bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–04–17
ten papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology.
  2. Mitochondrial shape alteration by metabolites.
  3. Mitochondrial Dynamics in the Metabolic Memory of Diabetic Retinopathy.
  4. Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy.
  5. The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology.
  6. Mfn2-mediated mitochondrial fusion alleviates doxorubicin-induced cardiotoxicity with enhancing its anticancer activity through metabolic switch.
  7. GJA1-20k and Mitochondrial Dynamics.
  8. PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.
  9. Myosin II proteins are required for organization of calcium-induced actin networks upstream of mitochondrial division.
  10. [Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression].
  1. Cells. 2022 Mar 31. pii: 1175. [Epub ahead of print]11(7):
    CARD19 Interacts with Mitochondrial Contact Site and Cristae Organizing System Constituent Proteins and Regulates Cristae Morphology.
    Kariana E Rios, Ming Zhou, Nathaniel M Lott, Chelsi R Beauregard, Dennis P McDaniel, Thomas P Conrads, Brian C Schaefer.
      CARD19 is a mitochondrial protein of unknown function. While CARD19 was originally reported to regulate TCR-dependent NF-κB activation via interaction with BCL10, this function is not recapitulated ex vivo in primary murine CD8+ T cells. Here, we employ a combination of SIM, TEM, and confocal microscopy, along with proteinase K protection assays and proteomics approaches, to identify interacting partners of CARD19 in macrophages. Our data show that CARD19 is specifically localized to the outer mitochondrial membrane. Through deletion of functional domains, we demonstrate that both the distal C-terminus and transmembrane domain are required for mitochondrial targeting, whereas the CARD is not. Importantly, mass spectrometry analysis of 3×Myc-CARD19 immunoprecipitates reveals that CARD19 interacts with the components of the mitochondrial intermembrane bridge (MIB), consisting of mitochondrial contact site and cristae organizing system (MICOS) components MIC19, MIC25, and MIC60, and MICOS-interacting proteins SAMM50 and MTX2. These CARD19 interactions are in part dependent on a properly folded CARD. Consistent with previously reported phenotypes upon siRNA silencing of MICOS subunits, absence of CARD19 correlates with irregular cristae morphology. Based on these data, we propose that CARD19 is a previously unknown interacting partner of the MIB and the MIC19-MIC25-MIC60 MICOS subcomplex that regulates cristae morphology.
    Keywords:  BinCARD; CARD proteins; CARD19; MIB; MICOS; cristae
    DOI:  https://doi.org/10.3390/cells11071175
  2. Nat Cell Biol. 2022 Apr 13.
    Mitochondrial shape alteration by metabolites.
    Till Klecker, Benedikt Westermann.
      
    DOI:  https://doi.org/10.1038/s41556-022-00889-w
  3. J Diabetes Res. 2022 ;2022 3555889
    Mitochondrial Dynamics in the Metabolic Memory of Diabetic Retinopathy.
    Ghulam Mohammad, Renu A Kowluru.
      Mitochondria play a central role in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. Mitochondria have a regulated fusion fission process, which is essential for their homeostasis. One of the major fission proteins, dynamin-related protein 1 (Drp1), is recruited to the mitochondria by fission protein 1 (Fis1) to initiate fragmentation. Our aim is to investigate the role of Drp1 in the altered mitochondrial dynamics in the continued progression of diabetic retinopathy. Methods. Drp1 activation, mitochondrial transport, and Drp1-Fis1 interactions were analyzed in retinal endothelial cells incubated in 20 mM glucose (HG), followed by 5 mM glucose (NG), for four days each (HG-NG group). The results were confirmed in retinal microvessels from streptozotocin-induced diabetic rats with poor glycemia (>350 mg/dl blood glucose, PC group), followed by normal glycemia (~100 mg/dl), for four months each (PC-GC group). Results. GTPase activity of Drp1, Fis1-Drp1 interactions, mitochondrial levels of Drp1, and fragmentation of the mitochondria were elevated in HG group. Mitochondrial Division Inhibitor 1 (Mdiv) or Drp1-siRNA attenuated Drp1 activation, mitochondrial fragmentation, and DNA damage. In HG-NG group, NG failed to ameliorate Drp1 activation and Drp1-Fis1 interactions, and the mitochondria remained fragmented. However, Mdiv supplementation in normal glucose, which had followed four days of high glucose (HG-NG/Mdiv group), inhibited Drp1 activation, mitochondrial fragmentation, and increase in ROS and prevented mitochondrial damage. Retinal microvessels from the rats in PC and PC-GC groups had similar Drp1 activation. Conclusion. Thus, Drp1 plays a major role in mitochondrial homeostasis in diabetic retinopathy and in the metabolic memory phenomenon associated with its continued progression. Supplementation of normal glycemia with a Drp1 inhibitor could retard development and further progression of diabetic retinopathy.
