bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024‒01‒21
23 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Homocysteine and mitochondrial quality control in diabetic retinopathy.
  2. Interaction of PINK1 with nucleotides and kinetin.
  3. G-quadruplex in mitochondria as a possible biomarker for mitophagy detection.
  4. Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.
  5. Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
  6. Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
  7. Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer.
  8. Mitophagy in hypertension-mediated organ damage.
  9. USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
  10. Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.
  11. NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
  12. Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.
  13. Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.
  14. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.
  15. In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
  16. Conjugated Linoleic Acid Ameliorates Hydrogen Peroxide-Induced Mitophagy and Inflammation via the DRP1-mtDNA-STING Pathway in Bovine Hepatocytes.
  17. Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma.
  18. Using MitER for 3D analysis of mitochondrial morphology and ER contacts.
  19. Effects of environmental hypoxia on the goldfish skeletal muscle: Focus on oxidative status and mitochondrial dynamics.
  20. Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.
  21. Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.
  22. The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro.
  23. Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal.
  1. Eye Vis (Lond). 2024 Jan 16. 11(1): 5
    Homocysteine and mitochondrial quality control in diabetic retinopathy.
    Pooja Malaviya, Renu A Kowluru.
      BACKGROUND: Diabetic retinopathy is a progressive disease, and one of the key metabolic abnormalities in the pathogenesis of diabetic retinopathy, mitochondrial damage, is also influenced by the duration of hyperglycemia. Mitochondrial quality control involves a coordination of mitochondrial dynamics, biogenesis and removal of the damaged mitochondria. In diabetes, these processes are impaired, and the damaged mitochondria continue to produce free radicals. Diabetic patients also have high homocysteine and reduced levels of hydrogen sulfide, and hyperhomocysteinemia is shown to exacerbate diabetes-induced mitochondrial damage and worsen their dynamics. This study aims to investigate the temporal relationship between hyperhomocysteinemia and retinal mitochondrial quality control in diabetic retinopathy.METHODS: Human retinal endothelial cells incubated in 20 mM D-glucose for 24 to 96 h, in the absence or presence of 100 µM homocysteine, with/without a hydrogen sulfide donor GYY4137, were analyzed for mitochondrial ROS (MitoSox fluorescence), DNA damage (transcripts of mtDNA-encoded ND6 and CytB), copy numbers, oxygen consumption rate (Seahorse XF analyzer) and mitophagy (mitophagosomes immunofluorescence labeling and flow cytometry). Results were confirmed in the retina from mice genetically manipulated for hyperhomocysteinemia (cystathionine β-synthase deficient mice, Cbs+/-), streptozotocin-induced diabetic for 8 to 24 weeks. At 24 weeks of diabetes, vascular health was evaluated by counting acellular capillaries in the trypsin digested retinal vasculature and by fluorescein angiography.
    RESULTS: Homocysteine, in high glucose medium, exacerbated mitochondrial ROS production, mtDNA damage and impaired mitochondrial respiration within 24 h, and slowed down/worsened mitochondrial biogenesis and mitophagy, as compared to 48 to 96 h in high glucose alone. GYY4137 supplementation ameliorated homocysteine + high glucose-induced mitochondrial damage and impairment in biogenesis and mitophagy. Similar results were obtained from Cbs+/- mice-mitochondrial ROS, mtDNA damage and decline in biogenesis and mitophagy were observed within eight weeks of diabetes vs. 16 to 24 weeks of diabetes in Cbs+/+ mice, and at 24 weeks of diabetes, Cbs+/- mice had significantly higher acellular capillaries and vascular leakage.
    CONCLUSIONS: Hyperhomocysteinemia, in a hyperglycemic environment, overwhelms the mitochondria, accelerating and exacerbating their dysfunction, and also delays/worsens their removal, augmenting the development of diabetic retinopathy. Thus, our results strengthen the importance of maintaining homocysteine-hydrogen sulfide balance during the early stages of diabetes for a patient to prevent/retard vision loss.
