bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–04–10
nine papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. Defining the Role of Mitochondrial Fission in Corneal Myofibroblast Differentiation.
  2. Evolution and diversification of mitochondrial protein import systems.
  3. Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1.
  4. Drp1-Mediated Mitochondrial Metabolic Dysfunction Inhibits the Tumor Growth of Pituitary Adenomas.
  5. Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons.
  6. Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
  7. The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
  8. DELE1 tracks perturbed protein import and processing in human mitochondria.
  9. Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
  1. Invest Ophthalmol Vis Sci. 2022 Apr 01. 63(4): 2
    Defining the Role of Mitochondrial Fission in Corneal Myofibroblast Differentiation.
    Kye-Im Jeon, Ankita Kumar, Kaitlin T Wozniak, Keith Nehrke, Krystel R Huxlin.
       Purpose: Fibrosis caused by corneal wounding can lead to scar formation, impairing vision. Although preventing fibroblast-to-myofibroblast differentiation has therapeutic potential, effective mechanisms for doing so remain elusive. Recent work shows that mitochondria contribute to differentiation in several tissues. Here, we tested the hypothesis that mitochondrial dynamics, and specifically fission, are key for transforming growth factor (TGF)-β1-induced corneal myofibroblast differentiation.
    Methods: Mitochondrial fission was inhibited pharmacologically in cultured primary cat corneal fibroblasts. We measured its impact on molecular markers of myofibroblast differentiation and assessed changes in mitochondrial morphology through fluorescence imaging. The phosphorylation status of established regulatory proteins, both of myofibroblast differentiation and mitochondrial fission, was assessed by Western analysis.
    Results: Pharmacological inhibition of mitochondrial fission suppressed TGF-β1-induced increases in alpha-smooth muscle actin, collagen 1, and fibronectin expression, and prevented phosphorylation of c-Jun N-terminal kinase (JNK), but not small mothers against decapentaplegic 3, p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase 1 (ERK1), or protein kinase B (AKT). TGF-β1 increased phosphorylation of dynamin-related protein 1 (DRP1), a mitochondrial fission regulator, and caused fragmentation of the mitochondrial network. Although inhibition of JNK, ERK1, or AKT prevented phosphorylation of DRP1, none sufficed to independently suppress TGF-β1-induced fragmentation.
    Conclusions: Mitochondrial dynamics play a key role in early corneal fibrogenesis, acting together with profibrotic signaling. This is consistent with mitochondria's role as signaling hubs that coordinate metabolic decision-making. This suggests a feed-forward cascade through which mitochondria, at least in part through fission, reinforce noncanonical TGF-β1 signaling to attain corneal myofibroblast differentiation.
    DOI:  https://doi.org/10.1167/iovs.63.4.2
  2. Curr Opin Cell Biol. 2022 Apr 04. pii: S0955-0674(22)00023-0. [Epub ahead of print]75 102077
    Evolution and diversification of mitochondrial protein import systems.
    André Schneider.
      More than 95% of mitochondrial proteins are encoded in the nucleus, synthesised in the cytosol and imported into the organelle. The evolution of mitochondrial protein import systems was therefore a prerequisite for the conversion of the α-proteobacterial mitochondrial ancestor into an organelle. Here, I review that the origin of the mitochondrial outer membrane import receptors can best be understood by convergent evolution. Subsequently, I discuss an evolutionary scenario that was proposed to explain the diversification of the inner membrane carrier protein translocases between yeast and mammals. Finally, I illustrate a scenario that can explain how the two specialised inner membrane protein translocase complexes found in most eukaryotes were reduced to a single multifunctional one in trypanosomes.
    DOI:  https://doi.org/10.1016/j.ceb.2022.102077
  3. Front Pharmacol. 2022 ;13 832707
    Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1.
    Yan Hu, Yile Zhou, Yajie Yang, Haihong Tang, Yuan Si, Zhouyi Chen, Yi Shi, Hao Fang.
      Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment. Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals. Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice. Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment.
    Keywords:  apoptosis; cognitive dysfunction; diabetes; dynamin-related protein 1; mitochondrial fission; reactive oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2022.832707
  4. Oxid Med Cell Longev. 2022 ;2022 5652586
    Drp1-Mediated Mitochondrial Metabolic Dysfunction Inhibits the Tumor Growth of Pituitary Adenomas.
