DOCSLIB.ORG

PARL Deficiency in Mouse Causes Complex III Defects, Coenzyme Q Depletion, and Leigh-Like Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PARL Deficiency in Mouse Causes Complex III Defects, Coenzyme Q Depletion, and Leigh-Like Syndrome PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome Marco Spinazzia,b,1, Enrico Radaellic, Katrien Horréa,b, Amaia M. Arranza,b, Natalia V. Gounkoa,b,d, Patrizia Agostinise, Teresa Mendes Maiaf,g,h, Francis Impensf,g,h, Vanessa Alexandra Moraisi, Guillermo Lopez-Lluchj,k, Lutgarde Serneelsa,b, Placido Navasj,k, and Bart De Stroopera,b,l,1 aVIB Center for Brain and Disease Research, 3000 Leuven, Belgium; bDepartment of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; cComparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051; dElectron Microscopy Platform, VIB Bio Imaging Core, 3000 Leuven, Belgium; eCell Death Research & Therapy Laboratory, Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; fVIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; gVIB Proteomics Core, VIB, 9000 Ghent, Belgium; hDepartment for Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; iInstituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; jCentro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas-Junta de Andalucía, 41013 Seville, Spain; kCentro de Investigaciones Biomédicas en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain; and lUK Dementia Research Institute, University College London, WC1E 6BT London, United Kingdom Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved November 21, 2018 (received for review July 11, 2018) The mitochondrial intramembrane rhomboid protease PARL has been proposed that PARL exerts proapoptotic effects via misprocessing implicated in diverse functions in vitro, but its physiological role in of the mitochondrial Diablo homolog (hereafter DIABLO) (10). − − vivo remains unclear. Here we show that Parl ablation in mouse However, this is difficult to reconcile with the lethality of Parl / causes a necrotizing encephalomyelopathy similar to Leigh syndrome, mice and the proposed protective function of PARL (3). Overall, a mitochondrial disease characterized by disrupted energy produc- the available data have led to contradictory speculations with regard tion. Mice with conditional PARL deficiency in the nervous system, to the role of PARL in apoptosis (3, 10), mitochondrial function (3, but not in muscle, develop a similar phenotype as germline Parl KOs, 14), morphology (3, 14, 15), and mitophagy (16–18), and claims demonstrating the vital role of PARL in neurological homeostasis. have not been further substantiated in vivo. More importantly, the − − Genetic modification of two major PARL substrates, PINK1 and causeofdeathoftheParl / mice, and therefore the physiological −/− PGAM5, do not modify this severe neurological phenotype. Parl role of this protease, has remained unresolved. To address these NEUROSCIENCE brain mitochondria are affected by progressive ultrastructural questions, we reinvestigated PARL-deficient mice. In contrast with changes and by defects in Complex III (CIII) activity, coenzyme Q our previous report, we find now that, in addition to the described (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is phenotypes in peripheral tissues, PARL deficiency causes a necro- necessary for the stable expression of TTC19, which is required for tizing encephalomyelopathy closely resembling Leigh syndrome, a CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, human mitochondrial disease caused by impaired energy metabo- − − PARL plays a previously overlooked constitutive role in the main- lism (19). A similar multisystem phenotype is seen in the full Parl / tenance of the respiratory chain in the nervous system, and its and in ParlL/L::NesCre mice with a specific deletion of PARL in the deficiency causes progressive mitochondrial dysfunction and nervous system. The striking neurodegeneration is not associ- structural abnormalities leading to neuronal necrosis and Leigh- ated with altered apoptosis but with massive necrosis, raising like syndrome. Significance rhomboid protease | mitochondria | neurodegeneration | respiratory chain | Leigh syndrome PARL is a peculiar protease in the inner membrane of mito- chondria with important but unclear physiological roles and ARL represents the only known mitochondrial member of with links to Parkinson’s disease and diabetes. Most studies, Pthe rhomboid family (1). Rhomboids are evolutionary con- including the original characterization of the Parl-KO mouse served intramembrane cleaving proteases and pseudoproteases and others performed in vitro, have focused on apoptosis. Here involved in a variety of functions (2). Their broad biological we show that PARL deficiency in the nervous system alone or significance is reflected in their pathological relevance for in the complete animal causes severe neurodegeneration as- prevalent human diseases, including cancer and neurodegener- sociated with necrosis resembling the human mitochondrial ative diseases (2). disease Leigh syndrome. By combining genetic, biochemical, The crucial role of PARL in cellular homeostasis is illustrated and proteomic approaches, we show that PARL plays an es- −/− by the lethal multisystem phenotype of PARL-deficient (Parl ) sential physiological role in the nervous system being required mice, associated with muscle atrophy and increased apoptosis in for the maintenance of mitochondrial structure and function at thymus and spleen (3). The faster cytochrome c release and the level of Complex III, coenzyme Q, and calcium metabolism. − − cristae remodeling in vitro, and the increased cell death of Parl / mouse embryonic fibroblasts (MEFs) treated with apoptosis-inducing Author contributions: M.S., L.S., P.N., and B.D.S. designed research; M.S., E.R., K.H., agents rescued by overexpressed intermembrane space-targeted A.M.A., N.V.G., F.I., V.A.M., and G.L.-L. performed research; P.A. contributed new re- agents/analytic tools; M.S., E.R., K.H., A.M.A., T.M.M., F.I., G.L.-L., L.S., P.N., and B.D.S. OPA1, led to the proposal that PARL plays a role in cristae analyzed data; M.S. and B.D.S. wrote the paper; and P.A. provided critical feedback. remodeling and cytochrome c release during apoptosis. The authors The authors declare no conflict of interest. suggested that decreased OPA1 processing by PARL was causative This article is a PNAS Direct Submission. of these apoptotic phenotypes. Later studies identified OMA1 and Published under the PNAS license. YME1L (4) as the proteases cleaving OPA1 and questioned Data deposition: The MS proteomics data have been deposited to the ProteomeXchange OPA1 as a PARL substrate. More recently, PARL has been im- Consortium via the PRIDE partner repository with the dataset identifier PXD008908. – plicated in the processing of other substrates in cultured cells (5 1To whom correspondence may be addressed. Email: [email protected] or 10). Two substrates, PINK1 and PGAM5, are of particular interest [email protected]. because they are implicated in Parkinson’s disease (11, 12). Both This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. −/− accumulate in Parl cells (6–9, 13), but it is unclear whether this 1073/pnas.1811938116/-/DCSupplemental. accumulation is detrimental (1). A recent elegant cell-biology study Published online December 21, 2018. www.pnas.org/cgi/doi/10.1073/pnas.1811938116 PNAS | January 2, 2019 | vol. 116 | no. 1 | 277–286 Downloaded by guest on September 30, 2021 the question of the underlying mechanism. We show that necrosis were already affected by severe neurological deficits. Conversely, − − in Parl / brains is preceded by progressive mitochondrial struc- deletion of PARL in striated muscle in ParlL/L::CkmmCre KO mice tural changes and by early respiratory chain defects at the level of using Cre expression driven by the creatine kinase promoter Complex III (CIII) and coenzyme Q (CoQ), and is associated with did not compromise survival, at least up to the age of 18 mo, altered mitochondrial calcium metabolism. Thus, PARL has an nor did it lead to overt locomotor deficits (n = 13; Fig. 1I). essential physiological role in the maintenance of mitochondrial Altogether, these data suggest that PARL deficiency in the structure and