    Keywords:  Diabetic retinopathy; Homocysteine; Hydrogen sulfide; Mitochondria; Mitophagy; Retina
    DOI:  https://doi.org/10.1186/s40662-023-00362-1
  2. Sci Adv. 2024 Jan 19. 10(3): eadj7408
    Interaction of PINK1 with nucleotides and kinetin.
    Zhong Yan Gan, Sylvie Callegari, Thanh N Nguyen, Nicholas S Kirk, Andrew Leis, Michael Lazarou, Grant Dewson, David Komander.
      The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin triphosphate (KTP) were reported to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson's disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the dodecamer assembly of Pediculus humanus corporis (Ph) PINK1 and determine PINK1 structures bound to AMP-PNP and ADP, revealing conformational changes in the kinase N-lobe that help establish PINK1's ubiquitin binding site. Notably, we find that KTP is unable to bind PhPINK1 or human (Hs) PINK1 due to a steric clash with the kinase "gatekeeper" methionine residue, and mutation to Ala or Gly is required for PINK1 to bind and use KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. HsPINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.adj7408
  3. Int J Biol Macromol. 2024 Jan 11. pii: S0141-8130(24)00140-5. [Epub ahead of print]259(Pt 2): 129337
    G-quadruplex in mitochondria as a possible biomarker for mitophagy detection.
    Boyang Zhang, Ranran Sun, Ruiyang Bai, Zhicheng Sun, Ruping Liu, Wenchao Li, Li Yao, Hongxia Sun, Yalin Tang.
      Mitochondrial autophagy (mitophagy) is a key physiological process that maintains the homeostasis of mitochondrial quality and quantity. Monitoring mitophagy is of great significance for detecting cellular abnormalities and developing therapeutic drugs. However, there are still very few biomarkers specifically developed for monitoring mitophagy. Here, we propose for the first time that mitochondrial G-quadruplex may serve as a biomarker for mitophagy detection, and develope a fluorescent light-up probe AMTC to monitor mitophagy in live cells. During mitophagy, AMTC fluorescence is significantly enhanced, but once mitophagy is inhibited, its fluorescence immediately decreases. The fluorescence behavior of AMTC implicates an increase in the formation of mitochondrial G-quadruplex during mitophagy. This inference has also been supported by the other two G-quadruplex probes. Taken together, this work provides a new possible biomarker and detection tool for the study of mitophagy.
    Keywords:  Biomarker; Mitochondrial G-quadruplex; Mitophagy monitoring
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129337
  4. Pharmacol Res. 2024 Jan 14. pii: S1043-6618(23)00412-7. [Epub ahead of print] 107056
    Low-dose Olaparib improves septic cardiac function by reducing ferroptosis via accelerated mitophagy flux.
    Ruixue Liu, Fengjuan Li, Shuai Hao, Dongyao Hou, Xue Zeng, He Huang, Gautam Sethi, Jun Guo, Chenyang Duan.
      Sepsis is a dysregulated response to infection that can result in life-threatening organ failure, and septic cardiomyopathy is a serious complication involving ferroptosis. Olaparib, a classic targeted drug used in oncology, has demonstrated potential protective effects against sepsis. However, the exact mechanisms underlying its action remain to be elucidated. In our study, we meticulously screened ferroptosis genes associated with sepsis, and conducted comprehensive functional enrichment analyses to delineate the relationship between ferroptosis and mitochondrial damage. Eight sepsis-characterized ferroptosis genes were identified in sepsis patients, including DPP4, LPIN1, PGD, HP, MAPK14, POR, GCLM, and SLC38A1, which were significantly correlated with mitochondrial quality imbalance. Utilizing DrugBank and molecular docking, we demonstrated a robust interaction of Olaparib with these genes. Lipopolysaccharide (LPS)-stimulated HL-1 cells and monocytes were used to establish an in vitro sepsis model. Additionally, an in vivo model was developed using mice subjected to cecal ligation and perforation (CLP). Intriguingly, low-dose Olaparib (5mg/kg) effectively targeted and mitigated markers associated with ferroptosis, concurrently improving mitochondrial quality. This led to a marked enhancement in cardiac function and a significant increase in survival rates in septic mice (p < 0.05). The mechanism through which Olaparib ameliorates ferroptosis in cardiac and leukocyte cells post-sepsis is attributed to its facilitation of mitophagy, thus favoring mitochondrial integrity. In conclusion, our findings suggest that low-dose Olaparib can improve mitochondrial quality by accelerating mitophagy flux, consequently inhibiting ferroptosis and preserving cardiac function after sepsis.