    DOI:  https://doi.org/10.1155/2022/3555889
  4. Redox Biol. 2022 Apr 06. pii: S2213-2317(22)00076-3. [Epub ahead of print]52 102304
    Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy.
    Ying Jiang, Sarah Krantz, Xiang Qin, Shun Li, Hirushi Gunasekara, Young-Mee Kim, Adriana Zimnicka, Misuk Bae, Ke Ma, Peter T Toth, Ying Hu, Ayesha N Shajahan-Haq, Hemal H Patel, Saverio Gentile, Marcelo G Bonini, Jalees Rehman, Yiyao Liu, Richard D Minshall.
      As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria. Moreover, limiting mitochondrial recruitment of Mfn2 diminished formation of the PINK1/Mfn2/Parkin complex required for initiation of mitophagy resulting in accumulation of damaged mitochondria and ROS (mtROS). Thus, these studies indicate that phospho-Cav-1 may be an important switch mechanism in cancer cell survival which could lead to novel strategies for complementing cancer therapies.
    Keywords:  Cav-1; Dynamin-related protein 1; Mitochondrial dynamics; Mitofusin 2; Mitophagy; mtROS
    DOI:  https://doi.org/10.1016/j.redox.2022.102304
  5. Front Cell Dev Biol. 2022 ;10 858286
    The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology.
    Mashiat Zaman, Timothy E Shutt.
      The Mitofusin 2 protein (MFN2), encoded by the MFN2 gene, was first described for its role in mediating mitochondrial fusion. However, MFN2 is now recognized to play additional roles in mitochondrial autophagy (mitophagy), mitochondrial motility, lipid transfer, and as a tether to other organelles including the endoplasmic reticulum (ER) and lipid droplets. The tethering role of MFN2 is an important mediator of mitochondrial-ER contact sites (MERCs), which themselves have many important functions that regulate mitochondria, including calcium homeostasis and lipid metabolism. Exemplifying the importance of MFN2, pathogenic variants in MFN2 are established to cause the peripheral neuropathy Charcot-Marie-Tooth Disease Subtype 2A (CMT2A). However, the mechanistic basis for disease is not clear. Moreover, additional pathogenic phenotypes such as lipomatosis, distal myopathy, optic atrophy, and hearing loss, can also sometimes be present in patients with CMT2A. Given these variable patient phenotypes, and the many cellular roles played by MFN2, the mechanistic underpinnings of the cellular impairments by which MFN2 dysfunction leads to disease are likely to be complex. Here, we will review what is known about the various functions of MFN2 that are impaired by pathogenic variants causing CMT2A, with a specific emphasis on the ties between MFN2 variants and MERCs.
    Keywords:  CMT2A; MFN2; lipid homeostasis; mitochondria; mitochondrial dynamics; mitochondrial endoplasmic reticulum contact sites; mitophagy; mtDNA
    DOI:  https://doi.org/10.3389/fcell.2022.858286
  6. Redox Biol. 2022 Apr 05. pii: S2213-2317(22)00083-0. [Epub ahead of print]52 102311
    Mfn2-mediated mitochondrial fusion alleviates doxorubicin-induced cardiotoxicity with enhancing its anticancer activity through metabolic switch.
    Mingge Ding, Rui Shi, Shuli Cheng, Man Li, Dema De, Chaoyang Liu, Xiaoming Gu, Juan Li, Shumiao Zhang, Min Jia, Rong Fan, Jianming Pei, Feng Fu.
