bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒01‒09
ten papers selected by
Avinash N. Mukkala, University of Toronto
  1. Temporal Analysis of Protein Ubiquitylation and Phosphorylation During Parkin-dependent Mitophagy.
  2. A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.
  3. The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.
  4. The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases.
  5. Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30.
  6. Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.
  7. Nek4 regulates mitochondrial respiration and morphology.
  8. Standpoints in Mitochondrial Dysfunction: Underlying Mechanisms in Search of Therapeutic Strategies.
  9. A novel perfusion culture system for screening mitochondrial toxicity in primary mouse hepatocytes.
  10. FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway.
  1. Mol Cell Proteomics. 2021 Dec 30. pii: S1535-9476(21)00163-8. [Epub ahead of print] 100191
    Temporal Analysis of Protein Ubiquitylation and Phosphorylation During Parkin-dependent Mitophagy.
    Katharina I Zittlau, Anna Lechado Terradas, Nicolas Nalpas, Sven Geisler, Philipp J Kahle, Boris Macek.
      Mitophagy, the selective degradation of mitochondria by autophagy, affects defective mitochondria following damage or stress. At the onset of mitophagy, parkin ubiquitylates proteins on the mitochondrial outer membrane (MOM). While the role of parkin at the onset of mitophagy is well understood, less is known about its activity during later stages of the process. Here we used HeLa cells expressing catalytically active or inactive parkin to perform temporal analysis of the proteome, ubiquitylome and phosphoproteome during 18 hours after induction of mitophagy by mitochondrial uncoupler carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Abundance profiles of proteins downregulated in parkin-dependent manner revealed a stepwise, "outside-in" directed degradation of mitochondrial subcompartments. While ubiquitylation of MOM proteins was enriched among early parkin-dependent targets, numerous mitochondrial inner membrane, matrix and cytosolic proteins were also found ubiquitylated at later stages of mitophagy. Phosphoproteome analysis revealed a possible cross-talk between phosphorylation and ubiquitylation during mitophagy on key parkin targets, such as VDAC1/2.
    Keywords:  Mitochondria; Mitophagy; Parkin; Quantitative proteomics; Ubiquitin
    DOI:  https://doi.org/10.1016/j.mcpro.2021.100191
  2. J Cardiovasc Pharmacol. 2021 Dec 31.
    A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.
    Miyuki Kobara, Hiroe Toba, Tetsuo Nakata.
      ABSTRACT: Glucagon-like peptide 1 (GLP-1) analogues improve glycemic control in diabetes and protect the heart against ischemia-reperfusion injury. However, the mechanisms underlying this protection remain unclear. Mitochondria are essential for myocyte homeostasis. Therefore, we herein examined the effects of a GLP-1 analogue on mitochondria after the hypoxia-reoxygenation of rat neonatal cultured cardiomyocytes. Cardiomyocytes were subjected to hypoxia for 5 hours followed by reoxygenation for 30 minutes in the presence or absence of exendin 4 (50 nmol/L), a GLP-1 analogue. Hypoxia-reoxygenation increased lactate dehydrogenase and caspase-3 activities, indicators of lethal myocyte injury and apoptosis, respectively, and exendin 4 attenuated these increases. The content of ATP in myocytes decreased after hypoxia-reoxygenation, but was preserved by exendin 4. The membrane potential and shape of mitochondria were assessed using a fluorescent probe. Exendin 4 attenuated the hypoxia-reoxygenation-induced disruption of the mitochondrial membrane potential and shortening. Mitochondrial quality control-related factors, such as optic atrophy protein 1 (OPA1), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and parkin, were examined by Western blotting. Exendin 4 significantly increased the expression of the fusion proteins, OPA1 and Mfn2, and decreased that of the mitophagy-related protein, parkin, without altering Drp1 expression levels. Exendin 4 also preserved Akt phosphorylation levels after hypoxia-reoxygenation, while wortmannin, an inhibitor of the PI3K-Akt pathway, blunted exendin 4-induced myocyte protection and its effects on mitochondrial quality control factors. In conclusion, exendin 4 protected mitochondria by preserving the phosphorylation of Akt and fusion proteins, leading to the attenuation of hypoxia-reoxygenation-induced injury in cultured myocytes.
