bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2021–12–12
ten papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
  2. The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
  3. Mitochondrial dynamics and diabetic kidney disease: Missing pieces for the puzzle of therapeutic approaches.
  4. Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction.
  5. MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
  6. Mitochondria-Shaping Proteins and Chemotherapy.
  7. Live-imaging of Mitochondrial System in Cultured Astrocytes.
  8. Mitochondrial Fission Complex is Required for Long-Term Heat Tolerance of Arabidopsis.
  9. Mitochondrial Fission in Allograft Endothelial Cells: A Novel Actionable Target.
  10. Surveying the mitochondrial proteome.
  1. Nat Cell Biol. 2021 Dec 06.
    MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
    Tim König, Hendrik Nolte, Mari J Aaltonen, Takashi Tatsuta, Michiel Krols, Thomas Stroh, Thomas Langer, Heidi M McBride.
      Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+ MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.
    DOI:  https://doi.org/10.1038/s41556-021-00798-4
  2. Nat Metab. 2021 Dec 06.
    The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites.
    Camilla Bean, Matteo Audano, Tatiana Varanita, Francesca Favaretto, Marta Medaglia, Marco Gerdol, Lena Pernas, Fabio Stasi, Marta Giacomello, Stèphanie Herkenne, Maheswany Muniandy, Sini Heinonen, Emma Cazaly, Miina Ollikainen, Gabriella Milan, Alberto Pallavicini, Kirsi H Pietiläinen, Roberto Vettor, Nico Mitro, Luca Scorrano.
      White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.
    DOI:  https://doi.org/10.1038/s42255-021-00497-2
  3. J Cell Mol Med. 2021 Dec 09.
    Mitochondrial dynamics and diabetic kidney disease: Missing pieces for the puzzle of therapeutic approaches.
    Phoom Narongkiatikhun, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Diabetic kidney disease (DKD) is a common microvascular complication among diabetic patients. Once the DKD has developed, most of the patients inevitably progress to the end-stage renal disease (ESRD). Although many new therapeutic strategies have attempted to demolish the root of the pathogenesis of DKD, the residual risks of ESRD still remained. Alteration of mitochondrial dynamics towards mitochondrial fission concurrent with the mitochondrial dysfunction is the characteristic that is usually seen in various diseases, including DKD. It has been proposed that those perturbation and their cooperative networks could be responsible for the residual risk of ESRD in DKD patients. In this review, the collective evidence of alteration in mitochondrial dynamics and their associations with the mitochondrial function from in vitro, in vivo and clinical reports of DKD are comprehensively summarized and discussed. In addition, both basic and clinical reports regarding the pharmacological interventions that showed an impact on the mitochondrial dynamics, and the correlation with the renal parameters in DKD is presented. Understanding these complex mechanisms in combination with the existing therapeutic modalities could bring a new opportunity to overcome the unresolvable problem of DKD.
    Keywords:  diabetic kidney disease; mitochondrial dynamics; mitochondrial functions; pathogenesis; pharmacological interventions
    DOI:  https://doi.org/10.1111/jcmm.17116
  4. Free Radic Biol Med. 2021 Dec 04. pii: S0891-5849(21)00855-8. [Epub ahead of print]178 134-146
    Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction.
    Yan Yang, Yue Liu, Jixiang Zhu, Shiyu Song, Yulin Huang, Wei Zhang, Yu'e Sun, Jing Hao, Xuli Yang, Qian Gao, Zhengliang Ma, Juan Zhang, Xiaoping Gu.
      Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.
    Keywords:  Calcineurin; Drp1; Mitochondrial function; Neuroinflammation; POCD
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.004
  5. J Cell Sci. 2021 Dec 06. pii: jcs.257808. [Epub ahead of print]
    MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
    Rajdeep Das, Izaz Monir Kamal, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.
      Mutations in Mitofusin2 (MFN2), associated with the pathology of the debilitating neuropathy, Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutant, R364W results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1. The Ubiquitin E3 ligase MITOL is known to ubiquitylate both MFN2 and DRP1. Interaction with and its subsequent ubiquitylation by MITOL is stronger in presence of WT-MFN2 than R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multimonoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown before.
    Keywords:  CMT2A-linked MFN2 mutant; DRP1; MITOL; Mitochondrial hyperfusion; Ubiquitylation
    DOI:  https://doi.org/10.1242/jcs.257808
  6. Front Oncol. 2021 ;11 769036
    Mitochondria-Shaping Proteins and Chemotherapy.