    Kexia Fan, Xiao Ding, Zhenle Zang, Yin Zhang, Xiaoshuang Tang, Xiangdong Pei, Qingbo Chen, Huachun Yin, Xin Zheng, Yong Chen, Song Li, Hui Yang.
      Metabolic changes have been suggested to be a hallmark of tumors and are closely associated with tumorigenesis. In a previous study, we demonstrated the role of lactate dehydrogenase in regulating abnormal glucose metabolism in pituitary adenomas (PA). As the key organelle of oxidative phosphorylation (OXPHOS), mitochondria play a vital role in the energy supply for tumor cells. However, few attempts have been made to elucidate mitochondrial metabolic homeostasis in PA. Dynamin-related protein 1 (Drp1) is a member of the dynamin superfamily of GTPases, which mediates mitochondrial fission. This study is aimed at investigating whether Drp1 affects the progression of PA through abnormal mitochondrial metabolism. We analyzed the expression of dynamin-related protein 1 (Drp1) in 20 surgical PA samples. The effects of Drp1 on PA growth were assessed in vitro and in xenograft models. We found an upregulation of Drp1 in PA samples with a low proliferation index. Knockdown or inhibition of Drp1 enhanced the proliferation of PA cell lines in vitro, while overexpression of Drp1 could reversed such effects. Mechanistically, overexpressed Drp1 damaged mitochondria by overproduction of reactive oxygen species (ROS), which induced mitochondrial OXPHOS inhibition and decline of ATP production. The energy deficiency inhibited proliferation of PA cells. In addition, overexpressed Drp1 promoted cytochrome c release from damaged mitochondria into the cytoplasm and then activated the downstream caspase apoptotic cascade reaction, which induced apoptosis of PA cells. Moreover, the decreased ATP production induced by Drp1 overexpressing activated the AMPK cellular energy stress sensor and enhanced autophagy through the AMPK-ULK1 pathway, which might play a protective role in PA growth. Furthermore, overexpression of Drp1 repressed PA growth in vivo. Our data indicates that Drp1-mediated mitochondrial metabolic dysfunction inhibits PA growth by affecting cell proliferation, apoptosis, and autophagy. Selectively targeting mitochondrial metabolic homeostasis stands out as a promising antineoplastic strategy for PA therapy.
    DOI:  https://doi.org/10.1155/2022/5652586
  5. Cell Death Dis. 2022 Apr 08. 13(4): 321
    Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons.
    Xiang Li, Haiying Li, Zhongmou Xu, Cheng Ma, Tianyi Wang, Wanchun You, Zhengquan Yu, Haitao Shen, Gang Chen.
      Neuronal mitochondrial dynamics are disturbed after ischemic stroke. Optic atrophy 1 (OPA1) and its GTPase activity are involved in maintaining mitochondrial cristae and inner membrane fusion. This study aimed to explore the role of OMA1-mediated OPA1 cleavage (S1-OPA1) in neurons exposed to cerebral ischemia and reperfusion. After oxygen-glucose deprivation (OGD) for 60 min, we found that mitochondrial fragmentation occurred successively in the axon and soma of neurons, accompanied by an increase in S1-OPA1. In addition, S1-OPA1 overexpression significantly aggravated mitochondrial damage in neurons exposed to OGD for 60 min and 24 h after OGD/R, characterized by mitochondrial fragmentation, decreased mitochondrial membrane potential, mitochondrial cristae ultrastructural damage, increased superoxide production, decreased ATP production and increased mitochondrial apoptosis, which was inhibited by the lysine 301 to alanine mutation (K301A). Furthermore, we performed neuron-specific overexpression of S1-OPA1 in the cerebral cortex around ischemia of middle cerebral artery occlusion/reperfusion (MCAO/R) mice. The results further demonstrated in vivo that S1-OPA1 exacerbated neuronal mitochondrial ultrastructural destruction and injury induced by cerebral ischemia-reperfusion, while S1-OPA1-K301 overexpression had no effect. In conclusion, ischemia induced neuronal OMA1-mediated cleavage of OPA1 at the S1 site. S1-OPA1 aggravated neuronal mitochondrial fragmentation and damage in a GTPase-dependent manner, and participated in neuronal ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1038/s41419-022-04782-0
  6. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00367-9. [Epub ahead of print]39(1): 110619
    Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
    Chantal Priesnitz, Lena Böttinger, Nicole Zufall, Michael Gebert, Bernard Guiard, Martin van der Laan, Thomas Becker.
