOI:  https://doi.org/10.1016/j.phrs.2024.107383
  30. Free Radic Biol Med. 2024 Aug 28. pii: S0891-5849(24)00630-0. [Epub ahead of print]
    Mechanism of cigarette smoke in promoting small airway remodeling in mice via STAT 3 / PINK 1-Parkin / EMT.
    Yunjie Wei, Qiqi Li, Kaiye He, Guopeng Liao, Lingyun Cheng, Meihua Li, Zhiyi He.
      BACKGROUND: Airway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify.METHODS: Animals:Healthy male C57BL/6 mice aged 4-6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining,immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues,transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS).
    RESULTS: CS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice,with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation,increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT.
    CONCLUSION: CS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover,activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.
    Keywords:  COPD; STAT3; airway remodeling; epithelial and interstitial transformation; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.036
  31. Mol Neurobiol. 2024 Sep 04.
    TUBB4A Inhibits Glioma Development by Regulating ROS-PINK1/Parkin-Mitophagy Pathway.
    Xueru Xi, Suqin Chen, Xiaoli Zhao, Zimu Zhou, Shanjie Zhu, Xurui Ren, Xiaomei Wang, Jing Wu, Shuai Mu, Xianwen Li, Enfang Shan, Yan Cui.
      Glioma is a refractory malignant tumor with a powerful capacity for invasiveness and a poor prognosis. This study aims to investigate the role and mechanism of tubulin beta class IVA (TUBB4A) in glioma progression. The differential expression of TUBB4A in humans was obtained from databases and analyzed. Glioma cells U251-MG and U87-MG were intervened by pcDNA3.1(+) and TUBB4A overexpression plasmid. MTT, CCK8, LDH, wound healing, transwell, and western blotting were used to explore whether TUBB4A participates in the development of glioma. Reactive oxygen species (ROS) were detected by the DCFH-DA probe. Mitochondrial membrane potential (MMP) was examined by JC-1. It was found that TUBB4A expression level correlated with tumor grade, IDH1 status, 1p/19q status, and poor survival in glioma patients. In addition, TUBB4A overexpression inhibited the proliferation, migration, and invasion of U251-MG and U87-MG, while increasing the degree of apoptosis. Notably, TUBB4A overexpression promotes ROS generation and MMP depolarization, and induces mitophagy through the PINK1/Parkin pathway. Interestingly, mitochondria-targeted ROS scavenger reversed the effect of TUBB4A overexpression on PINK1/Parkin expression and mitophagy, whereas mitophagy inhibitor did not affect ROS production. And the effect of TUBB4A overexpression on mitophagy and glioma progression was consistent with that of PINK1/Parkin agonist. In conclusion, TUBB4A is a molecular marker for predicting the prognosis of glioma patients and an effective target for inhibiting glioma progression by regulating ROS-PINK1/Parkin-mitophagy pathway.
    Keywords:  Glioma; Mitophagy; PINK1/Parkin; ROS; TUBB4A
    DOI:  https://doi.org/10.1007/s12035-024-04459-z
  32. Int Immunopharmacol. 2024 Aug 29. pii: S1567-5769(24)01532-7. [Epub ahead of print]141 113011
    AdipoRon exerts an antidepressant effect by inhibiting NLRP3 inflammasome activation in microglia via promoting mitophagy.
    Yaqi Liu, Xiying Fu, Jiangjin Sun, Ranji Cui, Wei Yang.
      Depression is a serious mental disorder that threatens patients' physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy.
    Keywords:  AdipoRon; Depression; Microglia; Mitophagy; NLRP3 inflammasome; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.intimp.2024.113011
  33. BMC Pulm Med. 2024 Aug 31. 24(1): 431
    Protection of Parkin over-expression on lung in rats with exertional heat stroke by activating mitophagy.
    Jiaxing Wang, Ran Meng, Zhengzhong Sun, Lyv Xuan, Jiao Wang, Yan Gu, Yuxiang Zhang.