    DOI:  https://doi.org/10.1097/FJC.0000000000001218
  3. EMBO Rep. 2022 Jan 07. e48754
    The SUMO protease SENP3 regulates mitochondrial autophagy mediated by Fis1.
    Emily Waters, Kevin A Wilkinson, Amy L Harding, Ruth E Carmichael, Darren Robinson, Helen E Colley, Chun Guo.
      Mitochondria are unavoidably subject to organellar stress resulting from exposure to a range of reactive molecular species. Consequently, cells operate a poorly understood quality control programme of mitophagy to facilitate elimination of dysfunctional mitochondria. Here, we used a model stressor, deferiprone (DFP), to investigate the molecular basis for stress-induced mitophagy. We show that mitochondrial fission 1 protein (Fis1) is required for DFP-induced mitophagy and that Fis1 is SUMOylated at K149, an amino acid residue critical for Fis1 mitochondrial localization. We find that DFP treatment leads to the stabilization of the SUMO protease SENP3, which is mediated by downregulation of the E3 ubiquitin (Ub) ligase CHIP. SENP3 is responsible for Fis1 deSUMOylation and depletion of SENP3 abolishes DFP-induced mitophagy. Furthermore, preventing Fis1 SUMOylation by conservative K149R mutation enhances Fis1 mitochondrial localization. Critically, expressing a Fis1 K149R mutant restores DFP-induced mitophagy in SENP3-depleted cells. Thus, we propose a model in which SENP3-mediated deSUMOylation facilitates Fis1 mitochondrial localization to underpin stress-induced mitophagy.
    Keywords:  Fis1; SENP3; SUMO; mitophagy; organellar stress
    DOI:  https://doi.org/10.15252/embr.201948754
  4. Front Physiol. 2021 ;12 807654
    The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases.
    Lei Liu, Yimei Li, Quan Chen.
      Mitochondria are highly dynamic organelles and play essential role in ATP synthase, ROS production, innate immunity, and apoptosis. Mitochondria quality control is critical for maintaining the cellular function in response to cellular stress, growth, and differentiation Signals. Damaged or unwanted mitochondria are selectively removed by mitophagy, which is a crucial determinant of cell viability. Mitochondria-associated Endoplasmic Reticulum Membranes (MAMs) are the cellular structures that connect the ER and mitochondria and are involved in calcium signaling, lipid transfer, mitochondrial dynamic, and mitophagy. Abnormal mitochondrial quality induced by mitophagy impairment and MAMs dysfunction is associated with many diseases, including cardiovascular diseases (CVDs), metabolic syndrome, and neurodegenerative diseases. As a mitophagy receptor, FUNDC1 plays pivotal role in mitochondrial quality control through regulation of mitophagy and MAMs and is closely related to the occurrence of several types of CVDs. This review covers the regulation mechanism of FUNDC1-mediated mitophagy and MAMs formation, with a particular focus on its role in CVDs.
    Keywords:  FUNDC1; cardiovascular diseases; mitochondria; mitochondria quality/dynamics; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2021.807654
  5. Autophagy. 2022 Jan 06. 1-20
    Identification of an autoinhibitory, mitophagy-inducing peptide derived from the transmembrane domain of USP30.
    Xuan Qin, Rui Wang, Hongkun Xu, Licheng Tu, Hailing Chen, Heng Li, Na Liu, Jinpeng Wang, Shuiming Li, Feng Yin, Naihan Xu, Zigang Li.