    Keywords:  Olaparib; cardiac function; ferroptosis; mitophagy; sepsis
    DOI:  https://doi.org/10.1016/j.phrs.2023.107056
  5. Cell Death Differ. 2024 Jan 18.
    Activation of Ca2+ phosphatase Calcineurin regulates Parkin translocation to mitochondria and mitophagy in flies.
    Elena Marchesan, Alice Nardin, Sofia Mauri, Greta Bernardo, Vivek Chander, Simone Di Paola, Monica Chinellato, Sophia von Stockum, Joy Chakraborty, Stephanie Herkenne, Valentina Basso, Emilie Schrepfer, Oriano Marin, Laura Cendron, Diego L Medina, Luca Scorrano, Elena Ziviani.
      Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.
    DOI:  https://doi.org/10.1038/s41418-023-01251-9
  6. Cell Death Dis. 2024 Jan 15. 15(1): 51
    Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury.
    Ari Kwon, Na Young Lee, Jae-Hyun Yu, Myeung Gi Choi, Jeongwoo Park, Ja Hyun Koo.
      Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.
    DOI:  https://doi.org/10.1038/s41419-024-06448-5
  7. Cell Death Dis. 2024 Jan 17. 15(1): 65
    Phosphorylation of INF2 by AMPK promotes mitochondrial fission and oncogenic function in endometrial cancer.
    Yan Ding, Zeheng Lv, Wenxin Cao, Wenming Shi, Qizhi He, Kun Gao.
      Mitochondria are highly dynamic organelles capable of altering their sizes and shapes to maintain metabolic balance through coordinated fission and fusion processes. In various cancer types, mitochondrial hyperfragmentation has been frequently observed, contributing to the progression of cancer toward metastasis. Inverted formin 2 (INF2), which resides in the endoplasmic reticulum (ER), has been found to accelerate actin polymerization and drive mitochondrial fission. In this study, we demonstrate that INF2 expression is significantly upregulated in endometrial cancer (EC) and is associated with a poor prognosis in EC patients. INF2 promotes anchorage-dependent and independent EC cell growth in part by facilitating mitochondrial fission. Furthermore, in conditions of energy stress, AMP-activated protein kinase (AMPK) phosphorylates INF2 at Ser1077, leading to increased localization of INF2 to the ER and enhanced recruitment of the dynamin-related protein 1 (DRP1) to mitochondria. This AMPK-mediated phosphorylation of INF2 at Ser1077 facilitates mitochondrial division and promotes EC cell growth. Pathological examination using immunohistochemical analyses revealed a positive correlation between AMPK activity and phosphorylated INF2 (Ser1077) in EC specimens. Collectively, our findings uncover novel molecular mechanisms involving the AMPK-INF2 axis, which regulates mitochondrial dynamics and malignant cell growth in EC.
    DOI:  https://doi.org/10.1038/s41419-024-06431-0
  8. Front Cardiovasc Med. 2023 ;10 1309863
    Mitophagy in hypertension-mediated organ damage.
    Yulong Ma, Xunjie Zhou, Mingtai Gui, Lei Yao, Jianhua Li, Xiaozhe Chen, Mingzhu Wang, Bo Lu, Deyu Fu.
      Hypertension constitutes a pervasive chronic ailment on a global scale, frequently inflicting damage upon vital organs, such as the heart, blood vessels, kidneys, brain, and others. And this is a complex clinical dilemma that requires immediate attention. The mitochondria assume a crucial function in the generation of energy, and it is of utmost importance to eliminate any malfunctioning or surplus mitochondria to uphold intracellular homeostasis. Mitophagy is considered a classic example of selective autophagy, an important component of mitochondrial quality control, and is closely associated with many physiological and pathological processes. The ubiquitin-dependent pathway, facilitated by PINK1/Parkin, along with the ubiquitin-independent pathway, orchestrated by receptor proteins such as BNIP3, NIX, and FUNDC1, represent the extensively investigated mechanisms underlying mitophagy. In recent years, research has increasingly shown that mitophagy plays an important role in organ damage associated with hypertension. Exploring the molecular mechanisms of mitophagy in hypertension-mediated organ damage could represent a critical avenue for future research in the development of innovative therapeutic modalities. Therefore, this article provides a comprehensive review of the impact of mitophagy on organ damage due to hypertension.
