bims-midbra Biomed News
on Mitochondrial dynamics in brain cells
Issue of 2022‒04‒10
six papers selected by
Ana Paula Mendonça
University of Padova
  1. Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns.
  2. WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
  3. Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons.
  4. ER-Mitochondria contacts modulate ROS-mediated signaling and oxidative stress in brain disorders: the key role of Sigma-1 receptor.
  5. Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria.
  6. The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
  1. Front Cell Dev Biol. 2022 ;10 837337
    Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns.
    Cuckoo Teresa Jetto, Akshaya Nambiar, Ravi Manjithaya.
      Macroautophagy (henceforth autophagy) an evolutionary conserved intracellular pathway, involves lysosomal degradation of damaged and superfluous cytosolic contents to maintain cellular homeostasis. While autophagy was initially perceived as a bulk degradation process, a surfeit of studies in the last 2 decades has revealed that it can also be selective in choosing intracellular constituents for degradation. In addition to the core autophagy machinery, these selective autophagy pathways comprise of distinct molecular players that are involved in the capture of specific cargoes. The diverse organelles that are degraded by selective autophagy pathways are endoplasmic reticulum (ERphagy), lysosomes (lysophagy), mitochondria (mitophagy), Golgi apparatus (Golgiphagy), peroxisomes (pexophagy) and nucleus (nucleophagy). Among these, the main focus of this review is on the selective autophagic pathway involved in mitochondrial turnover called mitophagy. The mitophagy pathway encompasses diverse mechanisms involving a complex interplay of a multitude of proteins that confers the selective recognition of damaged mitochondria and their targeting to degradation via autophagy. Mitophagy is triggered by cues that signal the mitochondrial damage such as disturbances in mitochondrial fission-fusion dynamics, mitochondrial membrane depolarisation, enhanced ROS production, mtDNA damage as well as developmental cues such as erythrocyte maturation, removal of paternal mitochondria, cardiomyocyte maturation and somatic cell reprogramming. As research on the mechanistic aspects of this complex pathway is progressing, emerging roles of new players such as the NIPSNAP proteins, Miro proteins and ER-Mitochondria contact sites (ERMES) are being explored. Although diverse aspects of this pathway are being investigated in depth, several outstanding questions such as distinct molecular players of basal mitophagy, selective dominance of a particular mitophagy adapter protein over the other in a given physiological condition, molecular mechanism of how specific disease mutations affect this pathway remain to be addressed. In this review, we aim to give an overview with special emphasis on molecular and signalling pathways of mitophagy and its dysregulation in neurodegenerative disorders.
    Keywords:  mitochondrial dynamics; mitochondrial dysfunction; mitophagy; neurodegenaration; phosphorylation; ubiquitination
    DOI:  https://doi.org/10.3389/fcell.2022.837337
  2. Autophagy. 2022 Apr 07. 1-15
    WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
    Guang Lu, Hayden Weng Siong Tan, Tomas Schmauck-Medina, Liming Wang, Jiaqing Chen, Yik-Lam Cho, Kelie Chen, Jing-Zi Zhang, Weifeng He, Yihua Wu, Dajing Xia, Jing Zhou, Evandro F Fang, Lei Fang, Wei Liu, Han-Ming Shen.
      The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.Abbreviations: ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
    Keywords:  Autophagy; PINK1; PRKN; VCP; WIPI2; cell death; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2052461
  3. 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
  4. Antioxid Redox Signal. 2022 Apr 04.
    ER-Mitochondria contacts modulate ROS-mediated signaling and oxidative stress in brain disorders: the key role of Sigma-1 receptor.
    Rosa Resende, Tânia Fernandes, Ana Catarina Pereira, Ana Patrícia Marques, Cláudia Fragão Pereira.
      SIGNIFICANCE: Mitochondria-Associated Membranes (MAMs) are highly dynamic endoplasmic reticulum (ER)-mitochondria contact sites that, due to the transfer of lipids and Ca2+ between these organelles, modulate several physiologic processes, such as ER stress response, mitochondrial bioenergetics and fission/fusion events, autophagy and inflammation. In addition, these contacts are implicated in the modulation of the cellular redox status since several MAMs-resident proteins are involved in the generation of reactive oxygen species (ROS), which can act both as signaling mediators or deleterious molecules, depending on their intracellular levels.RECENT ADVANCES: In the last years, structural and functional alterations of MAMs have been associated with the pathophysiology of several neurodegenerative diseases that are closely associated with impairment of several MAMs-associated events, including perturbation of the redox state upon accumulation of high ROS levels.
    CRITICAL ISSUES: Inter-organelle contacts must be tightly regulated to preserve cellular functioning by maintaining Ca2+ and protein homeostasis, lipid metabolism, mitochondrial dynamics and energy production, as well as ROS signaling. Simultaneously, these contacts should avoid mitochondrial Ca2+ overload, which might lead to energetic deficits and deleterious ROS accumulation, culminating in oxidative stress-induced activation of apoptotic cell death pathways, which are common features of many neurodegenerative diseases.
    FUTURE DIRECTIONS: Given that Sig-1R is an ER resident chaperone highly enriched at the MAMs and controls ER to mitochondria Ca2+ flux, as well as oxidative and ER stress responses, its potential as a therapeutic target for neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer, Parkinson and Huntington diseases should be further explored.
    DOI:  https://doi.org/10.1089/ars.2020.8231
  5. Autophagy. 2022 Apr 03. 1-14
    Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria.
    Rishith Ravindran, Anoop Kumar G Velikkakath, Nikhil Dev Narendradev, Aneesh Chandrasekharan, T R Santhoshkumar, Srinivasa M Srinivasula.
      Mutations in the ubiquitin ligase PRKN (parkin RBR E3 ubiquitin protein ligase) are associated with Parkinson disease and defective mitophagy. Conceptually, PRKN-dependent mitophagy is classified into two phases: 1. PRKN recruits to and ubiquitinates mitochondrial proteins; 2. formation of phagophore membrane, sequestering mitochondria for degradation. Recently, endosomal machineries are reported to contribute to the later stage for membrane assembly. We reported a role for endosomes in the events upstream of phase 1. We demonstrate that the endosomal ubiquitin ligase RFFL (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) associated with damaged mitochondria, and this association preceded that of PRKN. RFFL interacted with PRKN, and stable recruitment of PRKN to damaged mitochondria was substantially reduced in RFFL KO cells. Our study unraveled a novel role of endosomes in modulating upstream pathways of PRKN-dependent mitophagy initiation.Abbreviations CCCP: carbonyl cyanide 3-chlorophenylhydrazone; DMSO: dimethyl sulfoxide; EGFP: enhanced green fluorescence protein; KO: knockout; PRKN: parkin RBR E3 ubiquitin protein ligase; RFFL: ring finger and FYVE like domain containing E3 ubiquitin protein ligase; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; WT: wild-type.
    Keywords:  Endosomes; PRKN; RFFL; mitophagy; ubiquitin ligases
    DOI:  https://doi.org/10.1080/15548627.2022.2052460
  6. 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
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