bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2024‒02‒18
sixteen papers selected by
Omkar Joshi, Turku Bioscience
  1. Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
  2. Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
  3. Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
  4. The HRI branch of the integrated stress response selectively triggers mitophagy.
  5. The role of mitophagy in metabolic diseases and its exercise intervention.
  6. FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.
  7. Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
  8. Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.
  9. Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.
  10. Mitochondrial derived vesicle-carrying protein MIGA2 promotes copper-induced autophagosomes-lysosomes fusion by regulating ATG14.
  11. Effects of bursty synthesis in organelle biogenesis.
  12. BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
  13. Alpha-ketoglutaric acid attenuates oxidative stress and modulates mitochondrial dynamics and autophagy of spleen in a piglet model of lipopolysaccharide-induced sepsis.
  14. Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
  15. Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
  16. Pre-fusion motion state determines the heterogeneity of membrane fusion dynamics for large dense-core vesicles.
  1. Nat Commun. 2024 Feb 13. 15(1): 1328
    Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
    Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.
      Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.
    DOI:  https://doi.org/10.1038/s41467-024-45524-4
  2. Development. 2024 Feb 12. pii: dev.201732. [Epub ahead of print]
    Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.
    Bhavin Uttekar, Rahul Kumar Verma, Darshika Tomer, Richa Rikhy.
      Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1 depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2, and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2, and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1 depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation, and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.
    Keywords:   Drosophila ; APKC; Drp1; Epithelial polarity; Mitochondria; Opa1; ROS
    DOI:  https://doi.org/10.1242/dev.201732
  3. Nat Commun. 2024 Feb 10. 15(1): 1252
    Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
    Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.
      Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41467-024-45651-y
  4. Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]
    The HRI branch of the integrated stress response selectively triggers mitophagy.
    Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.
      To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.
    Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control
    DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
  5. Front Physiol. 2024 ;15 1339128
    The role of mitophagy in metabolic diseases and its exercise intervention.
    Shaokai Tang, Yuanwen Geng, Qinqin Lin.
      Mitochondria are energy factories that sustain life activities in the body, and their dysfunction can cause various metabolic diseases that threaten human health. Mitophagy, an essential intracellular mitochondrial quality control mechanism, can maintain cellular and metabolic homeostasis by removing damaged mitochondria and participating in developing metabolic diseases. Research has confirmed that exercise can regulate mitophagy levels, thereby exerting protective metabolic effects in metabolic diseases. This article reviews the role of mitophagy in metabolic diseases, the effects of exercise on mitophagy, and the potential mechanisms of exercise-regulated mitophagy intervention in metabolic diseases, providing new insights for future basic and clinical research on exercise interventions to prevent and treat metabolic diseases.
    Keywords:  exercise; exerkine; metabolic disease; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2024.1339128
  6. Redox Biol. 2024 Feb 09. pii: S2213-2317(24)00057-0. [Epub ahead of print]70 103081
    FBXL4 protects against HFpEF through Drp1-Mediated regulation of mitochondrial dynamics and the downstream SERCA2a.
    Miyesaier Abudureyimu, Xuanming Luo, Lingling Jiang, Xuejuan Jin, Cuizhen Pan, Wei Yu, Junbo Ge, Yingmei Zhang, Jun Ren.
      AIMS: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF.METHOD AND RESULTS: Adult mice were placed on a high fat diet plus l-NAME in drinking water ('two-hit' challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in 'two-hit' mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a 'double-damage' insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated 'double-damage'-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated 'two-hit' or 'double-damage'-induced changes in SERCA2a, phospholamban and mitochondrial injury.
    CONCLUSION: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.
    Keywords:  Drp1; FBXL4; HFpEF; Intracellular Ca(2+); Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.redox.2024.103081
  7. FEBS J. 2024 Feb 16.
    Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.
    Ilaria Goglia, Ewelina Węglarz-Tomczak, Claudio Gioia, Yanhua Liu, Assunta Virtuoso, Marcella Bonanomi, Daniela Gaglio, Noemi Salmistraro, Ciro De Luca, Michele Papa, Lilia Alberghina, Hans V Westerhoff, Anna Maria Colangelo.
      Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.
    Keywords:  NGF differentiation; computational modeling; metabolism; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1111/febs.17083
  8. Curr Neuropharmacol. 2024 Jan 31.
    Modulating Mitochondrial Dynamics Mitigates Cognitive Impairment in Rats with Myocardial Infarction.