      Imbalanced mitochondrial dynamics including inhibited mitochondrial fusion is associated with cardiac dysfunction as well as tumorigenesis. This study sought to explore the effects of promoting mitochondrial fusion on doxorubicin(Dox)-induced cardiotoxicity and its antitumor efficacy, with a focus on the underlying metabolic mechanisms. Herein, the inhibition of Mfn2-mediated mitochondrial fusion was identified as a key phenotype in Dox-induced cardiotoxicity. Restoration of Mfn2-mediated mitochondrial fusion enhanced mitochondrial oxidative metabolism, reduced cellular injury/apoptosis and inhibited mitochondria-derived oxidative stress in the Dox-treated cardiomyocytes. Application of lentivirus expressing Drp1 (mitochondrial fusion inhibitor) or Rote/Anti A (mitochondrial complex I/III inhibitors) blunted the above protective effects of Mfn2. Cardiac-specific Mfn2 transgenic mice showed preserved mitochondrial fusion and attenuated myocardial injury upon Dox exposure in vivo. The suppression of Mfn2-mediated mitochondrial fusion was induced by Dox-elicited upregulation of FoxO1, which inhibited the transcription of Mfn2 by binding to its promoter sites. In the B16 melanoma, Mfn2 upregulation not only attenuated tumor growth alone but also further delayed tumor growth in the presence of Dox. Mechanistically, Mfn2 synergized with the inhibitory action of Dox on glycolysis metabolism in the tumor cells. One common feature in both cardiomyocytes and tumor cells was that Mfn2 increased the ratio of oxygen consumption rate to extracellular acidification rate, suggesting Mfn2 triggered a shift from aerobic glycolysis to mitochondrial oxidative metabolism. In conclusion, targeting Mfn2-mediated mitochondrial fusion may provide a dual therapeutic advantage in Dox-based chemotherapy by simultaneously defending against Dox-induced cardiotoxicity and boosting its antitumor potency via metabolic shift.
    Keywords:  Doxorubicin cardiotoxicity; FoxO1; Metabolism; Mfn2; Mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.redox.2022.102311
  7. Front Physiol. 2022 ;13 867358
    GJA1-20k and Mitochondrial Dynamics.
    Daisuke Shimura, Robin M Shaw.
      Connexin 43 (Cx43) is the primary gap junction protein of mammalian heart ventricles and is encoded by the gene Gja1 which has a single coding exon and therefore cannot be spliced. We previously identified that Gja1 mRNA undergoes endogenous internal translation initiated at one of several internal AUG (M) start codons, generating N-terminal truncated protein isoforms that retain the C-terminus distal to the start site. GJA1-20k, whose translation initiates at mRNA M213, is usually the most abundant isoform in cells and greatly increases after ischemic and metabolic stress. GJA1-20k consists of a small segment of the last transmembrane domain and the complete C-terminus tail of Cx43, with a total size of about 20 kDa. The original role identified for GJA1-20k is as an essential subunit that facilitates the trafficking of full-length Cx43 hexameric hemichannels to cell-cell contacts, generating traditional gap junctions between adjacent cells facilitating, in cardiac muscle, efficient spread of electrical excitation. GJA1-20k deficient mice (generated by a M213L substitution in Gja1) suffer poor electrical coupling between cardiomycytes and arrhythmogenic sudden death two to 4 weeks after their birth. We recently identified that exogenous GJA1-20k expression also mimics the effect of ischemic preconditioning in mouse heart. Furthermore, GJA1-20k localizes to the mitochondrial outer membrane and induces a protective and DRP1 independent form of mitochondrial fission, preserving ATP production and generating less reactive oxygen species (ROS) under metabolic stress, providing powerful protection of myocardium to ischemic insult. In this manuscript, we focus on the detailed roles of GJA1-20k in mitochondria, and its interaction with the actin cytoskeleton.
    Keywords:  GJA1-20k; actin; connexin43; ischemia; mitochondria; trafficking
    DOI:  https://doi.org/10.3389/fphys.2022.867358
  8. Signal Transduct Target Ther. 2022 Apr 15. 7(1): 103
    PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.