    Keywords:  hypertension; mitochondria; mitochondrial quality control; mitophagy; organ damage
    DOI:  https://doi.org/10.3389/fcvm.2023.1309863
  9. Cell Death Dis. 2024 Jan 15. 15(1): 52
    USP30 inhibition induces mitophagy and reduces oxidative stress in parkin-deficient human neurons.
    Justyna Okarmus, Jette Bach Agergaard, Tina C Stummann, Henriette Haukedal, Malene Ambjørn, Kristine K Freude, Karina Fog, Morten Meyer.
      Ubiquitination of mitochondrial proteins plays an important role in the cellular regulation of mitophagy. The E3 ubiquitin ligase parkin (encoded by PARK2) and the ubiquitin-specific protease 30 (USP30) have both been reported to regulate the ubiquitination of outer mitochondrial proteins and thereby mitophagy. Loss of E3 ligase activity is thought to be pathogenic in both sporadic and inherited Parkinson's disease (PD), with loss-of-function mutations in PARK2 being the most frequent cause of autosomal recessive PD. The aim of the present study was to evaluate whether mitophagy induced by USP30 inhibition provides a functional rescue in isogenic human induced pluripotent stem cell-derived dopaminergic neurons with and without PARK2 knockout (KO). Our data show that healthy neurons responded to CCCP-induced mitochondrial damage by clearing the impaired mitochondria and that this process was accelerated by USP30 inhibition. Parkin-deficient neurons showed an impaired mitophagic response to the CCCP challenge, although mitochondrial ubiquitination was enhanced. USP30 inhibition promoted mitophagy in PARK2 KO neurons, independently of whether left in basal conditions or treated with CCCP. In PARK2 KO, as in control neurons, USP30 inhibition balanced oxidative stress levels by reducing excessive production of reactive oxygen species. Interestingly, non-dopaminergic neurons were the main driver of the beneficial effects of USP30 inhibition. Our findings demonstrate that USP30 inhibition is a promising approach to boost mitophagy and improve cellular health, also in parkin-deficient cells, and support the potential relevance of USP30 inhibitors as a novel therapeutic approach in diseases with a need to combat neuronal stress mediated by impaired mitochondria.
    DOI:  https://doi.org/10.1038/s41419-024-06439-6
  10. Open Biol. 2024 Jan;14(1): 230279
    Significance of quantitative analyses of the impact of heterogeneity in mitochondrial content and shape on cell differentiation.
    Swati Agarwala, Sukhamoy Dhabal, Kasturi Mitra.
      Mitochondria, classically known as the powerhouse of cells, are unique double membrane-bound multifaceted organelles carrying a genome. Mitochondrial content varies between cell types and precisely doubles within cells during each proliferating cycle. Mitochondrial content also increases to a variable degree during cell differentiation triggered after exit from the proliferating cycle. The mitochondrial content is primarily maintained by the regulation of mitochondrial biogenesis, while damaged mitochondria are eliminated from the cells by mitophagy. In any cell with a given mitochondrial content, the steady-state mitochondrial number and shape are determined by a balance between mitochondrial fission and fusion processes. The increase in mitochondrial content and alteration in mitochondrial fission and fusion are causatively linked with the process of differentiation. Here, we critically review the quantitative aspects in the detection methods of mitochondrial content and shape. Thereafter, we quantitatively link these mitochondrial properties in differentiating cells and highlight the implications of such quantitative link on stem cell functionality. Finally, we discuss an example of cell size regulation predicted from quantitative analysis of mitochondrial shape and content. To highlight the significance of quantitative analyses of these mitochondrial properties, we propose three independent rationale based hypotheses and the relevant experimental designs to test them.
