bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2024‒03‒24
eleven papers selected by
Omkar Joshi, Turku Bioscience
  1. Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
  2. Mitochondria-ER contact sites expand during mitosis.
  3. A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
  4. Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.
  5. Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
  6. Quantifying nanoscopic alterations associated with mitochondrial dysfunction using three-dimensional single-molecule localization microscopy.
  7. Mitochondrial dynamics: Regulating cell metabolism, homoeostasis, health and disease.
  8. Mitochondria-lysosome-extracellular vesicles axis and nanotheranostics in neurodegenerative diseases.
  9. Rhodamine-based fluorescent probe for dynamic STED imaging of mitochondria.
  10. A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
  11. The small yeast GTPase Rho5 requires specific mitochondrial outer membrane proteins for translocation under oxidative stress and interacts with the VDAC Por1.
  1. Life Sci. 2024 Mar 14. pii: S0024-3205(24)00164-4. [Epub ahead of print]344 122575
    Future perspectives on the roles of mitochondrial dynamics in the heart in obesity and aging.
    Chayodom Maneechote, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Increasing global obesity rates and an aging population are independently linked to cardiac complications. Consequently, it is crucial to comprehensively understand the mechanisms behind these conditions to advance innovative therapies for age-related diseases. Mitochondrial dysfunction, specifically defects in mitochondrial fission/fusion processes, has emerged as a central regulator of cardiac complications in aging and age-related diseases (e.g., obesity). Since excessive fission and impaired fusion of cardiac mitochondria lead to disruptions in mitochondrial dynamics and cellular metabolism in aging and obesity, modulating mitochondrial dynamics with either fission inhibitors or fusion promoters has offered cardioprotection against these pathological conditions in preclinical models. This review explores the molecular mechanisms governing mitochondrial dynamics as well as the disturbances observed in aging and obesity. Additionally, pharmaceutical interventions that specifically target the processes of mitochondrial fission and fusion are presented and discussed. By establishing a connection between mitochondrial dynamism through fission and fusion and the advancement or mitigation of age-related diseases, particularly obesity, this review provides valuable insights into the progression and potential prevention strategies for such conditions.
    Keywords:  Aging; Cardiovascular disease; Mitochondria; Mitochondrial dynamics; Obesity
    DOI:  https://doi.org/10.1016/j.lfs.2024.122575
  2. iScience. 2024 Apr 19. 27(4): 109379
    Mitochondria-ER contact sites expand during mitosis.
    Fang Yu, Raphael Courjaret, Lama Assaf, Asha Elmi, Ayat Hammad, Melanie Fisher, Mark Terasaki, Khaled Machaca.
      Mitochondria-ER contact sites (MERCS) are involved in energy homeostasis, redox and Ca2+ signaling, and inflammation. MERCS are heavily studied; however, little is known about their regulation during mitosis. Here, we show that MERCS expand during mitosis in three cell types using various approaches, including transmission electron microscopy, serial EM coupled to 3D reconstruction, and a split GFP MERCS marker. We further show enhanced Ca2+ transfer between the ER and mitochondria using either direct Ca2+ measurements or by quantifying the activity of Ca2+-dependent mitochondrial dehydrogenases. Collectively, our results support a lengthening of MERCS in mitosis that is associated with improved Ca2+ coupling between the two organelles. This augmented Ca2+ coupling could be important to support the increased energy needs of the cell during mitosis.
    Keywords:  Biological sciences; Cell biology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.109379
  3. Mol Neurodegener. 2024 Mar 19. 19(1): 26
    A partial Drp1 knockout improves autophagy flux independent of mitochondrial function.
    Rebecca Z Fan, Carolina Sportelli, Yanhao Lai, Said S Salehe, Jennifer R Pinnell, Harry J Brown, Jason R Richardson, Shouqing Luo, Kim Tieu.