    Kewarin Jinawong, Chanon Piamsiri, Nattayaporn Apaijai, Chayodom Maneechote, Busarin Arunsak, Wichwara Nawara, Chanisa Thonusin, Hiranya Pintana, Nipon Chattipakorn, Siriporn C Chattipakorn.
      BACKGROUND: We have previously demonstrated that oxidative stress and brain mitochondrial dysfunction are key mediators of brain pathology during myocardial infarction (MI). <P> Objective: To investigate the beneficial effects of mitochondrial dynamic modulators, including mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promotor (M1), on cognitive function and molecular signaling in the brain of MI rats in comparison with the effect of enalapril.METHODS: Male rats were assigned to either sham or MI operation. In the MI group, rats with an ejection Fraction less than 50% were included, and then they received one of the following treatments for 5 weeks: vehicle, enalapril, Mdivi-1, or M1. Cognitive function was tested, and the brains were used for molecular study. <P> Results: MI rats exhibited cardiac dysfunction with systemic oxidative stress. Cognitive impairment was found in MI rats, along with dendritic spine loss, blood-brain barrier (BBB) breakdown, brain mitochondrial dysfunction, and decreased mitochondrial and increased glycolysis metabolism, without the alteration of APP, BACE-1, Tau and p-Tau proteins. Treatment with Mdivi-1, M1, and enalapril equally improved cognitive function in MI rats. All treatments decreased dendritic spine loss, brain mitochondrial oxidative stress, and restored mitochondrial metabolism. Brain mitochondrial fusion was recovered only in the Mdivi-1-treated group. <P> Conclusion: Mitochondrial dynamics modulators improved cognitive function in MI rats through a reduction of systemic oxidative stress and brain mitochondrial dysfunction and the enhancement of mitochondrial metabolism. In addition, this mitochondrial fission inhibitor increased mitochondrial fusion in MI rats.
    Keywords:  Myocardial infarction; brain metabolism; cognitive impairment; mitochondrial dysfunction.; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.2174/1570159X22666240131114913
  9. Cancer Immunol Immunother. 2024 Feb 10. 73(2): 40
    Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.
    Jietao Ma, Jun Song, Xiaofang Yi, Shuling Zhang, Li Sun, Letian Huang, Chengbo Han.
      BACKGROUND: Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells.METHODS: We investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model.
    RESULTS: High expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells.
    CONCLUSIONS: Our findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.
    Keywords:  Dynamin-related protein 1; Immunotherapy; Lung cancer; Programmed cell death protein 1; T cells
    DOI:  https://doi.org/10.1007/s00262-023-03582-5
  10. J Hazard Mater. 2024 Feb 04. pii: S0304-3894(24)00282-6. [Epub ahead of print]467 133703
    Mitochondrial derived vesicle-carrying protein MIGA2 promotes copper-induced autophagosomes-lysosomes fusion by regulating ATG14.
    Quanwei Li, Pan Guo, Shaofeng Wang, Yuanhong Feng, Hui Zhang, Wenlan Yu, Jianzhao Liao, Zhaoxin Tang.
      As an environmental pollution metal, copper (Cu) exposure-induced toxicity is closely related to mitochondrial damage. Mitochondrial-derived vesicles (MDVs) plays an essential role in mitochondrial quality control and cellular metabolism. However, the mechanism by which MDVs are involved in cellular metabolism under Cu exposure remains unclear. Here, the MDV-carrying protein MIGA2 was identified as a crucial molecule involved in the Cu-induced autophagosomes-lysosomes fusion. Furthermore, Cu exposure significantly promoted MDVs secretion, accompanied by a markedly increased MIGA2 expression in MDVs, as well as accelerated the autophagosomes-lysosomes fusion. However, small RNA interference of SNX9 (the MDVs secretion inductor) and MIGA2 blocked autophagic flux induced by Cu, leading to failure of autophagosomes degradation. Co-immunoprecipitation assay further demonstrated that ATG14 was a regulation target protein of MIGA2. Overexpression and knockdown of ATG14 significantly affected the autophagosomes-lysosomes fusion induced by Cu. Meanwhile, knockdown of ATG14 dramatically reversed the effect of MIGA2-overexpression in promoting autophagosomes-lysosomes fusion, while overexpression of ATG14 shows the opposite effect. These results demonstrated that MDVs-carrying MIGA2 protein promoted autophagosomes-lysosomes fusion induced by Cu. This study demonstrated that MDVs is involved in regulating organelles-to-organelles communication, providing a new insight into the toxicity mechanism of Cu exposure on hepatocytes.