    Keywords:  cell differentiation; cell proliferation; mitochondrial content; mitochondrial heterogeneity; mitochondrial shape; stem cells
    DOI:  https://doi.org/10.1098/rsob.230279
  11. J Cell Biochem. 2024 Jan 15.
    NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
    Bin Ye, Yingting Pei, Lujing Wang, Dehao Meng, Yu Zhang, Shuang Zou, Henian Li, Jinying Liu, Ziying Xie, Changhong Tian, Yuqi Jiang, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma.
      Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.
    Keywords:  SASP; cGAS-STING; mitochondria; nicotinamide mononucleotide; senescence
    DOI:  https://doi.org/10.1002/jcb.30522
  12. Cell Signal. 2024 Jan 17. pii: S0898-6568(24)00029-9. [Epub ahead of print] 111061
    Loss of the WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain.
    Chatrawee Duangjan, Ronald W Irwin, Sean P Curran.
      Mitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of several nuclear coded mitochondrial resident proteins in the brain. Wdr23KO also increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which have established roles in mediating mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain.
    Keywords:  Complex I; Homeostasis; Mitochondria; Wdr23; hippocampus
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111061
  13. J Ethnopharmacol. 2024 Jan 16. pii: S0378-8741(24)00034-5. [Epub ahead of print] 117734
    Fangji Huangqi decoction ameliorates membranous nephropathy through the upregulation of BNIP3-mediated mitophagy.
    Yuxin Wang, Yuhua Ma, Yanrong Ke, Xiaocheng Jiang, Jian Liu, Yang Xiao, Hong Zheng, Chaojun Wang, Xue Chen, Manman Shi.
      ETHNOPHARMACOLOGICAL RELEVANCE: Fangji Huangqi Decoction (FJHQ), a traditional Chinese medicinal formula outlined in Zhang Zhongjing's "Jin Gui Yao Lue" during the Han Dynasty, is often used to treat conditions characterized by symptoms like edema and dysuria, including membranous nephropathy (MN). Despite its proven clinical effectiveness, the exact mechanisms through which FJHQ acts on MN remain elusive.AIM OF THE STUDY: This study aimed to investigate whether FJHQ enhances BNIP3-mediated mitophagy in podocytes by promoting BNIP3 expression and whether this improvement leads to the amelioration of MN.
    MATERIALS AND METHODS: In this study, by establishing passive Heyman nephritis (PHN) rats, an experimental rat model of MN induced by sheep anti-rat Fx1A serum, we evaluated the effects of FJHQ in vivo. In vitro experiments were carried out by treating primary podocytes with experimental rat serum. Furthermore, the potential mechanism by which FJHQ acts through BNIP3 was further examined by transfecting primary podocytes with the siRNA of BNIP3 or the corresponding control vector.
    RESULTS: After 4 weeks, significant kidney damage was observed in the rats in the model group, comparatively, FJHQ markedly decreased urine volume, 24-h urinary protein, blood urea nitrogen (BUN), creatinine (Scr), and increased serum total albumin (ALB). Histology showed that FJHQ caused significant improvements in glomerular hyperplasia, and IgG immune complex deposition in MN rats. JC-1 fluorescence labelling and flow cytometry analysis showed that FJHQ could significantly increase mitochondrial membrane potential in vivo. In the mitochondria of MN model rats, FJHQ was able to down-regulate the expression of P62 and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I, according to Western blot and immunofluorescence studies. Furthermore, FJHQ has been shown to significantly up-regulate mitochondrial membrane potential, down-regulate P62 expression in mitochondria, and up-regulate the expression of BNIP3, LC3B, and LC3 II/LC3 I in mitochondria at the cellular level. After the administration of the autophagy inhibitor chloroquine, the serum of rats treated with FJHQ further increased the expression of LC3 II/LC3 I in primary podocytes, showing higher autophagy flow. After the interference of BNIP3 in podocytes, the effect of FJHQ on mitochondrial membrane potential and autophagy-related proteins almost disappeared.
    CONCLUSION: FJHQ enhanced mitophagy in podocytes by promoting the expression of BNIP3, thereby contributing to the amelioration of MN. This work reveals the possible underlying mechanism by which FJHQ improves MN and provides a new avenue for MN treatment.