    Longlong Xie, Tiansheng Zhou, Yujun Xie, Ann M Bode, Ya Cao.
      The emergence, in recent decades, of an entirely new area of "Mitochondrial dynamics", which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as "shaping proteins". Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.
    Keywords:  Mitochondria-shaping proteins; chemotherapy; energy metabolism; targeted drugs; virus
    DOI:  https://doi.org/10.3389/fonc.2021.769036
  7. J Vis Exp. 2021 Nov 16.
    Live-imaging of Mitochondrial System in Cultured Astrocytes.
    Jeanne Espourteille, Valentin Zufferey, Jean-Honoré Laurent, Kevin Richetin.
      While much attention has been given to mitochondrial alterations at the neuronal level, recent evidence demonstrates that mitochondrial dynamics and function in astrocytes are implicated in cognition. This article describes the method for time-lapse imaging of astrocyte cultures equipped with a mitochondrial biosensor: MitoTimer. MitoTimer is a powerful and unique tool to assess mitochondrial dynamics, mobility, morphology, biogenesis, and redox state. Here, the different procedures for culture, image acquisitions, and subsequent mitochondrial analysis are presented.
    DOI:  https://doi.org/10.3791/62957
  8. Plant Cell Physiol. 2021 Dec 01. pii: pcab171. [Epub ahead of print]
    Mitochondrial Fission Complex is Required for Long-Term Heat Tolerance of Arabidopsis.
    Ryo Tsukimoto, Kazuho Isono, Takuma Kajino, Satoshi Iuchi, Akihisa Shinozawa, Izumi Yotsui, Yoichi Sakata, Teruaki Taji.
      Plants are often exposed not only to short-term (S) heat stress but also to long-term (L) heat stress over several consecutive days. A few Arabidopsis mutants defective in L-heat tolerance have been identified, but the molecular mechanisms involved are less well understood than those involved in S-heat tolerance. To elucidate the mechanisms, we isolated the new sensitive to long-term heat5 (sloh5) mutant from EMS-mutagenized seeds of L-heat-tolerant Col-0. The sloh5 mutant was hypersensitive to L-heat but not to S-heat, osmo-shock, salt-shock, or oxidative stress. The causal gene, SLOH5, is identical to ELONGATED MITOCHONDRIA1 (ELM1), which plays an important role in mitochondrial fission in conjunction with dynamin-related proteins DRP3A and DRP3B. Transcript levels of ELM1, DRP3A, and DRP3B were time-dependently increased by L-heat stress, and drp3a drp3b double mutants were hypersensitive to L-heat stress. The sloh5 mutant contained massively elongated mitochondria. L-heat stress caused mitochondrial dysfunction and cell death in sloh5. Furthermore, WT plants treated with a mitochondrial myosin ATPase inhibitor were hypersensitive to L-heat stress. These findings suggest that mitochondrial fission and function are important in L-heat tolerance of Arabidopsis.
    Keywords:   Arabidopsis thaliana ; heat; long-term heat; mitochondrial fission; tolerance
    DOI:  https://doi.org/10.1093/pcp/pcab171
  9. Am J Transplant. 2021 Dec 05.
    Mitochondrial Fission in Allograft Endothelial Cells: A Novel Actionable Target.
    Clancy W Mullan, Jordan S Pober.
      Allograft vascular endothelial cells (ECs) largely remain of donor origin in clinical transplantation (1) and form the primary interface between the recipient and the allograft. Post-transplant, graft ECs sustain normal graft function but also can initiate host anti-graft immune responses(2). Human graft ECs can present both class I and II major histocompatibility molecules, display co-stimulatory ligands that specifically affect memory T cells, and express various adhesion molecules and chemokines responsible for leukocyte recruitment. Many of these EC surface molecules are expressed at low levels or completely absent in resting ECs but may be induced by pro-inflammatory cytokines in the local milieu(2, 3), and EC activation is likely a prerequisite for rejection. However, EC responses to cytokines vary both among and within transplanted organs depending on anatomic location and on exposure to pathological processes, such as ischemia reperfusion injury (IRI). IRI can induce fission and fragmentation of mitochondria, resulting in activation of numerous intracellular and extracellular signaling pathways(4).
    DOI:  https://doi.org/10.1111/ajt.16911
  10. Nat Cell Biol. 2021 Dec 06.
    Surveying the mitochondrial proteome.
    Dominic Winter, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s41556-021-00801-y
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