    Keywords:  ATG14; Autophagosome-lysosome fusion; Copper; Hepatocytes; MIGA2; Mitochondria-derived vesicles
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.133703
  11. Math Biosci. 2024 Feb 10. pii: S0025-5564(24)00016-6. [Epub ahead of print]370 109156
    Effects of bursty synthesis in organelle biogenesis.
    Binayak Banerjee, Dipjyoti Das.
      A fundamental question of cell biology is how cells control the number of organelles. The processes of organelle biogenesis, namely de novo synthesis, fission, fusion, and decay, are inherently stochastic, producing cell-to-cell variability in organelle abundance. In addition, experiments suggest that the synthesis of some organelles can be bursty. We thus ask how bursty synthesis impacts intracellular organelle number distribution. We develop an organelle biogenesis model with bursty de novo synthesis by considering geometrically distributed burst sizes. We analytically solve the model in biologically relevant limits and provide exact expressions for the steady-state organelle number distributions and their means and variances. We also present approximate solutions for the whole model, complementing with exact stochastic simulations. We show that bursts generally increase the noise in organelle numbers, producing distinct signatures in noise profiles depending on different mechanisms of organelle biogenesis. We also find different shapes of organelle number distributions, including bimodal distributions in some parameter regimes. Notably, bursty synthesis broadens the parameter regime of observing bimodality compared to the 'non-bursty' case. Together, our framework utilizes number fluctuations to elucidate the role of bursty synthesis in producing organelle number heterogeneity in cells.
    Keywords:  Organelle biogenesis; Organelle number distribution; Stochastic process
    DOI:  https://doi.org/10.1016/j.mbs.2024.109156
  12. bioRxiv. 2024 Feb 04. pii: 2024.02.02.578646. [Epub ahead of print]
    BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
    Brandon Chen, Theophilus M Lynn-Nguyen, Pankaj Jadhav, Benjamin S Halligan, Nicholas J Rossiter, Rachel M Guerra, Sergei Koshkin, Imhoi Koo, Pietro Morlacchi, David A Hanna, Jason Lin, Ruma Banerjee, David J Pagliarini, Andrew D Patterson, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.
    DOI:  https://doi.org/10.1101/2024.02.02.578646
  13. Free Radic Biol Med. 2024 Feb 10. pii: S0891-5849(24)00089-3. [Epub ahead of print]214 80-86
    Alpha-ketoglutaric acid attenuates oxidative stress and modulates mitochondrial dynamics and autophagy of spleen in a piglet model of lipopolysaccharide-induced sepsis.
    Guangmang Liu, Jiajia Lu, Weixiao Sun, Gang Jia, Hua Zhao, Xiaoling Chen, Jing Wang.
      Alpha-ketoglutaric acid (2-ketoglutaric acid or 2-oxoglutaric acid, AKG), a crucial intermediate in the tricarboxylic acid cycle, is pivotal in animal antioxidative process. The purpose of this study was to investigate whether AKG has the efficacy to mitigate spleen oxidative stress in lipopolysaccharide (LPS)-induced sepsis piglets through the modulation of mitochondrial dynamics and autophagy. Utilizing a 2 × 2 factorial design, the study encompassed 24 piglets subjected to varying diets (basal or 1% AKG) and immune stimulations (saline or LPS) over 21 days. Subsequently, they were injected intraperitoneally with either LPS or saline solution. The results showed that LPS decreased antioxidant capacity, whereas AKG supplementation increased antioxidant activities compared to control group. LPS elevated mitochondrial fission factor, mitochondrial elongation factor 1, mitochondrial elongation factor 2, dynamin-related protein 1, voltage-dependent anion channel 1, and fission 1 mRNA abundance, but reduced mRNA abundance of mitofusin 1, mitofusin 2, and optic atrophy 1 compared to controls. LPS elevated mRNA abundance of autophagy related protein 5, autophagy related protein 7, P62, Beclin1, and interleukin-1β mRNA abundance compared to controls. However, AKG supplementation mitigated these effects induced by LPS. Additionally, AKG intake was associated with lower protein expressions of microtubule-associated protein light chain 3, Parkin, and PTEN-induced putative kinase 1 compared to LPS-challenged piglets. These results suggested that AKG could alleviate spleen oxidative stress caused by LPS by regulating mitochondrial dynamics and autophagy.