    Keywords:  BNIP3; Fangji Huangqi decoction; Membranous nephropathy; Mitophagy; Podocyte
    DOI:  https://doi.org/10.1016/j.jep.2024.117734
  14. bioRxiv. 2023 Dec 29. pii: 2023.12.29.573615. [Epub ahead of print]
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Mfn2 and Opa1.
    Sivakumar Boopathy, Camila Makhlouta Lugo, Bridget E Luce, Julie L McDonald, Pusparanee Hakim, Jackeline Ponce, Beatrix 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 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-Opa1-Mfn1/2 complex. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and the helical repeat 1 region of Mfn2 interacts with the SLC25A46 N-terminus. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    DOI:  https://doi.org/10.1101/2023.12.29.573615
  15. EMBO J. 2024 Jan 15.
    In situ architecture of Opa1-dependent mitochondrial cristae remodeling.
    Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao.
      Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.
    Keywords:  Cristae Remodeling; Cryo-Electron Tomography; Cryo-Focused Ion Beam Milling; Mitochondrial Biology
    DOI:  https://doi.org/10.1038/s44318-024-00027-2
  16. J Agric Food Chem. 2024 Jan 18.
    Conjugated Linoleic Acid Ameliorates Hydrogen Peroxide-Induced Mitophagy and Inflammation via the DRP1-mtDNA-STING Pathway in Bovine Hepatocytes.
    Wan Xie, Huimin Shi, Rankun Zuo, Shendong Zhou, Nana Ma, Hongzhu Zhang, Guangjun Chang, Xiangzhen Shen.
      Oxidative stress is tightly associated with liver dysfunction and injury in dairy cows. Previous studies have shown that cis-9, trans-11 conjugated linoleic acid (CLA) possesses anti-inflammatory and antioxidative abilities. In this study, the bovine hepatocytes were pretreated with CLA for 6 h, followed by treatment with hydrogen peroxide (H2O2) for another 6 h to investigate the antioxidative effect of CLA and uncover the underlying mechanisms. The results demonstrated that H2O2 treatment elevated the level of mitophagy, promoted mitochondrial DNA (mtDNA) leakage into the cytosol, and activated the stimulator of interferon genes (STING)/nuclear factor kappa B (NF-κB) signaling pathway to trigger an inflammatory response in bovine hepatocytes. In addition, the dynamin-related protein 1(DRP1)-mtDNA-STING-NF-κB axis contributed to the H2O2-induced oxidative injury of bovine hepatocytes. CLA could reduce mitophagy and the inflammatory response to attenuate oxidative damage via the DRP1/mtDNA/STING pathway in bovine hepatocytes. These findings offer a theoretical foundation for the hepatoprotective effect of CLA against oxidative injury in dairy cows.
    Keywords:  DRP1; STING; conjugated linoleic acid; mtDNA; oxidative injury
    DOI:  https://doi.org/10.1021/acs.jafc.3c02755
  17. Cancer Lett. 2024 Jan 17. pii: S0304-3835(24)00015-6. [Epub ahead of print] 216621
    Icaritin with autophagy/mitophagy inhibitors synergistically enhances anticancer efficacy and apoptotic effects through PINK1/Parkin-mediated mitophagy in hepatocellular carcinoma.
    Piao Luo, Yehai An, Jingqian He, Xuefeng Xing, Qian Zhang, Xueying Liu, Yu Chen, Haitao Yuan, Junhui Chen, Yin-Kwan Wong, Jingnan Huang, Zipeng Gong, Qingfeng Du, Wei Xiao, Jigang Wang.
