bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2023‒08‒13
nine papers selected by
Omkar Joshi, Turku Bioscience
  1. Mitochondrial fission fueled by fasting.
  2. The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate.
  3. A Novel Interaction between MFN2/Marf and MARK4/PAR-1 is Implicated in Synaptic Defects and Mitochondrial Dysfunction.
  4. The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
  5. Protein disorder in the regulatory control of mitophagy.
  6. New Insights into Metabolic Alterations and Mitochondria Re-Arrangements in Pancreatic Adenocarcinoma.
  7. A novel role for astrocytic fragmented mitochondria in regulating morphine addiction.
  8. DELE1 oligomerization promotes integrated stress response activation.
  9. Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.
  1. Sci Signal. 2023 08 08. 16(797): eadk1008
    Mitochondrial fission fueled by fasting.
    Wei Wong.
      Fasting activates mTORC2 to stimulate mitochondrial fission and support mitochondrial respiration.
    DOI:  https://doi.org/10.1126/scisignal.adk1008
  2. Int J Mol Sci. 2023 Jul 29. pii: 12181. [Epub ahead of print]24(15):
    The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate.
    Ilario Amato, Sébastien Meurant, Patricia Renard.
      The study of the mechanisms underlying stem cell differentiation is under intensive research and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has strengthened the interest in the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission, and mitophagy processes as well as emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.
    Keywords:  RISP; asymmetric; differentiation; epigenetic; metabolism; mitochondria; stem cell
    DOI:  https://doi.org/10.3390/ijms241512181
  3. eNeuro. 2023 Aug 04. pii: ENEURO.0409-22.2023. [Epub ahead of print]
    A Novel Interaction between MFN2/Marf and MARK4/PAR-1 is Implicated in Synaptic Defects and Mitochondrial Dysfunction.
    Yeongmi Cheon, Sunggyu Yoon, Jae-Hyuk Lee, Kiyoung Kim, Hyung-Jun Kim, Sung Wook Hong, Ye-Rang Yun, Jiwon Shim, Sung-Hak Kim, Bingwei Lu, Mihye Lee, Seongsoo Lee.
      As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, MFN2/Marf, plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, are not clearly understood. Here, we identified a novel interaction between MFN2/Marf and MARK4/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Taken together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.Significance StatementWe identified a novel interaction between MFN2/Marf and a kinase MARK4/PAR-1 in Drosophila and mammalian cells. The MFN2/Marf and MARK4/PAR-1 interaction was critical for maintaining the synaptic structure of neuromuscular junctions in Drosophila In addition, we found that concomitant knockdown of MARK4/PAR-1 could rescue the mitochondrial hyperfusion and aberrant respiratory function caused by MFN2/Marf overexpression. Our study provides new insights into the link between mitochondrial defects and neurodegeneration, which makes a significant contribution to the understanding of neurologic pathogenesis and therapeutic development.
    Keywords:  Drosophila melanogaster; MARK4/PAR-1; MFN2/Marf; Mitochondrial dynamics; Neurodegenerative disease
    DOI:  https://doi.org/10.1523/ENEURO.0409-22.2023
  4. Front Neurosci. 2023 ;17 1144896
    The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
    Kelley C Atkinson, Marvellous Osunde, Seema K Tiwari-Woodruff.
      Multiple sclerosis (MS) is a demyelinating, degenerating disorder of the central nervous system (CNS) that is accompanied by mitochondria energy production failure. A loss of myelin paired with a deficit in energy production can contribute to further neurodegeneration and disability in patients in MS. Mitochondria are essential organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation in all cells in the CNS, including neurons, oligodendrocytes, astrocytes, and immune cells. In the context of demyelinating diseases, mitochondria have been shown to alter their morphology and undergo an initial increase in metabolic demand. This is followed by mitochondrial respiratory chain deficiency and abnormalities in mitochondrial transport that contribute to progressive neurodegeneration and irreversible disability. The current methodologies to study mitochondria are limiting and are capable of providing only a partial snapshot of the true mitochondria activity at a particular timepoint during disease. Mitochondrial functional studies are mostly performed in cell culture or whole brain tissue, which prevents understanding of mitochondrial pathology in distinct cell types in vivo. A true understanding of cell-specific mitochondrial pathophysiology of MS in mouse models is required. Cell-specific mitochondria morphology, mitochondria motility, and ATP production studies in animal models of MS will help us understand the role of mitochondria in the normal and diseased CNS. In this review, we present currently used methods to investigate mitochondria function in MS mouse models and discuss the current advantages and caveats with using each technique. In addition, we present recently developed mitochondria transgenic mouse lines expressing Cre under the control of CNS specific promoters to relate mitochondria to disease in vivo.
    Keywords:  EAE; cuprizone; demyelination; inflammation; mitochondria; multiple sclerosis; myelin; remyelination
    DOI:  https://doi.org/10.3389/fnins.2023.1144896
  5. Autophagy Rep. 2023 ;pii: 2242054. [Epub ahead of print]2(1):
    Protein disorder in the regulatory control of mitophagy.
    Sheridan Mikhail, Scott A Soleimanpour.