function, which is severely impaired when PARL is nervous system is sufficient to recapitulate the lethal mul- − − ablated, causing Leigh-like neurodegeneration. We discuss how tisystem phenotype of germline Parl / mice, except for the − − these insights affect our previous interpretations of the Parl / gonad atrophy. phenotype in vivo. PARL Deficiency Causes Early Neuronal Mitochondrial Ultrastructural Results Abnormalities Followed by Neuronal Necrosis. To characterize mi- PARL Deficiency in the Nervous System Leads to a Severe tochondrial ultrastructure and the morphological features of cell − − Encephalomyelopathy Resembling Leigh Syndrome. Parl / mice death induced by PARL deficiency in the brain, we performed EM. At 3 wk of age, which is before the occurrence of clinical develop normally up to the age of 40 d, after which they pro- − − gressively lose weight (3). From the age of 6 wk, they show signs or histopathological lesions, Parl / but not WT neurons of rapidly progressive locomotor impairment, paresis of the lower medulla oblongata displayed scattered swollen
Load more

Recommended publications
  • Cloning and Sequence Analysis of Canine Apoptosis-Associated Molecules
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2007 Cloning and sequence analysis of canine apoptosis-associated molecules Schade, Benjamin Abstract: The aim of the study was to clone and sequence the coding sequences of a representative set of proteins, primarily from the intrinsic apoptotic pathway in dogs and to assess their conservation with hu- man and murine orthologues. cDNA for these proteins, including Bcl-2 family members (Bcl-XL, Bcl-w, Mcl-1, Bax, Bak, Bad, Noxa), caspases (Caspase-3, Caspase-8, Caspase-9), Inhibitors of Apoptosis Pro- teins (XIAP, cIAP-1, cIAP-2, Survivin), their mitochondrial inhibitors (Smac/ DIABLO, Omi/HtrA2) and p53, were generated by RT-PCR with RNA extracted from two canine non-neoplastic cell lines. Eleven sequences are novel for the dog. Interspecies comparison revealed strongest similarity between the sequences of human and canine intrinsic apoptosis pathway members. Differences with potential func- tional impact, however, were observed in both dogs and mice. In dogs, these changes involve the putative Inhibitor of Apoptosis Protein binding motif of canine Omi/HtrA2, some caspase substrate recognition motifs and some functionally relevant residues of p53. Canine XIAP yields a caspase-cleavage site reported as unique to humans. In conclusion, the generally high degree of similarity of canine apoptosis-associated proteins as compared to human counterparts is supportive of the use of dogs as a model for human dis- eases. Single interspecies sequence variations with potential functional relevance under physiologic and neoplastic conditions do exist, however, and will require further analysis.
    [Show full text]
  • Supplementary Materials For
    Supplementary Materials for Elucidating cellular population dynamics by molecular density function perturbations 1 2,3, Thanneer Malai Perumal ​ and Rudiyanto Gunawan *​ ​ ​ 1 Sage Bionetworks, Seattle, Washington, USA; [email protected] 2 Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland; [email protected] 3 Swiss Institute of Bioinformatics, Lausanne, Switzerland * Correspondence: [email protected]; Tel.: +41-44-633-2134 Supplementary Material S1. Probability Distance Metrics Signed Engineering Metric: ∞ 2 ∆ (f A (t, x )||f B (t, x )) = sign(∆μ ) ∫ (x f A (t, x ) − x f B (t, x )) dx (S. 1) E Xi i Xi i Xi i Xi i i Xi i i −∞ Signed Jeffrey Divergence: ∞ f A (t,x ) A B A B Xi i ∆ (f (t, x )||f (t, x )) = sgn(∆μ ) ∫ (f (t, x ) − f (t, x ))ln ( B ) )dx (S. 2) JD Xi i Xi i Xi Xi i Xi i f (t,x ) i −∞ Xi i Signed Kullback-Leibler Distance: ∞ f B (t,x ) A B B Xi i ∆ (f (t, x )||f (t, x )) = sgn(∆μ ) ∫ f (t, x )ln ( A ) dx (S. 3) KLD Xi i Xi i Xi Xi i f (t,x ) i −∞ Xi i Signed Jensen-Shannon Divergence: f + (t,x )+f − (t,x ) Xi i Xi i ∆ f (t, x ) = sgn(∆μ ) (S. 4) JSD Xi i Xi 2 Signed Kolmogorov-Smirnov Metric: ∆ (f A (t, x )||f B (t, x )) = sgn(∆μ )sup|F A (t, x ) − F B (t, x )| (S. 5) KS Xi i Xi i Xi Xi i Xi i Supplementary Material S2.