      Hepatocellular carcinoma (HCC) is among the deadliest malignancies worldwide and still a pressing clinical problem. Icaritin, a natural compound obtained from the Epimedium genus plant, has garnered significant attention as a potential therapeutic drug for HCC therapies. Mitophagy plays a crucial role in mitochondrial quality control through efficiently eliminating damaged mitochondria. However, the specific mechanisms of the interplay between mitophagy and apoptosis in HCC is still unclear. We aimed to explore the cross-talk between icaritin-induced mitophagy and apoptosis in HCC cells and investigate its potential mechanisms. Firstly, we confirmed that icaritin inhibits proliferation and migration while inducing mitochondrial damage and reactive oxygen species (ROS) production in HCC cells. Secondly, based on proteomics analysis, we discovered that icaritin inhibits the growth of tumor cells and disrupts their mitochondrial homeostasis through the regulation of both mitophagy and apoptosis. Thirdly, icaritin causes mitophagy mediated by PINK1-Parkin signaling via regulating feedforward loop. Furthermore, knockdown of PINK1/Parkin leads to inhibition of mitophagy, which promotes cell death induced by icaritin in HCC cells. Finally, autophagy/mitophagy inhibitors remarkably enhance icaritin-induced cell death and anticancer efficacy. Collectively, our findings reveal that icaritin suppresses growth, proliferation and migration of HCC cell through induction of mitophagy and apoptosis, while inhibition of mitophagy significantly increased the anti-cancer and pro-apoptotic effects of icaritin, indicating that targeting autophagy or mitophagy is a novel approach to overcome drug resistance and enhance anticancer therapies.
    Keywords:  Apoptosis; Hepatocellular carcinoma; Icaritin; Mitophagy; PINK1-Parkin
    DOI:  https://doi.org/10.1016/j.canlet.2024.216621
  18. Cell Rep Methods. 2024 Jan 11. pii: S2667-2375(23)00378-8. [Epub ahead of print] 100692
    Using MitER for 3D analysis of mitochondrial morphology and ER contacts.
    Therese Kichuk, Satyen Dhamankar, Saurabh Malani, William A Hofstadter, Scott A Wegner, Ileana M Cristea, José L Avalos.
      We have developed an open-source workflow that allows for quantitative single-cell analysis of organelle morphology, distribution, and inter-organelle contacts with an emphasis on the analysis of mitochondria and mitochondria-endoplasmic reticulum (mito-ER) contact sites. As the importance of inter-organelle contacts becomes more widely recognized, there is a concomitant increase in demand for tools to analyze subcellular architecture. Here, we describe a workflow we call MitER (pronounced "mightier"), which allows for automated calculation of organelle morphology, distribution, and inter-organelle contacts from 3D renderings by employing the animation software Blender. We then use MitER to quantify the variations in the mito-ER networks of Saccharomyces cerevisiae, revealing significantly more mito-ER contacts within respiring cells compared to fermenting cells. We then demonstrate how this workflow can be applied to mammalian systems and used to monitor mitochondrial dynamics and inter-organelle contact in time-lapse studies.
    Keywords:  CP: Imaging; Saccharomyces cerevisea; image analysis; imaging; inter-organelle contact; mitochondrial-ER contact; organelle distribution; organelle morphology
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100692
  19. J Contam Hydrol. 2024 Jan 12. pii: S0169-7722(24)00003-2. [Epub ahead of print]261 104299
    Effects of environmental hypoxia on the goldfish skeletal muscle: Focus on oxidative status and mitochondrial dynamics.
    Mariacristina Filice, Alessia Caferro, Alfonsina Gattuso, Emilio Sperone, Claudio Agnisola, Caterina Faggio, Maria Carmela Cerra, Sandra Imbrogno.
      The skeletal muscle is a highly plastic tissue. Its ability to respond to external stimuli and challenges allows it to face the functional needs of the organism. In the goldfish Carassius auratus, a model of hypoxia resistance, exposure to reduced oxygen is accompanied by an improvement of the swimming performance, relying on a sustained contractile behavior of the skeletal muscle. At the moment, limited information is available on the mechanisms underlying these responses. We here evaluated the effects of short- (4 days) and long- (20 days) term exposure to moderate water hypoxia on the goldfish white skeletal muscle, focusing on oxidative status and mitochondrial dynamics. No differences in lipid peroxidation, measured as 2-thiobarbituric acid-reacting substances (TBARS), and oxidatively modified proteins (OMP) were detected in animals exposed to hypoxia with respect to their normoxic counterparts. Exposure to short-term hypoxia was characterized by an enhanced SOD activity and expression, paralleled by increased levels of Nrf2, a regulator of the antioxidant cell response, and HSP70, a chaperone also acting as a redox sensor. The expression of markers of mitochondrial biogenesis (TFAM) and abundance (VDAC) and of the mtDNA/nDNA ratio was similar under normoxia and under both short- and long-term hypoxia, thus excluding a rearrangement of the mitochondrial apparatus. Only an increase of PGC1α (a transcription factor involved in mitochondrial dynamics) was detected after 20 days of hypoxia. Our results revealed novel aspects of the molecular mechanisms that in the goldfish skeletal muscle may sustain the response to hypoxia, thus contributing to adequate tissue function to organism requirements.