      BACKGROUND: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial dynamics. Partial inhibition of this protein is protective in experimental models of neurological disorders such as Parkinson's disease and Alzheimer's disease. The protective mechanism has been attributed primarily to improved mitochondrial function. However, the observations that Drp1 inhibition reduces protein aggregation in such neurological disorders suggest the involvement of autophagy. To investigate this potential novel protective mechanism of Drp1 inhibition, a model with impaired autophagy without mitochondrial involvement is needed.METHODS: We characterized the effects of manganese (Mn), which causes parkinsonian-like symptoms in humans, on autophagy and mitochondria by performing dose-response studies in two cell culture models (stable autophagy HeLa reporter cells and N27 rat immortalized dopamine neuronal cells). Mitochondrial function was assessed using the Seahorse Flux Analyzer. Autophagy flux was monitored by quantifying the number of autophagosomes and autolysosomes, as well as the levels of other autophagy proteins. To strengthen the in vitro data, multiple mouse models (autophagy reporter mice and mutant Drp1+/- mice and their wild-type littermates) were orally treated with a low chronic Mn regimen that was previously reported to increase α-synuclein aggregation and transmission via exosomes. RNAseq, laser captured microdissection, immunofluorescence, immunoblotting, stereological cell counting, and behavioural studies were used. RESULTS IN VITRO: data demonstrate that at low non-toxic concentrations, Mn impaired autophagy flux but not mitochondrial function and morphology. In the mouse midbrain, RNAseq data further confirmed autophagy pathways were dysregulated but not mitochondrial related genes. Additionally, Mn selectively impaired autophagy in the nigral dopamine neurons but not the nearby nigral GABA neurons. In cells with a partial Drp1-knockdown and Drp1+/- mice, Mn induced autophagic impairment was significantly prevented. Consistent with these observations, Mn increased the levels of proteinase-K resistant α-synuclein and Drp1-knockdown protected against this pathology.
    CONCLUSIONS: This study demonstrates that improved autophagy flux is a separate mechanism conferred by Drp1 inhibition independent of its role in mitochondrial fission. Given that impaired autophagy and mitochondrial dysfunction are two prominent features of neurodegenerative diseases, the combined protective mechanisms targeting these two pathways conferred by Drp1 inhibition make this protein an attractive therapeutic target.
    Keywords:  Autophagy; Dynamin related protein 1; Manganese; Mitochondrial dynamics; Mitochondrial dysfunction; Parkinson’s disease; Protein aggregation; α-synuclein
    DOI:  https://doi.org/10.1186/s13024-024-00708-w
  4. Cell Death Discov. 2024 Mar 20. 10(1): 148
    Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.
    Yong Liu, Jin-Ling Huo, Kaidi Ren, Shaokang Pan, Hengdao Liu, Yifeng Zheng, Jingfang Chen, Yingjin Qiao, Yang Yang, Qi Feng.
      Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one of the most serious chronic heart diseases and has become a major cause of heart failure worldwide. At present, the pathogenesis of DCM is unclear, and there is still a lack of effective therapeutics. Previous studies have shown that the homeostasis of mitochondria and the endoplasmic reticulum (ER) play a core role in maintaining cardiovascular function, and structural and functional abnormalities in these organelles seriously impact the occurrence and development of various cardiovascular diseases, including DCM. The interplay between mitochondria and the ER is mediated by the mitochondria-associated ER membrane (MAM), which participates in regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, ER stress, inflammation, and other cellular processes. Recent studies have proven that MAM is closely related to the initiation and progression of DCM. In this study, we aim to summarize the recent research progress on MAM, elaborate on the key role of MAM in DCM, and discuss the potential of MAM as an important therapeutic target for DCM, thereby providing a theoretical reference for basic and clinical studies of DCM treatment.
    DOI:  https://doi.org/10.1038/s41420-024-01918-3
  5. Mitochondrion. 2024 Mar 17. pii: S1567-7249(24)00031-X. [Epub ahead of print]76 101873
    Revolutionizing cellular energy: The convergence of mitochondrial dynamics and delivery technologies.