      OBJECTIVE: To investigate the role of Parkin overexpression-induecd mitophagy in alleviating acute lung injury of exertional heat stroke(EHS) rats.METHODS: Eighty SD rats were divided into four groups: Control group (CON group), Control Parkin overexpression group (CON + Parkin group), exertional heat stroke group (EHS group), and exertional heat stroke Parkin overexpression group (EHS + Parkin group). Adeno-associated virus carrying the Parkin gene was intravenously injected into the rats to overexpress Parkin in the lung tissue. An exertional heat stroke rat model was established, and survival curves were plotted. Lung Micro-CT was performed, and lung coefficient and pulmonary microvascular permeability were measured. Enzyme-linked immunosorbent assays(ELISA) were used to determine the levels of interleukin-6(IL-6), interleukin-1β(IL-1β), Tumor necrosis factor-α(TNF-α), and reactive oxygen species(ROS). The morphology of mitochondria in type II epithelial cells of lung tissue was observed using transmission electron microscopy. The apoptosis of lung tissue, the level of mitophagy, and the co-localization of Pink1 and Parkin were determined using immunofluorescence. The expression of Pink1, Parkin, MFN2, PTEN-L, PTEN, p62, and microtubule associated protein 1 light chain 3 (LC3) in rat lung tissue was measured by western blot.
    RESULTS: Compared with the CON group, there were more severe lung injury and more higher levels of IL-6, IL-1β, TNF-α in EHS rats. Both of the LC3-II/LC3-I ratio and the co-localization of LC3 and Tom20 in the lung tissue of EHS rats decreased. Compared with the EHS group, the survival rate of rats in the EHS + Parkin overexpression group was significantly increased, lung coefficient and pulmonary microvascular permeability were reduced, and pathological changes such as exudation and consolidation were significantly alleviated. The levels of IL-6, IL-1β, TNF-α, and ROS were significantly decreased; the degree of mitochondrial swelling in type II alveolar epithelial cells was reduced, and no vacuolization was observed. Lung tissue apoptosis was reduced, and the colocalization fluorescence of Pink1 and Parkin, as well as LC3 and Tom20, were increased. The expression of Parkin and LC3-II/LC3-I ratio in lung tissue were both increased, while the expression of P62, Pink1, MFN2, and PTEN-L was decreased.
    CONCLUSION: Pink1/Parkin-mediated mitophagy dysfunction is one of the mechanisms underlying acute lung injury in rats with EHS, and activation of Parkin overexpression induced-mitophagy can alleviate acute lung injury caused by EHS.
    Keywords:  Exertional heat stroke; Lung injury; Mitophagy; Parkin; Pink1
    DOI:  https://doi.org/10.1186/s12890-024-03222-3
  34. Life Sci Alliance. 2024 Nov;pii: e202402764. [Epub ahead of print]7(11):
    Mitochondrial double-stranded RNA homeostasis depends on cell-cycle progression.
    Vanessa Xavier, Silvia Martinelli, Ryan Corbyn, Rachel Pennie, Kai Rakovic, Ian R Powley, Leah Officer-Jones, Vincenzo Ruscica, Alison Galloway, Leo M Carlin, Victoria H Cowling, John Le Quesne, Jean-Claude Martinou, Thomas MacVicar.
      Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.
    DOI:  https://doi.org/10.26508/lsa.202402764
  35. Sci Total Environ. 2024 Aug 30. pii: S0048-9697(24)06078-9. [Epub ahead of print] 175922
    Parkin deficiency exacerbates particulate matter-induced injury by enhancing airway epithelial necroptosis.
    Yuting Lin, Meiyu Quan, Xibin Wang, Wanqi Miao, Haibo Xu, Baiqi He, Bin Liu, Yanxia Zhang, Yijing Chen, Binqian Zhou, Mengying Xu, Li Dong, Xuru Jin, Zhenkun Lou, Jin-San Zhang, Chengshui Chen.
      Exposure to fine particulate matter (PM) disrupts the function of airway epithelial barriers causing cellular stress and damage. However, the precise mechanisms underlying PM-induced cellular injury and the associated molecular pathways remain incompletely understood. In this study, we used intratracheal instillation of PM in C57BL6 mice and PM treatment of the BEAS-2B cell line as in vivo and in vitro models, respectively, to simulate PM-induced cellular damage and inflammation. We collected lung tissues and bronchoalveolar lavage fluids to assess histopathological changes, necroptosis, and airway inflammation. Our findings reveal that PM exposure induces necroptosis in mouse airway epithelial cells. Importantly, concurrent administration of a receptor interacting protein kinases 3 (RIPK3) inhibitor or the deletion of the necroptosis effector mixed-lineage kinase domain-like protein (MLKL) effectively attenuated PM-induced airway inflammation. PM exposure dose-dependently induces the expression of Parkin, an E3 ligase we recently reported to play a pivotal role in necroptosis through regulating necrosome formation. Significantly, deletion of endogenous Parkin exacerbates inflammation by enhancing epithelial necroptosis. These results indicate that PM-induced Parkin expression plays a crucial role in suppressing epithelial necroptosis, thereby reducing airway inflammation. Overall, these findings offer valuable mechanistic insights into PM-induced airway injury and identify a potential target for clinical intervention.