      The mitochondrial-anchored deubiquitinating enzyme USP30 (ubiquitin specific peptidase 30) antagonizes PRKN/parkin-mediated mitophagy, making it a potential target for treating Parkinson disease. However, few inhibitors targeting USP30 have been reported. Here, we report a novel peptide (Q14) derived from the transmembrane (TM) domain of USP30 that can target mitochondrial-anchored USP30 directly and increase mitophagy through two intriguing and distinct mechanisms: a novel autoinhibition mechanism in USP30 and accelerated autophagosome formation via the LC3-interacting region (LIR) of the Q14 peptide. We identified the potential binding sites between the Q14 peptide and USP30 and postulated that an allosteric autoinhibition mechanism regulates USP30 activity. Furthermore, the LIR motif in the Q14 peptide offers additional binding with LC3 and accelerated autophagosome formation. The two mechanisms synergistically enhance mitophagy. Our work provides novel insight and direction to the design of inhibitors for USP30 or other deubiquitinating enzymes (DUBs).Abbreviations: 3-MA: 3-methyladenine; ATTEC: autophagosome-tethering compound; BafA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DMSO: dimethyl sulfoxide; FP: fluorescence polarization; FUNDC1: FUN14 domain containing 1; HCQ: hydroxychloroquine; LIR: LC3-interacting region; MST: microscale thermophoresis; mtDNA: mitochondrial DNA; mtPA-GFP: mitochondria-targeted photoactive fluorescence protein; OMM: outer mitochondrial membrane; PINK1: PTEN induced kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; Rap: rapamycin; SA: streptavidin; TM: transmembrane; Ub: ubiquitin; Ub-AMC: Ub-7-amido-4-methylcoumarin; UPS: ubiquitin-protease system; USP: ubiquitin specific peptidase; USP30: ubiquitin specific peptidase 30.
    Keywords:  Autoinhibition; USP30; mitophagy; peptide inhibitor; transmembrane
    DOI:  https://doi.org/10.1080/15548627.2021.2022360
  6. J Proteome Res. 2022 Jan 05.
    Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.
    Vasiliki-Iris Perivolidi, Foteini Violitzi, Elisavet Ioannidou, Vagelis Rinotas, George Stamatakis, Martina Samiotaki, George Panayotou, Eleni Douni.
      The outer mitochondrial membrane protein SLC25A46 has been recently identified as a novel genetic cause of a wide spectrum of neurological diseases. The aim of the present work was to elucidate the physiological role of SLC25A46 through the identification of its interactome with immunoprecipitation and proteomic analysis in whole cell extracts from the cerebellum, cerebrum, heart, and thymus of transgenic mice expressing ubiquitously SLC25A46-FLAG. Our analysis identified 371 novel putative interactors of SLC25A46 and confirmed 17 known ones. A total of 79 co-immunoprecipitated proteins were common in two or more tissues, mainly participating in mitochondrial activities such as oxidative phosphorylation (OXPHOS) and ATP production, active transport of ions or molecules, and the metabolism. Tissue-specific co-immunoprecipitated proteins were enriched for synapse annotated proteins in the cerebellum and cerebrum for metabolic processes in the heart and for nuclear processes and proteasome in the thymus. Our proteomic approach confirmed known mitochondrial interactors of SLC25A46 including MICOS complex subunits and also OPA1 and VDACs, while we identified novel interactors including the ADP/ATP translocases SLC25A4 and SLC25A5, subunits of the OXPHOS complexes and F1Fo-ATP synthase, and components of the mitochondria-ER contact sites. Our results show that SLC25A46 interacts with a large number of proteins and protein complexes involved in the mitochondria architecture, energy production, and flux and also in inter-organellar contacts.
    Keywords:  LC−MS/MS; SLC25A46; interactome; mitochondria; neurological diseases; quantitative proteomics; transgenic mice
    DOI:  https://doi.org/10.1021/acs.jproteome.1c00728
  7. FEBS J. 2022 Jan 05.
    Nek4 regulates mitochondrial respiration and morphology.
    Fernanda Luisa Basei, Camila de Castro Ferezin, Ana Luisa Rodrigues de Oliveira, Juan Pablo Muñoz, Antonio Zorzano, Jörg Kobarg.
      Nek4 is a serine/threonine kinase which has been implicated in primary cilia stabilization, DNA damage response, autophagy and epithelial-to-mesenchymal transition. The role of Nek4 in cancer cell survival and chemotherapy resistance has also been shown. However, the precise mechanisms by which Nek4 operates remain to be elucidated. Here, we show that Nek4 overexpression activates mitochondrial respiration coupled to ATP production, which is paralleled by increased mitochondrial membrane potential, and resistance to mitochondrial DNA damage. Congruently, Nek4 depletion reduced mitochondrial respiration and mtDNA integrity. Nek4 deficiency caused mitochondrial elongation, probably via reduced activity of the fission protein DRP1. In Nek4 overexpressing cells the increase in mitochondrial fission was concomitant to enhanced phosphorylation of DRP1 and Erk1/2 proteins, and the effects on mitochondrial respiration were abolished in the presence of a DRP1 inhibitor. This study shows Nek4 as a novel regulator of mitochondrial function that may explain the joint appearance of high mitochondrial respiration and mitochondrial fragmentation.
