bims-mikwok 2022-04-10 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2022‒04‒10
nine papers selected by
Avinash N. Mukkala
University of Toronto

Endosomal-associated RFFL facilitates mitochondrial clearance by enhancing PRKN/parkin recruitment to mitochondria.
Mitochondrial-derived vesicles in skeletal muscle remodeling and adaptation.
WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
DELE1 tracks perturbed protein import and processing in human mitochondria.
XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury.
Mitochondria-associated myosin 19 processively transports mitochondria on actin tracks in living cells.
The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria.
Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury.

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
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
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
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
Redox Biol. 2022 Mar 28. pii: S2213-2317(22)00077-5. [Epub ahead of print]52 102305

XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury.

Zheng Liu, Mingming Wang, Xun Wang, Qingfa Bu, Qi Wang, Wantong Su, Lei Li, Haoming Zhou, Ling Lu.

  Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, the function and mechanism of XBP1 in thioacetamide (TAA)-induced acute liver injury (ALI) remains unknown. Here, we investigated the effects of XBP1 inhibition on promoting hepatocellular pyroptosis to activate macrophage STING signaling during ALI. While both TAA- and LPS-induced ALI triggered XBP1 activation in hepatocytes, hepatocyte-specific XBP1 knockout mice exhibited exacerbated ALI with increased hepatocellular pyroptosis and enhanced macrophage STING activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing macrophage STING activation in a cGAS- and dose-dependent manner. XBP1 deficiency increased ROS production to promote hepatocellular pyroptosis by activating NLRP3/caspase-1/GSDMD signaling, which facilitated the extracellular release of mtDNA. Moreover, impaired mitophagy was found in XBP1 deficient hepatocytes, which was reversed by PINK1 overexpression. Mitophagy restoration also inhibited macrophage STING activation and ALI in XBP1 deficient mice. Activation of XBP1-mediated hepatocellular mitophagy and pyroptosis and macrophage STING signaling pathway were observed in human livers with ALI. Collectively, these findings demonstrate that XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA/cGAS/STING signaling of macrophages, providing potential therapeutic targets for ALI.

Keywords:  Acute liver injury; Mitophagy; Pyroptosis; STING; XBP1

DOI:  https://doi.org/10.1016/j.redox.2022.102305
J Biol Chem. 2022 Mar 30. pii: S0021-9258(22)00323-4. [Epub ahead of print] 101883

Mitochondria-associated myosin 19 processively transports mitochondria on actin tracks in living cells.

Osamu Sato, Tsuyoshi Sakai, Young-Yeon Choo, Reiko Ikebe, Tomonobu M Watanabe, Mitsuo Ikebe.

  Mitochondria are fundamentally important in cell function and their malfunction can cause the development of cancer, cardiovascular disease, and neuronal disorders. Myosin 19 (Myo19) shows discrete localization with mitochondria and is thought to play an important role in mitochondrial dynamics and function; however, the function of Myo19 in mitochondrial dynamics at the cellular and molecular levels is poorly understood. Critical missing information is whether Myo19 is a processive motor that is suitable for transportation of mitochondria. Here we show for the first time that single Myo19 molecules processively move on actin filaments and can transport mitochondria in cells. We demonstrate that Myo19 dimers having a leucine-zipper processively moved on cellular actin tracks in de-membraned cells with a velocity of 50-60 nm/s and a run length of ∼0.4 μm, similar to the movement of isolated mitochondria from Myo19 dimer-transfected cells on actin tracks, suggesting that the Myo19 dimer can transport mitochondria. Furthermore, we show single molecules of Myo19 dimers processively moved on single actin filaments with a large step size of ∼34 nm. Importantly, wild type Myo19 single molecules without the leucine-zipper processively move in filopodia in living cells similar to Myo19 dimers, while deletion of the tail domain abolished such active movement. These results suggest that Myo19 can processively move on actin filaments when two Myo19 monomers form a dimer, presumably as a result of tail-tail association. In conclusion, Myo19 molecules can directly transport mitochondria on actin tracks within living cells.

Keywords:  TIRF microscopy; Unconventional myosin; intracellular movement; mitochondria; single-molecule

DOI:  https://doi.org/10.1016/j.jbc.2022.101883
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
Front Pharmacol. 2022 ;13 854994

Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.

Shishi Liao, Jie Luo, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.

  Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.

Keywords:  damage-associated molecular patterns2; inflammation3; intestinal barrier function5; ischemia/reperfusion injury4; mitochondrial DNA1; multiple organ dysfunction syndrome7; systemic inflammatory response syndrome6

DOI:  https://doi.org/10.3389/fphar.2022.854994
Nat Commun. 2022 Apr 05. 13(1): 1823

ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury.

Anne-Katrin Rohlfing, Kyra Kolb, Manuel Sigle, Melanie Ziegler, Alexander Bild, Patrick Münzer, Jessica Sudmann, Valerie Dicenta, Tobias Harm, Mailin-Christin Manke, Sascha Geue, Marcel Kremser, Madhumita Chatterjee, Chunguang Liang, Hendrik von Eysmondt, Thomas Dandekar, David Heinzmann, Manina Günter, Saskia von Ungern-Sternberg, Manuela Büttcher, Tatsiana Castor, Stine Mencl, Friederike Langhauser, Katharina Sies, Diyaa Ashour, Mustafa Caglar Beker, Michael Lämmerhofer, Stella E Autenrieth, Tilman E Schäffer, Stefan Laufer, Paulina Szklanna, Patricia Maguire, Matthias Heikenwalder, Karin Anne Lydia Müller, Dirk M Hermann, Ertugrul Kilic, Ralf Stumm, Gustavo Ramos, Christoph Kleinschnitz, Oliver Borst, Harald F Langer, Dominik Rath, Meinrad Gawaz.

Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.

DOI: https://doi.org/10.1038/s41467-022-29341-1