    Keywords:  Airway injury; Necroptosis; Parkin, inflammation, transgenic mice; Particulate matter (PM)
    DOI:  https://doi.org/10.1016/j.scitotenv.2024.175922
  36. J Physiol Investig. 2024 Jul 01. 67(4): 215-224
    Allicin Mitigates Diabetic Retinopathy in Rats by Activating Phosphatase and Tensin Homolog-induced Kinase 1/Parkin-mitophagy and Inhibiting Oxidative Stress-mediated NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome.
    Yuanyuan Xu, Jia Yu.
      ABSTRACT: Diabetic retinopathy (DR) is one of the significant disabling outcomes of diabetes mellitus characterized by retinal microvascular damage, inflammation, and neuronal dysfunction. Allicin (Alc), a natural compound found in garlic, has garnered attention for its antioxidant and anti-inflammatory properties, positioning it as a potential therapeutic agent for DR. The aim of the present study was to investigate the therapeutic efficacy of Alc in DR management and elucidate its underlying mechanisms of action. We established a DR model in male Sprague-Dawley rats (n = 50, 200-250 g, 12 weeks old) using a high-fat diet for 8 weeks plus a low dose of streptozotocin administered at the start of the 4th week. The diabetic (Diab) animals were administered Alc (16 mg/kg/day, orally), either alone or in combination with mitochondrial division inhibitor-1 (Mdivi-1) as a mitophagy inhibitor, starting 28 days before tissue sampling. We evaluated histopathological changes, metabolic abnormalities associated with type 2 diabetes mellitus (T2DM), the expression of proteins regulating pyroptosis (NOD-like receptor family pyrin domain containing 3, cleaved-caspase 1, and gasdermin D-N terminal) and mitophagy (phosphatase and tensin homolog-induced kinase 1 [PINK1] and Parkin), as well as the levels of oxidative stress mediators and proinflammatory cytokines. Alc treatment effectively ameliorated histopathological changes and metabolic abnormalities associated with T2DM. It downregulated pyroptosis-related proteins, upregulated mitophagy-related proteins, reduced proinflammatory cytokine levels, and attenuated oxidative stress. Treatment with Mdivi-1 suppressed the beneficial effects of Alc. Our findings highlight the therapeutic potential of Alc in managing DR by targeting multiple pathophysiological pathways, including pyroptosis, inflammation, and oxidative stress. The observed antipyroptotic effects of Alc were partially mediated by the activation of the PINK1/parkin-mediated mitophagy pathway. Additional studies are necessary to thoroughly understand the therapeutic mechanisms of Alc and its viability as a treatment choice for DR.
    DOI:  https://doi.org/10.4103/ejpi.EJPI-D-24-00039
  37. Phytomedicine. 2024 Aug 23. pii: S0944-7113(24)00633-0. [Epub ahead of print]134 155975
    Ligustilide alleviates oxidative stress during renal ischemia-reperfusion injury through maintaining Sirt3-dependent mitochondrial homeostasis.
    Kang Xia, Zeya Jin, Qiangmin Qiu, Yujie Zhou, Yifan Lu, Tao Qiu, Jiangqiao Zhou, Zhongbao Chen.
      BACKGROUND: Renal ischemia-reperfusion (I/R) injury is an inevitable complication during renal transplantation and is closely related to patient prognosis. Mitochondrial damage induced oxidative stress is the core link of renal I/R injury. Ligustilide (LIG), a natural compound extracted from ligusticum chuanxiong hort and angelica sinensis, has exhibited the potential to protect mitochondrial function. However, whether LIG can ameliorate renal I/R injury requires further investigation. Delving deeper into the precise targets and mechanisms of LIG's effect on renal I/R injury is crucial.PURPOSE: This study aimed to elucidate the specific mechanism of LIG's protective effect on renal I/R injury.