      Mitophagy is a central component of the mitochondrial quality control machinery, which is necessary for cellular viability and bioenergetics. The E3 ubiquitin ligase CLEC16A (C-type lectin domain containing 16A) forms a tripartite mitophagy regulatory complex together with the E3 ligase RNF41 (ring finger protein 41) and the ubiquitin-specific peptidase USP8 (ubiquitin specific peptidase 8), yet CLEC16A structural/functional domains relevant for mitophagy are unknown. We identify that CLEC16A contains an internal intrinsically disordered region (IDR), which is important for CLEC16A function and stability. IDRs are flexible domains lacking fixed secondary structure and regulate an emerging number of diverse processes, yet they have been largely unstudied in mitophagy. We observe that the internal CLEC16A IDR is essential for CLEC16A degradation and is bound by RNF41 to promote CLEC16A turnover. This IDR also promotes assembly of the CLEC16A-RNF41-USP8 mitophagy regulatory complex. Thus, our study revealed the importance of IDRs in mitophagy via the regulation of CLEC16A abundance by RNF41, opening new structural insights into mitochondrial quality control.
    Keywords:  autophagy; clec16a; intrinsically disordered protein; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1080/27694127.2023.2242054
  6. Cancers (Basel). 2023 Aug 01. pii: 3906. [Epub ahead of print]15(15):
    New Insights into Metabolic Alterations and Mitochondria Re-Arrangements in Pancreatic Adenocarcinoma.
    Ilaria Dando, Elisa Dalla Pozza.
      Among the most aggressive cancer types, pancreatic ductal adenocarcinoma (PDAC) represents one with the highest lethality due to its resistance to therapies and to the frequent metastatic spread [...].
    DOI:  https://doi.org/10.3390/cancers15153906
  7. Brain Behav Immun. 2023 Aug 03. pii: S0889-1591(23)00223-4. [Epub ahead of print]113 328-339
    A novel role for astrocytic fragmented mitochondria in regulating morphine addiction.
    Jie Rao, Weikang Sun, Xinran Wang, Jin Li, Zhichun Zhang, Feifan Zhou.
      Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous researches have shown that astrocytes contribute to brain diseases, the role of astrocyte in morphine addiction through induced neuroinflammation remain unexplored. Here we show that morphine-induced inflammation requires the crosstalk among neuron, astrocyte, and microglia. Specifically, astrocytes respond to morphine-induced neuronal activation by increasing glycolytic metabolism. The dysregulation of glycolysis leads to an increased in the generation of mitochondrial reactive oxygen species and causes excessive mitochondrial fragmentation in astrocytes. These fragmented, dysfunctional mitochondria are consequently released into extracellular environment, leading to activation of microglia and release of inflammatory cytokines. We also found that blocking the nicotinamide adenine dinucleotide salvage pathway with FK866 could inhibit astrocytic glycolysis and restore the mitochondrial homeostasis and effectively attenuate neuroinflammatory responses. Importantly, FK866 reversed morphine-induced addictive behaviors in mice. In summary, our findings illustrate an essential role of astrocytic immunometabolism in morphine induced neural and behavioral plasticity, providing a novel insight into the interactions between neurons, astrocytes, and microglia in the brain affected by chronic morphine exposure.
    Keywords:  Astrocyte; Glycolysis; Mitochondrial fragmentation; Morphine addiction
    DOI:  https://doi.org/10.1016/j.bbi.2023.07.030
  8. Nat Struct Mol Biol. 2023 Aug 07.
    DELE1 oligomerization promotes integrated stress response activation.
    Jie Yang, Kelsey R Baron, Daniel E Pride, Anette Schneemann, Xiaoyan Guo, Wenqian Chen, Albert S Song, Giovanni Aviles, Martin Kampmann, R Luke Wiseman, Gabriel C Lander.
      Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D4 symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.
    DOI:  https://doi.org/10.1038/s41594-023-01061-0
  9. Int J Mol Sci. 2023 Aug 06. pii: 12485. [Epub ahead of print]24(15):
    Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.
    Natalia V Belosludtseva, Dmitriy A Serov, Vlada S Starinets, Nikita V Penkov, Konstantin N Belosludtsev.
      The effect of hyperglycemia on the morphology of individual mitochondria and the state of the mitochondrial network in primary mouse lung microvascular endotheliocytes and human dermal fibroblasts has been investigated. The cells were exposed to high (30 mM) and low (5.5 mM) glucose concentrations for 36 h. In primary endotheliocytes, hyperglycemic stress induced a significant increase in the number of mitochondria and a decrease in the interconnectivity value of the mitochondrial network, which was associated with a decrease in the mean size of the mitochondria. Analysis of the mRNA level of the genes of proteins responsible for mitochondrial biogenesis and mitophagy revealed an increase in the expression level of the Ppargc1a, Pink1, and Parkin genes, indicating stimulated mitochondrial turnover in endotheliocytes under high glucose conditions. In primary fibroblasts, hyperglycemia caused a decrease in the number of mitochondria and an increase in their size. As a result, the mitochondria exhibited higher values for elongation. In parallel, the mRNA level of the Ppargc1a and Mfn2 genes in fibroblasts exposed to hyperglycemia was reduced. These findings indicate that high glucose concentrations induced cell-specific morphological rearrangements of individual mitochondria and the mitochondrial network, which may be relevant during mitochondria-targeted drug testing and therapy for hyperglycemic and diabetic conditions.
    Keywords:  diabetic hyperglycemia; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology; mitophagy
    DOI:  https://doi.org/10.3390/ijms241512485
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒22 at 12:16.