    Dilpreet Singh.
      The intersection of mitochondrial dynamics and delivery technologies heralds a paradigm shift in cellular biology and therapeutic intervention. Mitochondrial dynamics, encompassing fusion, fission, transport, and mitophagy, are critical for cellular energy production, signaling, and homeostasis. Dysregulation of these processes is implicated in a myriad of diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. Concurrently, advances in delivery technologies, such as nanocarriers, targeted delivery systems, and gene editing tools, offer unprecedented opportunities to manipulate mitochondrial function directly. This review synthesizes current knowledge on mitochondrial dynamics, examines recent breakthroughs in targeted delivery methods, and explores their potential convergence to modulate cellular energetics for therapeutic purposes. By integrating insights from biology, chemistry, and bioengineering, this review highlights the innovative approaches being developed to enhance mitochondrial function, underscoring the potential of this convergence to address complex diseases. This interdisciplinary perspective not only broadens our understanding of cellular processes but also paves the way for novel therapeutic strategies, marking a significant step forward in the quest for precision medicine and targeted interventions in mitochondrial-related diseases.
    Keywords:  Delivery; Mitochondria; Personalized medicine; Strategies; Technologies; Therapeutic effect
    DOI:  https://doi.org/10.1016/j.mito.2024.101873
  6. Biomed Opt Express. 2024 Mar 01. 15(3): 1571-1584
    Quantifying nanoscopic alterations associated with mitochondrial dysfunction using three-dimensional single-molecule localization microscopy.
    Benjamin Brenner, Fengyuanshan Xu, Yang Zhang, Junghun Kweon, Raymond Fang, Nader Sheibani, Sarah X Zhang, Cheng Sun, Hao F Zhang.
      Mitochondrial morphology provides unique insights into their integrity and function. Among fluorescence microscopy techniques, 3D super-resolution microscopy uniquely enables the analysis of mitochondrial morphological features individually. However, there is a lack of tools to extract morphological parameters from super-resolution images of mitochondria. We report a quantitative method to extract mitochondrial morphological metrics, including volume, aspect ratio, and local protein density, from 3D single-molecule localization microscopy images, with single-mitochondrion sensitivity. We validated our approach using simulated ground-truth SMLM images of mitochondria. We further tested our morphological analysis on mitochondria that have been altered functionally and morphologically in controlled manners. This work sets the stage to quantitatively analyze mitochondrial morphological alterations associated with disease progression on an individual basis.
    DOI:  https://doi.org/10.1364/BOE.510351
  7. Semin Cell Dev Biol. 2024 Mar 19. pii: S1084-9521(24)00023-5. [Epub ahead of print]161-162 20-21
    Mitochondrial dynamics: Regulating cell metabolism, homoeostasis, health and disease.
    Karoline D Raven, Ronan Kapetanovic.
      
    DOI:  https://doi.org/10.1016/j.semcdb.2024.02.002
  8. Exp Neurol. 2024 Mar 18. pii: S0014-4886(24)00083-9. [Epub ahead of print]376 114757
    Mitochondria-lysosome-extracellular vesicles axis and nanotheranostics in neurodegenerative diseases.
    Liang Kou, Yiming Wang, Jingwen Li, Wenkai Zou, Zongjie Jin, Sijia Yin, Xiaosa Chi, Yadi Sun, Jiawei Wu, Tao Wang, Yun Xia.