    METHODS: In this study, an in vivo model of renal ischemia-reperfusion (I/R) injury was developed in mice, along with an in vitro model of hypoxia-reoxygenation (H/R) using human proximal renal tubular epithelial cells (HK-2). To assess the impact of LIG on renal injury, various methods were employed, including serum creatinine (Cr) and blood urea nitrogen (BUN) testing, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) for kidney injury molecule-1 (KIM-1). The effects of LIG on oxidative stress were examined using fluorescent probes dihydroethidium (DHE) and dichlorodihydrofluorescein diacetate (DCFH-DA), TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry. Additionally, the influence of LIG on mitochondrial morphology and function was evaluated through transmission electron microscopy (TEM), Mito Tracker Red CMXRos staining, adenosine triphosphate (ATP) concentration assays, and JC-1 staining. The potential mechanism involving LIG and Sirt3 was explored by manipulating Sirt3 expression through cell transfection.
    RESULTS: The results showed that LIG could provide protective function for mitochondria to alleviate oxidative stress induced by renal I/R. Further mechanistic studies indicated that LIG maintained mitochondrial homeostasis by targeting Sirt3.
    CONCLUSION: Our findings demonstrated that LIG alleviated oxidative stress during renal I/R injury through maintaining Sirt3-dependent mitochondrial homeostasis. Overall, our data raised the possibility of LIG as a novel therapy for renal I/R injury.
    Keywords:  Ligustilide; Mitochondrial homeostasis; Oxidative stress; Renal ischemia-reperfusion injury; Sirt3
    DOI:  https://doi.org/10.1016/j.phymed.2024.155975
  38. J Nanobiotechnology. 2024 Sep 06. 22(1): 549
    Apoptotic metabolites ameliorate bone aging phenotypes via TCOF1/FLVCR1-mediated mitochondrial homeostasis.
    Yan Qu, Bowen Meng, Simin Cai, Benyi Yang, Yifan He, Chaoran Fu, Xiangxia Li, Peiyi Li, Zeyuan Cao, Xueli Mao, Wei Teng, Songtao Shi.
      Over 50 billion cells undergo apoptosis each day in an adult human to maintain tissue homeostasis by eliminating damaged or unwanted cells. Apoptotic deficiency can lead to age-related diseases with reduced apoptotic metabolites. However, whether apoptotic metabolism regulates aging is unclear. Here, we show that aging mice and apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) mice exhibit decreased apoptotic levels along with increased aging phenotypes in the skeletal bones, which can be rescued by the treatment with apoptosis inducer staurosporine (STS) and stem cell-derived apoptotic vesicles (apoVs). Moreover, embryonic stem cells (ESC)-apoVs can significantly reduce senescent hallmarks and mtDNA leakage to rejuvenate aging bone marrow mesenchymal stem cells (MSCs) and ameliorate senile osteoporosis when compared to MSC-apoVs. Mechanistically, ESC-apoVs use TCOF1 to upregulate mitochondrial protein transcription, resulting in FLVCR1-mediated mitochondrial functional homeostasis. Taken together, this study reveals a previously unknown role of apoptotic metabolites in ameliorating bone aging phenotypes and the unique role of TCOF1/FLVCR1 in maintaining mitochondrial homeostasis.
    Keywords:  Apoptosis; Apoptotic vesicles; Mitochondrial homeostasis; Senile osteoporosis
    DOI:  https://doi.org/10.1186/s12951-024-02820-x
  39. J Lipid Res. 2024 Sep 03. pii: S0022-2275(24)00144-5. [Epub ahead of print] 100639
    Dysregulation of mitochondrial dynamics and mitophagy are involved in High-fat diet-induced steroidogenesis inhibition.
    Zheng-Mei Lv, Chao Liu, Ping Wang, Yuan-Hua Chen.