    [Show full text]
  • Supplemental Table S1
    Entrez Gene Symbol Gene Name Affymetrix EST Glomchip SAGE Stanford Literature HPA confirmed Gene ID Profiling profiling Profiling Profiling array profiling confirmed 1 2 A2M alpha-2-macroglobulin 0 0 0 1 0 2 10347 ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7 1 0 0 0 0 3 10350 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 1 0 0 0 0 4 10057 ABCC5 ATP-binding cassette, sub-family C (CFTR/MRP), member 5 1 0 0 0 0 5 10060 ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 1 0 0 0 0 6 79575 ABHD8 abhydrolase domain containing 8 1 0 0 0 0 7 51225 ABI3 ABI gene family, member 3 1 0 1 0 0 8 29 ABR active BCR-related gene 1 0 0 0 0 9 25841 ABTB2 ankyrin repeat and BTB (POZ) domain containing 2 1 0 1 0 0 10 30 ACAA1 acetyl-Coenzyme A acyltransferase 1 (peroxisomal 3-oxoacyl-Coenzyme A thiol 0 1 0 0 0 11 43 ACHE acetylcholinesterase (Yt blood group) 1 0 0 0 0 12 58 ACTA1 actin, alpha 1, skeletal muscle 0 1 0 0 0 13 60 ACTB actin, beta 01000 1 14 71 ACTG1 actin, gamma 1 0 1 0 0 0 15 81 ACTN4 actinin, alpha 4 0 0 1 1 1 10700177 16 10096 ACTR3 ARP3 actin-related protein 3 homolog (yeast) 0 1 0 0 0 17 94 ACVRL1 activin A receptor type II-like 1 1 0 1 0 0 18 8038 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 1 0 0 0 0 19 8751 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 1 0 0 0 0 20 8728 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 1 0 0 0 0 21 81792 ADAMTS12 ADAM metallopeptidase with thrombospondin type 1 motif, 12 1 0 0 0 0 22 9507 ADAMTS4 ADAM metallopeptidase with thrombospondin type 1
    [Show full text]
  • Mitochondrial Rhomboid PARL Regulates Cytochrome C Release During Apoptosis Via OPA1-Dependent Cristae Remodeling
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling Sara Cipolat,1,7 Tomasz Rudka,2,7 Dieter Hartmann,2,7 Veronica Costa,1 Lutgarde Serneels,2 Katleen Craessaerts,2 Kristine Metzger,2 Christian Frezza,1 Wim Annaert,3 Luciano D’Adamio,5 Carmen Derks,2 Tim Dejaegere,2 Luca Pellegrini,6 Rudi D’Hooge,4 Luca Scorrano,1,* and Bart De Strooper2,* 1 Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padova, Italy 2 Neuronal Cell Biology and Gene Transfer Laboratory 3 Membrane Trafficking Laboratory Center for Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB4) and K.U.Leuven, Leuven, Belgium 4 Laboratory of Biological Psychology, K.U.Leuven, Leuven, Belgium 5 Albert Einstein College of Medicine, Bronx, NY 10461, USA 6 Centre de Recherche Robert Giffard, Universite` Laval, G1J 2G3 Quebec, Canada 7 These authors contribute equally to this work. *Contact: [email protected] (L.S.); [email protected] (B.D.S.) DOI 10.1016/j.cell.2006.06.021 SUMMARY been identified in D. melanogaster (Freeman, 2004), where they function as essential activators of the epidermal Rhomboids, evolutionarily conserved integral growth factor (EGF) signaling pathway, proteolytically membrane proteases, participate in crucial sig- cleaving the EGF receptor ligands Spitz, Gurken, and naling pathways. Presenilin-associated rhom- Keren. Since all Rhomboids share a conserved serine boid-like (PARL) is an inner mitochondrial protease catalytic dyad (Lemberg et al., 2005), it has membrane rhomboid of unknown function, been suggested that they are able to cleave proteins in whose yeast ortholog is involved in mito- the transmembrane domain.