      The intricate functional interactions between mitochondria and lysosomes play a pivotal role in maintaining cellular homeostasis and proper cellular functions. This dynamic interplay involves the exchange of molecules and signaling, impacting cellular metabolism, mitophagy, organellar dynamics, and cellular responses to stress. Dysregulation of these processes has been implicated in various neurodegenerative diseases. Additionally, mitochondrial-lysosomal crosstalk regulates the exosome release in neurons and glial cells. Under stress conditions, neurons and glial cells exhibit mitochondrial dysfunction and a fragmented network, which further leads to lysosomal dysfunction, thereby inhibiting autophagic flux and enhancing exosome release. This comprehensive review synthesizes current knowledge on mitochondrial regulation of cell death, organelle dynamics, and vesicle trafficking, emphasizing their significant contributions to neurodegenerative diseases. Furthermore, we explore the emerging field of nanomedicine in the management of neurodegenerative diseases. The review provides readers with an insightful overview of nano strategies that are currently advancing the mitochondrial-lysosome-extracellular vesicle axis as a therapeutic approach for mitigating neurodegenerative diseases.
    Keywords:  Extracellular vesicles axis; Lysosome; Mitochondria; Nanotheranostics; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.expneurol.2024.114757
  9. Biomed Opt Express. 2024 Mar 01. 15(3): 1595-1604
    Rhodamine-based fluorescent probe for dynamic STED imaging of mitochondria.
    Xinwei Gao, Songtao Cai, Luwei Wang, Yong Guo, Liwei Liu, Xiaoyu Weng, Kun Huang, Wei Yan, Junle Qu.
      Stimulated emission depletion (STED) microscopy holds tremendous potential and practical implications in the field of biomedicine. However, the weak anti-bleaching performance remains a major challenge limiting the application of STED fluorescent probes. Meanwhile, the main excitation wavelengths of most reported STED fluorescent probes were below 500 nm or above 600 nm, and few of them were between 500-600 nm. Herein, we developed a new tetraphenyl ethylene-functionalized rhodamine dye (TPERh) for mitochondrial dynamic cristae imaging that was rhodamine-based with an excitation wavelength of 560 nm. The TPERh probe exhibits excellent anti-bleaching properties and low saturating stimulated radiation power in mitochondrial STED super-resolution imaging. Given these outstanding properties, the TPERh probe was used to measure mitochondrial deformation, which has positive implications for the study of mitochondria-related diseases.
    DOI:  https://doi.org/10.1364/BOE.507770
  10. bioRxiv. 2024 Mar 07. pii: 2024.03.05.583623. [Epub ahead of print]
    A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3×3×3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities 11 , thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.
    DOI:  https://doi.org/10.1101/2024.03.05.583623
  11. Eur J Cell Biol. 2024 Mar 15. pii: S0171-9335(24)00022-0. [Epub ahead of print]103(2): 151405
    The small yeast GTPase Rho5 requires specific mitochondrial outer membrane proteins for translocation under oxidative stress and interacts with the VDAC Por1.
    Linnet Bischof, Franziska Schweitzer, Hans-Peter Schmitz, Jürgen J Heinisch.
      Yeast Rho5 is a small GTPase which mediates the response to nutrient and oxidative stress, and triggers mitophagy and apoptosis. We here studied the rapid translocation of a GFP-tagged Rho5 to mitochondria under such stress conditions by live-cell fluorescence microscopy in the background of strains lacking different mitochondrial outer membrane proteins (MOMP). Fun14, Msp1 and Alo1 were found to be required for efficient recruitment of the GTPase, whereas translocation of Dck1 and Lmo1, the subunits of its dimeric GDP/GTP exchange factor (GEF), remained unaffected. An influence of the voltage-dependent anion channel (VDAC) Por1 on the association of GFP-Rho5 with mitochondria under oxidative stress conditions appeared to be strain-dependent. However, epistasis analyses and bimolecular fluorescence complementation (BiFC) studies indicate a genetic and physical interaction. All four strains lacking a single MOMP were investigated for their effect on mitophagy.
    Keywords:  Rho-type GTPase; glucose starvation; mitochondria; oxidative stress; porin
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151405
This page is being maintained by Thomas Krichel. It was last updated on 2024‒03‒29 at 11:58.