      The presequence translocase (TIM23 complex) imports precursor proteins into the mitochondrial inner membrane and matrix. The presequence translocase-associated motor (PAM) provides a driving force for transport into the matrix. The J-protein Pam18 stimulates the ATPase activity of the mitochondrial Hsp70 (mtHsp70). Pam16 recruits Pam18 to the TIM23 complex to ensure protein import. The Pam16-Pam18 module also associates with components of the respiratory chain, but the function of the dual localization of Pam16-Pam18 is largely unknown. Here, we show that disruption of the Pam16-Pam18 heterodimer causes redistribution of Pam18 to the respiratory chain supercomplexes, where it forms a homodimer. Redistribution of Pam18 decreases protein import into mitochondria but stimulates mtHsp70-dependent assembly of respiratory chain complexes. We conclude that coupling to Pam16 differentially controls the dual function of Pam18. It recruits Pam18 to the TIM23 complex to promote protein import but attenuates the Pam18 function in the assembly of respiratory chain complexes.
    Keywords:  CP: Cell biology; CP: Metabolism; Pam18; TIM23 complex; cytochrome c oxidase; mitochondria; mtHsp70; protein sorting; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2022.110619
  7. J Mol Med (Berl). 2022 Apr 07.
    The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
    Klaudia K Maruszczak, Martin Jung, Shafqat Rasool, Jean-François Trempe, Doron Rapaport.
      Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinson's disease. PINK1, which is mutated in some cases of familial Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria. KEY MESSAGES: TOM70 is the main receptor for the import of PINK1 into mitochondria. TOM20 plays only a minor role in PINK1 recognition at the organellar outer membrane. PINK1 association with the TOM complex is reduced upon knock-down of TOM7. The lumen of the TOM pore is crucial for PINK1 association with the outer membrane. TcPINK1 blocks the TOM pore in depolarized mitochondria.
    Keywords:  Mitochondria; Outer membrane; PINK1; Parkinson’s disease; TOM complex
    DOI:  https://doi.org/10.1007/s00109-022-02191-6
  8. Nat Commun. 2022 Apr 06. 13(1): 1853
    DELE1 tracks perturbed protein import and processing in human mitochondria.
    Evelyn Fessler, Luisa Krumwiede, Lucas T Jae.
      Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.
    DOI:  https://doi.org/10.1038/s41467-022-29479-y
  9. Semin Cell Dev Biol. 2022 Mar 30. pii: S1084-9521(22)00095-7. [Epub ahead of print]
    Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
    Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Junior, Cecilia Bucci, Christiaan Leeuwenburgh, Emanuele Marzetti.
      Mitochondrial remodeling is crucial to meet the bioenergetic demand to support muscle contractile activity during daily tasks and muscle regeneration following injury. A set of mitochondrial quality control (MQC) processes, including mitochondrial biogenesis, dynamics, and mitophagy, are in place to maintain a well-functioning mitochondrial network and support muscle regeneration. Alterations in any of these pathways compromises mitochondrial quality and may potentially lead to impaired myogenesis, defective muscle regeneration, and ultimately loss of muscle function. Among MQC processes, mitophagy has gained special attention for its implication in the clearance of dysfunctional mitochondria via crosstalk with the endo-lysosomal system, a major cell degradative route. Along this pathway, additional opportunities for mitochondrial disposal have been identified that may also signal at the systemic level. This communication occurs via inclusion of mitochondrial components within membranous shuttles named mitochondrial-derived vesicles (MDVs). Here, we discuss MDV generation and release as a mitophagy-complementing route for the maintenance of mitochondrial homeostasis in skeletal myocytes. We also illustrate the possible role of muscle-derived MDVs in immune signaling during muscle remodeling and adaptation.
    Keywords:  Extracellular vesicles; Mitochondrial DNA damage; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.023
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