    [Show full text]
  • Neurodevelopmental Signatures of Narcotic and Neuropsychiatric Risk Factors in 3D Human-Derived Forebrain Organoids
    Molecular Psychiatry www.nature.com/mp ARTICLE OPEN Neurodevelopmental signatures of narcotic and neuropsychiatric risk factors in 3D human-derived forebrain organoids 1 1 1 1 2 2 3 Michael Notaras , Aiman Lodhi , Estibaliz✉ Barrio-Alonso , Careen Foord , Tori Rodrick , Drew Jones , Haoyun Fang , David Greening 3,4 and Dilek Colak 1,5 © The Author(s) 2021 It is widely accepted that narcotic use during pregnancy and specific environmental factors (e.g., maternal immune activation and chronic stress) may increase risk of neuropsychiatric illness in offspring. However, little progress has been made in defining human- specific in utero neurodevelopmental pathology due to ethical and technical challenges associated with accessing human prenatal brain tissue. Here we utilized human induced pluripotent stem cells (hiPSCs) to generate reproducible organoids that recapitulate dorsal forebrain development including early corticogenesis. We systemically exposed organoid samples to chemically defined “enviromimetic” compounds to examine the developmental effects of various narcotic and neuropsychiatric-related risk factors within tissue of human origin. In tandem experiments conducted in parallel, we modeled exposure to opiates (μ-opioid agonist endomorphin), cannabinoids (WIN 55,212-2), alcohol (ethanol), smoking (nicotine), chronic stress (human cortisol), and maternal immune activation (human Interleukin-17a; IL17a). Human-derived dorsal forebrain organoids were consequently analyzed via an array of unbiased and high-throughput analytical approaches, including state-of-the-art TMT-16plex liquid chromatography/mass- spectrometry (LC/MS) proteomics, hybrid MS metabolomics, and flow cytometry panels to determine cell-cycle dynamics and rates of cell death. This pipeline subsequently revealed both common and unique proteome, reactome, and metabolome alterations as a consequence of enviromimetic modeling of narcotic use and neuropsychiatric-related risk factors in tissue of human origin.
    [Show full text]
  • Location Analysis of Estrogen Receptor Target Promoters Reveals That
    Location analysis of estrogen receptor ␣ target promoters reveals that FOXA1 defines a domain of the estrogen response Jose´ e Laganie` re*†, Genevie` ve Deblois*, Ce´ line Lefebvre*, Alain R. Bataille‡, Franc¸ois Robert‡, and Vincent Gigue` re*†§ *Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montreal, QC, Canada H3A 1A1; †Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6; and ‡Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montre´al, Montreal, QC, Canada H2W 1R7 Communicated by Ronald M. Evans, The Salk Institute for Biological Studies, La Jolla, CA, July 1, 2005 (received for review June 3, 2005) Nuclear receptors can activate diverse biological pathways within general absence of large scale functional data linking these putative a target cell in response to their cognate ligands, but how this binding sites with gene expression in specific cell types. compartmentalization is achieved at the level of gene regulation is Recently, chromatin immunoprecipitation (ChIP) has been used poorly understood. We used a genome-wide analysis of promoter in combination with promoter or genomic DNA microarrays to occupancy by the estrogen receptor ␣ (ER␣) in MCF-7 cells to identify loci recognized by transcription factors in a genome-wide investigate the molecular mechanisms underlying the action of manner in mammalian cells (20–24). This technology, termed 17␤-estradiol (E2) in controlling the growth of breast cancer cells. ChIP-on-chip or location analysis, can therefore be used to deter- We identified 153 promoters bound by ER␣ in the presence of E2. mine the global gene expression program that characterize the Motif-finding algorithms demonstrated that the estrogen re- action of a nuclear receptor in response to its natural ligand.