    Keywords:  DRP1; Nek4; fission; mitochondrial function
    DOI:  https://doi.org/10.1111/febs.16343
  8. Mitochondrion. 2022 Jan 03. pii: S1567-7249(21)00181-1. [Epub ahead of print]
    Standpoints in Mitochondrial Dysfunction: Underlying Mechanisms in Search of Therapeutic Strategies.
    Luis A Videla, Andrea Marimán, Bastián Ramos, María José Silva, Andrea Del Campo.
      Mitochondrial dysfunction has been defined as a reduced efficiency of mitochondria to produce ATP given by a loss of mitochondrial membrane potential, alterations in the electron transport chain (ETC) function, with increase in reactive oxygen species (ROS) generation and decrease in oxygen consumption. During the last decades, mitochondrial dysfunction has been the focus of many researchers as a convergent point for the pathophysiology of several diseases. Numerous investigations have demonstrated that mitochondrial dysfunction is detrimental to cells, tissues and organisms, nevertheless, dysfunctional mitochondria can signal in a particular way in response to stress, a characteristic that may be useful to search for new therapeutic strategies with a common feature. The aim of this review addresses mitochondrial dysfunction and stress signaling as a promising target for future drug development.
    Keywords:  aged-associated diseases; mitochondrial UPR; mitochondrial dysfunction; mitochondrial morphology; mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2021.12.006
  9. J Toxicol Sci. 2022 ;47(1): 13-18
    A novel perfusion culture system for screening mitochondrial toxicity in primary mouse hepatocytes.
    Chika Yamamoto, Akinori Takemura, Sanae Ishii, Atsushi Doi, Isao Saito, Hideki Yamada, Yoko Sakai, Tamihide Matsunaga, Kousei Ito.
      The liver microphysiological system (MPS) model is an in-vitro culture method that mimics physiological blood flow, which enhances basal cellular functions. However, the liver MPS model has not been tested in the preclinical stage because of its obscure utility. It can overcome the major problem of conventional systems-rapid loss of mitochondrial activity in cultured hepatocytes due to limited oxygen supply-by supplying oxygen to cultured hepatocytes using a perfusion device. In this study, we developed a new perfusion culture system that can detect mitochondrial toxicity. Primary mouse hepatocytes were cultured under perfusion condition for 48 hr. The hepatocytes showed increased oxygen consumption and reduced lactate release. These results indicated that the ATP-production pathway was switched from glycolysis to mitochondrial oxidative phosphorylation in the perfusion culture system. Furthermore, ATP levels were considerably reduced in the perfusion culture system after exposure to phenformin, a mitochondrial complex I inhibitor. To summarize, the perfusion culture system could improve the mitochondrial activity in primary mouse hepatocytes, and thus, has potential implications in the detection of mitochondrial toxicity.
    Keywords:  Drug-induced liver injury; Microphysiological system; Mitochondrial toxicity; Perfusion culture; Primary mouse hepatocytes
    DOI:  https://doi.org/10.2131/jts.47.13
  10. J Cell Mol Med. 2022 Jan 04.
    FGF21 alleviates acute liver injury by inducing the SIRT1-autophagy signalling pathway.
    Xiaoning Yang, Zhongqian Jin, Danfeng Lin, Tianzhu Shen, Jiangnan Zhang, Dan Li, Xuye Wang, Chi Zhang, Zhuofeng Lin, Xiaokun Li, Fanghua Gong.
      Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4 )-induced ALI. We established CCl4 -induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro-inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor-alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule-associated protein light chain-3 beta (LC3 II) and autophagy key molecule coiled-coil myosin-like BCL2-interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4 -treated wild-type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti-SIRT1 lentit-RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1-mediated autophagy.
    Keywords:  Beclin1; CCl4; FGF21; LC3 II; SIRT1; autophagy; liver injury
    DOI:  https://doi.org/10.1111/jcmm.17144
This page is being maintained by Thomas Krichel. It was last updated on 2024‒07‒13 at 12:33.