    Keywords:  Alpha-ketoglutaric acid; Autophagy; Mitochondrial dynamics; Piglets; Spleen
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.02.009
  14. ACS Appl Mater Interfaces. 2024 Feb 12.
    Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson's Disease.
    Liku Biswal, Mohammed Nadim Sardoiwala, Avinash Chandra Kushwaha, Syamantak Mukherjee, Surajit Karmakar.
      The molecular pathways that melatonin follows as a Parkinson's disease (PD) antagonist remain poorly elucidated, despite it being a safe and a potential neurotherapeutic drug with a few limitations such as less bioavailability, premature oxidation, brain delivery, etc. Here, we used a biocompatible protein (HSA) nanocarrier for the delivery of melatonin to the brain. This nanomelatonin showed better antioxidative and neuroprotective properties, and it not only improves mitophagy to remove unhealthy mitochondria but also improves mitochondrial biogenesis to counteract rotenone-induced toxicity in an in vitro PD model. We also showed BMI1, a member of the PRC1 complex that regulates mitophagy, whose protein expression was enhanced after nanomelatonin dosage. These effects were translated to a rodent model, where nanomelatonin improves the TH+ve neuron population in SNPC and protects against rotenone-mediated toxicity. Our findings highlight the significantly better in vitro and in vivo neuroprotective effect of nanomelatonin as well as the molecular/cellular dynamics it influences to regulate mitophagy as a measure of the potential therapeutic candidate for PD.
    Keywords:  BMI1; PTEN; Parkinson’s disease; melatonin; mitophagy
    DOI:  https://doi.org/10.1021/acsami.3c17092
  15. Nat Ecol Evol. 2024 Feb 15.
    Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
    Isabel M Serrano, Misa Hirose, Charles C Valentine, Sharon Roesner, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.
      Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.
    DOI:  https://doi.org/10.1038/s41559-024-02338-3
  16. Acta Physiol (Oxf). 2024 Feb 14. e14115
    Pre-fusion motion state determines the heterogeneity of membrane fusion dynamics for large dense-core vesicles.
    Renhao Xue, Enming Zhang, Yu Wang.
      AIM: In neuroendocrine cells, large dense-core vesicles (LDCVs) undergo highly regulated pre-fusion processes before releasing hormones via membrane fusion. Significant heterogeneity has been found for LDCV population based on the dynamics of membrane fusion. However, how the pre-fusion status impacts the heterogeneity of LDCVs still remains unclear. Hence, we explored pre-fusion determinants of heterogeneous membrane fusion procedure of LDCV subpopulations.METHODS: We assessed the pre-fusion motion of two LDCV subpopulations with distinct membrane fusion dynamics individually, using total internal reflection fluorescence microscopy. These two subpopulations were isolated by blocking Rho GTPase-dependent actin reorganization using Clostridium difficile toxin B (ToxB), which selectively targets the fast fusion vesicle pool.
    RESULTS: We found that the fast fusion subpopulation was in an active motion mode prior to release, termed "active" LDCV pool, while vesicles from the slow fusion subpopulation were also moving but in a significantly more confined status, forming an "inert" pool. The depletion of the active pool by ToxB also eliminated fast fusion vesicles and was not rescued by pre-treatment with phorbol ester. A mild actin reorganization blocker, latrunculin A, that partially disrupted the active pool, only slightly attenuated the fast fusion subpopulation.
    CONCLUSION: The pre-fusion motion state of LDCVs also exhibits heterogeneity and dictates the heterogeneous fusion pore dynamics. Rearrangement of F-actin network mediates vesicle pre-fusion motion and subsequently determines the membrane fusion kinetics.
    Keywords:  exocytosis; large dense-core vesicle; membrane fusion; neuroendocrine cell; pre-fusion motion
    DOI:  https://doi.org/10.1111/apha.14115
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