    Keywords:  HSP70; Mitochondria; Nrf2; Oxidative stress; SOD
    DOI:  https://doi.org/10.1016/j.jconhyd.2024.104299
  20. Cell Stress Chaperones. 2023 Nov;pii: S1355-8145(24)00026-9. [Epub ahead of print]28(6): 675-688
    Roles of mitochondrial dynamics and mitophagy in diabetic myocardial microvascular injury.
    Tong Wang, Xinwei Wang, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xiao Zhang, Hao Zhou, Xing Chang, Ying Tong.
      Myocardial microvessels are composed of a monolayer of endothelial cells, which play a crucial role in maintaining vascular barrier function, luminal latency, vascular tone, and myocardial perfusion. Endothelial dysfunction is a key factor in the development of cardiac microvascular injury and diabetic cardiomyopathy. In addition to their role in glucose oxidation and energy metabolism, mitochondria also participate in non-metabolic processes such as apoptosis, intracellular ion handling, and redox balancing. Mitochondrial dynamics and mitophagy are responsible for regulating the quality and quantity of mitochondria in response to hyperglycemia. However, these endogenous homeostatic mechanisms can both preserve and/or disrupt non-metabolic mitochondrial functions during diabetic endothelial damage and cardiac microvascular injury. This review provides an overview of the molecular features and regulatory mechanisms of mitochondrial dynamics and mitophagy. Furthermore, we summarize findings from various investigations that suggest abnormal mitochondrial dynamics and defective mitophagy contribute to the development of diabetic endothelial dysfunction and myocardial microvascular injury. Finally, we discuss different therapeutic strategies aimed at improving endothelial homeostasis and cardiac microvascular function through the enhancement of mitochondrial dynamics and mitophagy.
    Keywords:  Cardiac microvascular injury; Diabetes; Endothelial cells; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1007/s12192-023-01384-3
  21. Cancer Cell Int. 2024 Jan 18. 24(1): 38
    Stress granules affect the dual PI3K/mTOR inhibitor response by regulating the mitochondrial unfolded protein response.
    Nan Lin, Liankun Sun, Jiannan Chai, Hang Qi, Yuanxin Zhao, Jiaoyan Ma, Meihui Xia, Xiaoqing Hu.
      Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPRmt) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.
    DOI:  https://doi.org/10.1186/s12935-024-03210-x
  22. Leuk Lymphoma. 2024 Jan 16. 1-13
    The CIpP activator, TR-57, is highly effective as a single agent and in combination with venetoclax against CLL cells in vitro.
    Narjis Fatima, Yandong Shen, Kyle Crassini, Olivia Burling, Lauren Thurgood, Edwin J Iwanowicz, Henk Lang, Donald S Karanewsky, Richard I Christopherson, Stephen P Mulligan, O Giles Best.
      Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease.The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR).Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family.The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL.
    Keywords:  Chronic lymphocytic leukemia; ClpP (mitochondrial ATP-dependent Caseinolytic protease P subunit); TR-compounds; imipridone; tumor microenvironment; venetoclax
    DOI:  https://doi.org/10.1080/10428194.2023.2300055
  23. J Clin Invest. 2024 Jan 18. pii: e171995. [Epub ahead of print]
    Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal.
    Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang.
      Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity, dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
    Keywords:  Addiction; Mitochondria; Neurological disorders; Neuroscience; Therapeutics
    DOI:  https://doi.org/10.1172/JCI171995
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