    Qingtao Gao, Runyi Tian, Hailong Han, Jesse Slone, Caifang Wang, Xiao Ke, Tongmei Zhang, Xiangyu Li, Yuhong He, Panlin Liao, Fang Wang, Ye Chen, Shiqing Fu, Kexuan Zhang, Fangfang Zeng, Yingxuan Yang, Zhuo Li, Jieqiong Tan, Jiada Li, Youming Lu, Taosheng Huang, Zhonghua Hu, Zhuohua Zhang.
      Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.
    DOI:  https://doi.org/10.1038/s41392-022-00933-z
  9. Mol Biol Cell. 2022 Apr 15. mbcE22010005
    Myosin II proteins are required for organization of calcium-induced actin networks upstream of mitochondrial division.
    Frieda Kage, Miguel Vicente-Manzanares, Brennan C McEwan, Arminja N Kettenbach, Henry N Higgs.
      The formin INF2 polymerizes a calcium-activated cytoplasmic network of actin filaments, which we refer to as CIA (calcium-induced actin). CIA plays important roles in multiple cellular processes, including mitochondrial dynamics and vesicle transport. Here, we show that non-muscle myosin II (NMII) is activated within 60 sec of calcium stimulation and rapidly recruited to the CIA network. Knock-out of any individual NMII in U2OS cells affects the organization of the CIA network, as well as three downstream effects: ER-to-mitochondrial calcium transfer, mitochondrial Drp1 recruitment, and mitochondrial division. Interestingly, while NMIIC is the least abundant NMII in U2OS cells (>200-fold less than NMIIA and >10-fold less than NMIIB), its knock-out is equally deleterious to CIA. Based on these results, we propose that myosin II filaments containing all three NMII heavy chains exert organizational and contractile roles in the CIA network. In addition, NMIIA knock-out causes a significant decrease in myosin regulatory light chain levels, which might have additional effects.
    DOI:  https://doi.org/10.1091/mbc.E22-01-0005
  10. Nan Fang Yi Ke Da Xue Xue Bao. 2022 Mar 20. 42(3): 330-337
    [Bax inhibitor 1 inhibits vascular calcification in mice by activating optic atrophy 1 expression].
    W Chen, H DU, G Qian, Y Zhou, Y Chen, Q Ma, X Wu, Y Sha.
       OBJECTIVE: To investigate the effects of Bax inhibitor 1 (BI- 1) and optic atrophy protein 1 (OPA1) on vascular calcification (VC).
    METHODS: Mouse models of VC were established in ApoE-deficient (ApoE-/-) diabetic mice by high-fat diet feeding for 12 weeks followed by intraperitoneal injections with Nε-carboxymethyl-lysine for 16 weeks. ApoE-/- mice (control group), ApoE-/- diabetic mice (VC group), ApoE-/- diabetic mice with BI-1 overexpression (VC + BI-1TG group), and ApoE-/- diabetic mice with BI-1 overexpression and OPA1 knockout (VC+BI-1TG+OPA1-/- group) were obtained for examination of the degree of aortic calcification using von Kossa staining. The changes in calcium content in the aorta were analyzed using ELISA. The expressions of Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP-2) were detected using immunohistochemistry, and the expression of cleaved caspase-3 was determined using Western blotting. Cultured mouse aortic smooth muscle cells were treated with 10 mmol/L β-glycerophosphate for 14 days to induce calcification, and the changes in BI-1 and OPA1 protein expressions were examined using Western blotting and cell apoptosis was detected using TUNEL staining.
    RESULTS: ApoE-/- mice with VC showed significantly decreased expressions of BI-1 and OPA1 proteins in the aorta (P=0.0044) with obviously increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P= 0.0041). Overexpression of BI-1 significantly promoted OPA1 protein expression and reduced calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 (P=0.0006). OPA1 knockdown significantly increased calcium deposition and expressions of RUNX2, BMP-2 and cleaved caspase-3 in the aorta (P=0.0007).
    CONCLUSION: BI-1 inhibits VC possibly by promoting the expression of OPA1, reducing calcium deposition and inhibiting osteogenic differentiation and apoptosis of the vascular smooth muscle cells.
    Keywords:  Bax inhibitor 1; apoptosis; optic atrophy protein 1; osteogenic differentiation; vascular calcification
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2022.03.03
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