    [Show full text]
  • PARL (Human) Recombinant Protein (P01)
    Produktinformation Diagnostik & molekulare Diagnostik Laborgeräte & Service Zellkultur & Verbrauchsmaterial Forschungsprodukte & Biochemikalien Weitere Information auf den folgenden Seiten! See the following pages for more information! Lieferung & Zahlungsart Lieferung: frei Haus Bestellung auf Rechnung SZABO-SCANDIC Lieferung: € 10,- HandelsgmbH & Co KG Erstbestellung Vorauskassa Quellenstraße 110, A-1100 Wien T. +43(0)1 489 3961-0 Zuschläge F. +43(0)1 489 3961-7 [email protected] • Mindermengenzuschlag www.szabo-scandic.com • Trockeneiszuschlag • Gefahrgutzuschlag linkedin.com/company/szaboscandic • Expressversand facebook.com/szaboscandic PARL (Human) Recombinant Protein Gene Alias: PRO2207, PSARL, PSARL1, PSENIP2, (P01) RHBDS1 Gene Summary: This gene encodes a mitochondrial Catalog Number: H00055486-P01 integral membrane protein. Following proteolytic Regulation Status: For research use only (RUO) processing of this protein, a small peptide (P-beta) is formed and translocated to the nucleus. This gene may Product Description: Human PARL full-length ORF ( be involved in signal transduction via regulated NP_061092.3, 1 a.a. - 379 a.a.) recombinant protein with intramembrane proteolysis of membrane-tethered GST-tag at N-terminal. precursor proteins. Variation in this gene has been associated with increased risk for type 2 diabetes. Sequence: Alternative splicing results in multiple transcript variants MAWRGWAQRGWGCGQAWGASVGGRSCEELTAVLT encoding different isoforms. [provided by RefSeq] PPQLLGRRFNFFIQQKCGFRKAPRKVEPRRSDPGTSG EAYKRSALIPPVEETVFYPSPYPIRSLIKPLFFTVGFTGC
    [Show full text]
  • Mitochondrial Protein Quality Control Mechanisms
    G C A T T A C G G C A T genes Review Mitochondrial Protein Quality Control Mechanisms Pooja Jadiya * and Dhanendra Tomar * Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA * Correspondence: [email protected] (P.J.); [email protected] (D.T.); Tel.: +1-215-707-9144 (D.T.) Received: 29 April 2020; Accepted: 15 May 2020; Published: 18 May 2020 Abstract: Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases. Keywords: mitochondria; proteome; ubiquitin; proteasome; chaperones; protease; mitophagy; mitochondrial protein quality control; mitochondria-associated degradation; mitochondrial unfolded protein response 1. Introduction Mitochondria are double membrane, dynamic, and semiautonomous organelles which have several critical cellular functions.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Whole-Exome Sequencing Reveals a Novel Homozygous
    www.nature.com/scientificreports OPEN Whole‑exome sequencing reveals a novel homozygous mutation in the COQ8B gene associated with nephrotic syndrome Mohd Fareed1,2*, Vikas Makkar3, Ravi Angral4, Mohammad Afzal5 & Gurdarshan Singh1,2 Nephrotic syndrome arising from monogenic mutations difers substantially from acquired ones in their clinical prognosis, progression, and disease management. Several pathogenic mutations in the COQ8B gene are known to cause nephrotic syndrome. Here, we used the whole‑exome sequencing (WES) technology to decipher the genetic cause of nephrotic syndrome (CKD stage‑V) in a large afected consanguineous family. Our study exposed a novel missense homozygous mutation NC_000019.9:g.41209497C > T; NM_024876.4:c.748G > A; NP_079152.3:p.(Asp250Asn) in the 9th exon of the COQ8B gene, co‑segregated well with the disease phenotype. Our study provides the frst insight into this homozygous condition, which has not been previously reported in 1000Genome, ClinVar, ExAC, and genomAD databases. In addition to the pathogenic COQ8B variant, the WES data also revealed some novel and recurrent mutations in the GLA, NUP107, COQ2, COQ6, COQ7 and COQ9 genes. The novel variants observed in this study have been submitted to the ClinVar database and are publicly available online with the accessions: SCV001451361.1, SCV001451725.1 and SCV001451724.1. Based on the patient’s clinical history and genomic data with in silico validation, we conclude that pathogenic mutation in the COQ8B gene was causing kidney failure in an autosomal recessive manner. We recommend WES technology for genetic testing in such a consanguineous family to not only prevent the future generation, but early detection can help in disease management and therapeutic interventions.
