bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2024–12–22
eight papers selected by
Gavin McStay, Liverpool John Moores University
  1. A molecular glue for Prkn/parkin.
  2. Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
  3. Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
  4. Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
  5. Mitophagosomes induced during EV-D68 infection promote viral nonlytic release.
  6. Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.
  7. Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
  8. Zinc Mitigates the Combined Neurotoxicity of Binary Metal Mixtures via Mitophagy and Mitochondrial Fusion.
  1. Autophagy. 2024 Dec 19.
    A molecular glue for Prkn/parkin.
    Véronique Sauvé, Kalle Gehring.
      Parkinson disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra, primarily due to mitochondria dysfunction. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN induced kinase 1) are linked to early-onset cases of PD and essential for the clearance of damaged mitochondria via selective mitochondrial autophagy (mitophagy). In a recent publication, we detail how a small molecule can activate PRKN mutants that are unable to be phosphorylated, restoring mitophagy in cellular assays. These findings offer hope for the design of therapeutic drugs for some forms of PD.
    Keywords:  Activator; PARK2; mitochondria; neurodegeneration; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2443232
  2. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02578-X. [Epub ahead of print] 108076
    Prohibitin 1 tethers lipid membranes and regulates OPA1-mediated membrane fusion.
    Tadato Ban, Kimiya Kuroda, Mitsuhiro Nishigori, Keisuke Yamashita, Keisuke Ohta, Takumi Koshiba.
      Prohibitins (PHBs) are ubiquitously expressed proteins in the mitochondrial inner membrane (MIM) that provide membrane scaffolds for both mitochondrial proteins and phospholipids. Eukaryotic PHB complexes contain two highly homologous PHB subunits, PHB1 and PHB2, which are involved in various cellular processes, including metabolic control through the regulation of mitochondrial dynamics and integrity. Their mechanistic actions at the molecular level, however, particularly those of PHB1, remain poorly understood. To gain insight into the mechanistic actions of PHB1, we established an overexpression system for the full-length recombinant protein using silkworm larvae and characterized its biophysical properties in vitro. Using recombinant PHB1 proteoliposomes reconstituted into MIM-mimicking phospholipids, we found that PHB1 forms an oligomer via its carboxy-terminal coiled-coil region. A proline substitution into the PHB1 coiled-coil collapsed its well-ordered oligomeric state, and its destabilization correlated with mitochondrial morphologic defects. Negative-staining electron microscopy revealed that homotypic PHB1-PHB1 interactions via the coiled-coil also induced liposome tethering with remodeling of the lipid membrane structure. We clarified that PHB1 promotes membrane fusion mediated by optic atrophy 1 (OPA1), a key regulator of MIM fusion. Additionally, the presence of PHB1 reduces the dependency of lipids and OPA1 for completing the fusion process. Our in vitro study provides structural insight into how the mitochondrial scaffold plays a crucial role in regulating mitochondrial dynamics. Modulating the structure and/or function of PHB1 may offer new therapeutic potential, not only for mitochondrial dysfunction but also for other cell-related disorders.
    Keywords:  Coiled-coil; Prohibitin 1; membrane fusion; mitochondria; proteoliposomes
    DOI:  https://doi.org/10.1016/j.jbc.2024.108076
  3. J Cell Sci. 2024 Dec 20. pii: jcs.263459. [Epub ahead of print]
    Fis1 regulates mitochondrial morphology, bioenergetics, and removal of mtDNA damage in irradiated glioblastoma cells.
    Yuli Buckley, Maria S K Stoll, Charles L Hoppel, Jason A Mears.
      In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress and uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered ETC activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.
    Keywords:  Bioenergetics; Fis1; Ionizing radiation; Mitochondrial fission; MtDNA
    DOI:  https://doi.org/10.1242/jcs.263459
  4. Autophagy. 2024 Dec 15.
    Endogenous interactomes of MFN1 and MFN2 provide novel insights into interorganelle communication and autophagy.