      Male obesity is a pandemic health issue and can disrupt testicular steroidogenesis. Here, we explored the mechanism by which High-fat diet (HFD)-induced steroidogenic inhibition. As expected, HFD induced lipid droplet accumulation and reduced the expression of StAR, P450scc, and 3β-HSD, three steroidogenic enzymes, in mouse testes. Palmitic acid (PA), a saturated fatty acid is usually used to trigger lipotoxicity in vitro, induced greater accumulation of lipid droplets and the downregulation of steroidogenic enzymes in TM3 cells. Mechanistically, both HFD and PA disturbed mitochondrial fusion/fission dynamics, and then induced mitochondrial dysfunction and mitophagy inhibition in mouse Leydig cells. Additionally, mitochondrial fusion promoter M1 attenuated PA-induced imbalance of mitochondrial dynamics, mitophagy inhibition, mitochondrial reactive oxygen species (ROS) production and mitochondrial dysfunction in TM3 cells. Mitofusin 2 (MFN2) knock-down further aggravated PA-induced imbalance of mitochondrial dynamics, mitochondrial ROS production and mitochondrial dysfunction in TM3 cells. Importantly, M1 rescued PA-induced downregulation of steroidogenic enzymes, whereas MFN2 knock-down further aggravated PA-induced downregulation of steroidogenic enzymes in TM3 cells. Overall, our results provide laboratory evidence that mitochondrial dysfunction and mitophagy inhibition caused by dysregulation of mitochondrial fusion may be involved in HFD-induced steroidogenesis inhibition in mouse Leydig cells.
    Keywords:  High-fat diet; mitochondrial dynamics; mitophagy; palmitic acid; steroidogenesis
    DOI:  https://doi.org/10.1016/j.jlr.2024.100639
  40. J Biol Chem. 2024 Sep 05. pii: S0021-9258(24)02216-6. [Epub ahead of print]300(9): 107715
    Correction: Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress.
    Qian Sun, Wentao Gao, Patricia Loughran, Rick Shapiro, Jie Fan, Timothy R Billiar, Melanie J Scott.
      
    DOI:  https://doi.org/10.1016/j.jbc.2024.107715
  41. J Nanobiotechnology. 2024 Sep 05. 22(1): 543
    Young small extracellular vesicles rejuvenate replicative senescence by remodeling Drp1 translocation-mediated mitochondrial dynamics.
    Yingying Peng, Tingting Zhao, Shuxuan Rong, Shuqing Yang, Wei Teng, Yunyi Xie, Yan Wang.
      BACKGROUND: Human mesenchymal stem cells have attracted interest in regenerative medicine and are being tested in many clinical trials. In vitro expansion is necessary to provide clinical-grade quantities of mesenchymal stem cells; however, it has been reported to cause replicative senescence and undefined dysfunction in mesenchymal stem cells. Quality control assessments of in vitro expansion have rarely been addressed in ongoing trials. Young small extracellular vesicles from the remnant pulp of human exfoliated deciduous teeth stem cells have demonstrated therapeutic potential for diverse diseases. However, it is still unclear whether young small extracellular vesicles can reverse senescence-related declines.RESULTS: We demonstrated that mitochondrial structural disruption precedes cellular dysfunction during bone marrow-derived mesenchymal stem cell replication, indicating mitochondrial parameters as quality assessment indicators of mesenchymal stem cells. Dynamin-related protein 1-mediated mitochondrial dynamism is an upstream regulator of replicative senescence-induced dysfunction in bone marrow-derived mesenchymal stem cells. We observed that the application of young small extracellular vesicles could rescue the pluripotency dissolution, immunoregulatory capacities, and therapeutic effects of replicative senescent bone marrow-derived mesenchymal stem cells. Mechanistically, young small extracellular vesicles could promote Dynamin-related protein 1 translocation from the cytoplasm to the mitochondria and remodel mitochondrial disruption during replication history.
    CONCLUSIONS: Our findings show that Dynamin-related protein 1-mediated mitochondrial disruption is associated with the replication history of bone marrow-derived mesenchymal stem cells. Young small extracellular vesicles from human exfoliated deciduous teeth stem cells alleviate replicative senescence by promoting Dynamin-related protein 1 translocation onto the mitochondria, providing evidence for a potential rejuvenation strategy.
    Keywords:  Mesenchymal stem cell; Mitochondrial dynamics; Replicative senescence; Small extracellular vesicles; Stem cells from the remnant pulp of human exfoliated deciduous teeth (SHED)
    DOI:  https://doi.org/10.1186/s12951-024-02818-5
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