    Isabel Gordaliza-Alaguero, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Laura Villarreal, Gianluca Arauz-Garofalo, Marina Gay, Marta Martinez-Vicente, Jorge Seco, Pau Martin-Malpartida, Marta Vilaseca, María J Macías, Manuel Palacin, Saška Ivanova, Antonio Zorzano.
      MFN1 (mitofusin 1) and MFN2 are key players in mitochondrial fusion, endoplasmic reticulum (ER)-mitochondria juxtaposition, and macroautophagy/autophagy. However, the mechanisms by which these proteins participate in these processes are poorly understood. Here, we studied the interactomes of these two proteins by using CRISPR-Cas9 technology to insert an HA-tag at the C terminus of MFN1 and MFN2, and thus generating HeLa cell lines that endogenously expressed MFN1-HA or MFN2-HA. HA-affinity isolation followed by mass spectrometry identified potential interactors of MFN1 and MFN2. A substantial proportion of interactors were common for MFN1 and MFN2 and were regulated by nutrient deprivation. We validated novel ER and endosomal partners of MFN1 and/or MFN2 with a potential role in interorganelle communication. We characterized RAB5C (RAB5C, member RAS oncogene family) as an endosomal modulator of mitochondrial homeostasis, and SLC27A2 (solute carrier family 27 (fatty acid transporter), member 2) as a novel partner of MFN2 relevant in autophagy. We conclude that MFN proteins participate in nutrient-modulated pathways involved in organelle communication and autophagy.
    Keywords:  Autophagosomes; endosomes; mitochondria; mitochondria-endoplasmic reticulum contact sites; mitochondrial dynamics; nutrient deprivation
    DOI:  https://doi.org/10.1080/15548627.2024.2440843
  5. bioRxiv. 2024 Dec 06. pii: 2024.12.05.627125. [Epub ahead of print]
    Mitophagosomes induced during EV-D68 infection promote viral nonlytic release.
    Alagie Jassey, Bimal Paudel, Michael A Wagner, Noah Pollack, I-Ting Cheng, Raquel Godoy-Ruiz, David J Weber, William T Jackson.
      Enterovirus-D68 (EV-D68) is a plus-strand RNA virus that primarily causes infant respiratory infections. In rare pediatric cases, infection with EV-D68 has been associated with acute flaccid myelitis, a polio-like paralytic disease. We have previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that EV-D68 induces mitophagy, the specific autophagic degradation of mitochondria. EV-D68 infection induces mitophagosome formation and several hallmarks of mitophagy, including mitochondrial fragmentation, mitochondrial membrane potential loss, and Parkin translocation to the mitochondria were observed in EV-D68 infected cells. The 3C protease of EV-D68 cleaves the mitochondrial fusion protein, mitofusin-2, near the C-terminal HR2 domain to induce mitochondrial fragmentation, and these fragmented mitochondria colocalized with double-stranded RNA (dsRNA), which labels viral RNA replication sites after peak viral RNA replication. Depleting components of mitophagy signaling specifically reduced EV-D68 release without impacting viral intracellular titers. Our results suggest that whereas the machinery of macroautophagy supports various stages of enterovirus replication, including viral genomic RNA replication and capsid maturation, mitophagy is the specific form of autophagy that regulates the nonlytic release of enteroviruses from cells.
    Keywords:  BCL2L13; EV-D68; Mitofusin-2; Mitophagy; PINK1; Parkin
    DOI:  https://doi.org/10.1101/2024.12.05.627125
  6. Biogerontology. 2024 Dec 20. 26(1): 29
    Quercetin preserves mitochondria-endoplasmic reticulum contact sites improving mitochondrial dynamics in aged myocardial cells.
    Ray Jiménez, Alejandra Zúñiga-Muñoz, Edith Álvarez-León, Wylly Ramsés García-Niño, Gabriela Navarrete-Anastasio, Elizabeth Soria-Castro, Israel Pérez-Torres, Elizabeth Lira-Silva, Natalia Pavón, Alfredo Cruz-Gregorio, Rebeca López-Marure, Cecilia Zazueta, Alejandro Silva-Palacios.
      Cardiomyocyte senescence plays a crucial role in the pathophysiology of age-related cardiovascular disease. Senescent cells with impaired contractility, mitochondrial dysfunction, and hypertrophic growth accumulate in the heart during aging, contributing to cardiac dysfunction and remodeling. Mitochondrial dynamics is altered in aging cells, leading to changes in their function and morphology. Such rearrangements can affect the spatially restricted region of the mitochondrial membrane that interacts with reticulum membrane fragments, termed mitochondria-endoplasmic reticulum (ER) contact sites (MERCs). Besides, oxidative stress associated with inefficient organelle turnover can drive cellular senescence. Therefore, in this study, we evaluated the possible association between the senolytic effect of the antioxidant quercetin (Q) and MERCs preservation in a D-galactose-induced cellular senescence model. We found that Q ameliorates the senescent phenotype of H9c2 cells in association with increased mitochondria-ER colocalization, reduced distance between both organelles, and lower ROS production. Moreover, regulation of fusion and fission processes was related with increased mitochondrial ATP production and enhanced transmembrane potential. Overall, our data provide evidence that the inhibitory effect of Q on cellular senescence is associated with preserved MERCs and improved mitochondrial function and morphology, which might contribute to the attenuation of cardiac dysfunction.
    Keywords:  Cardiac senescence; Mitochondria-endoplasmic reticulum contact sites; Mitochondrial dynamic; Quercetin; Senolysis
    DOI:  https://doi.org/10.1007/s10522-024-10174-y
  7. Life Sci. 2024 Dec 12. pii: S0024-3205(24)00907-X. [Epub ahead of print] 123317
    Targeting mitochondrial dynamics: A promising approach for intracerebral hemorrhage therapy.
    Mengnan Liu, Binru Li, Zhixue Yin, Lu Yin, Ye Luo, Qi Zeng, Dechou Zhang, Anguo Wu, Li Chen.
      Intracerebral hemorrhage (ICH) is a major global health issue with high mortality and disability rates. Following ICH, the hematoma exerts direct pressure on brain tissue, and blood entering the brain directly damages neurons and the blood-brain barrier. Subsequently, oxidative stress, inflammatory responses, apoptosis, brain edema, excitotoxicity, iron toxicity, and metabolic dysfunction around the hematoma further exacerbate brain tissue damage, leading to secondary brain injury (SBI). Mitochondria, essential for energy production and the regulation of oxidative stress, are damaged after ICH, resulting in impaired ATP production, excessive reactive oxygen species (ROS) generation, and disrupted calcium homeostasis, all of which contribute to SBI. Therefore, a central factor in SBI is mitochondrial dysfunction. Mitochondrial dynamics regulate the shape, size, distribution, and quantity of mitochondria through fusion and fission, both of which are crucial for maintaining their function. Fusion repairs damaged mitochondria and preserves their health, while fission helps mitochondria adapt to cellular stress and removes damaged mitochondria through mitophagy. When this balance is disrupted following ICH, mitochondrial dysfunction worsens, oxidative stress and metabolic failure are exacerbated, ultimately contributing to SBI. Targeting mitochondrial dynamics offers a promising therapeutic approach to restoring mitochondrial function, reducing cellular damage, and improving recovery. This review explores the latest research on modulating mitochondrial dynamics and highlights its potential to enhance outcomes in ICH patients.
    Keywords:  Intracerebral hemorrhage; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Neuroprotection strategies; Secondary brain injury
    DOI:  https://doi.org/10.1016/j.lfs.2024.123317
  8. Mol Neurobiol. 2024 Dec 14.
    Zinc Mitigates the Combined Neurotoxicity of Binary Metal Mixtures via Mitophagy and Mitochondrial Fusion.
    Haiqing Cai, Junxiu He, Wanting Zheng, Hong Cheng, Xiaoting Ge, Yu Bao, Yue Wei, Yanfeng Zhou, Xiaolin Liang, Xing Chen, Chaoqun Liu, Fei Wang, Xiaobo Yang.
      Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity.
    Keywords:  Combined neurotoxicity; Metal mixtures; Mitophagy and mitochondrial fusion; Zinc
    DOI:  https://doi.org/10.1007/s12035-024-04648-w
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