    [Show full text]
  • Cldn19 Clic2 Clmp Cln3
    NewbornDx™ Advanced Sequencing Evaluation When time to diagnosis matters, the NewbornDx™ Advanced Sequencing Evaluation from Athena Diagnostics delivers rapid, 5- to 7-day results on a targeted 1,722-genes. A2ML1 ALAD ATM CAV1 CLDN19 CTNS DOCK7 ETFB FOXC2 GLUL HOXC13 JAK3 AAAS ALAS2 ATP1A2 CBL CLIC2 CTRC DOCK8 ETFDH FOXE1 GLYCTK HOXD13 JUP AARS2 ALDH18A1 ATP1A3 CBS CLMP CTSA DOK7 ETHE1 FOXE3 GM2A HPD KANK1 AASS ALDH1A2 ATP2B3 CC2D2A CLN3 CTSD DOLK EVC FOXF1 GMPPA HPGD K ANSL1 ABAT ALDH3A2 ATP5A1 CCDC103 CLN5 CTSK DPAGT1 EVC2 FOXG1 GMPPB HPRT1 KAT6B ABCA12 ALDH4A1 ATP5E CCDC114 CLN6 CUBN DPM1 EXOC4 FOXH1 GNA11 HPSE2 KCNA2 ABCA3 ALDH5A1 ATP6AP2 CCDC151 CLN8 CUL4B DPM2 EXOSC3 FOXI1 GNAI3 HRAS KCNB1 ABCA4 ALDH7A1 ATP6V0A2 CCDC22 CLP1 CUL7 DPM3 EXPH5 FOXL2 GNAO1 HSD17B10 KCND2 ABCB11 ALDOA ATP6V1B1 CCDC39 CLPB CXCR4 DPP6 EYA1 FOXP1 GNAS HSD17B4 KCNE1 ABCB4 ALDOB ATP7A CCDC40 CLPP CYB5R3 DPYD EZH2 FOXP2 GNE HSD3B2 KCNE2 ABCB6 ALG1 ATP8A2 CCDC65 CNNM2 CYC1 DPYS F10 FOXP3 GNMT HSD3B7 KCNH2 ABCB7 ALG11 ATP8B1 CCDC78 CNTN1 CYP11B1 DRC1 F11 FOXRED1 GNPAT HSPD1 KCNH5 ABCC2 ALG12 ATPAF2 CCDC8 CNTNAP1 CYP11B2 DSC2 F13A1 FRAS1 GNPTAB HSPG2 KCNJ10 ABCC8 ALG13 ATR CCDC88C CNTNAP2 CYP17A1 DSG1 F13B FREM1 GNPTG HUWE1 KCNJ11 ABCC9 ALG14 ATRX CCND2 COA5 CYP1B1 DSP F2 FREM2 GNS HYDIN KCNJ13 ABCD3 ALG2 AUH CCNO COG1 CYP24A1 DST F5 FRMD7 GORAB HYLS1 KCNJ2 ABCD4 ALG3 B3GALNT2 CCS COG4 CYP26C1 DSTYK F7 FTCD GP1BA IBA57 KCNJ5 ABHD5 ALG6 B3GAT3 CCT5 COG5 CYP27A1 DTNA F8 FTO GP1BB ICK KCNJ8 ACAD8 ALG8 B3GLCT CD151 COG6 CYP27B1 DUOX2 F9 FUCA1 GP6 ICOS KCNK3 ACAD9 ALG9
    [Show full text]
  • PARL Deficiency in Mouse Causes Complex III Defects, Coenzyme Q Depletion, and Leigh-Like Syndrome
    PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome Marco Spinazzia,b,1, Enrico Radaellic, Katrien Horréa,b, Amaia M. Arranza,b, Natalia V. Gounkoa,b,d, Patrizia Agostinise, Teresa Mendes Maiaf,g,h, Francis Impensf,g,h, Vanessa Alexandra Moraisi, Guillermo Lopez-Lluchj,k, Lutgarde Serneelsa,b, Placido Navasj,k, and Bart De Stroopera,b,l,1 aVIB Center for Brain and Disease Research, 3000 Leuven, Belgium; bDepartment of Neurosciences, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; cComparative Pathology Core, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6051; dElectron Microscopy Platform, VIB Bio Imaging Core, 3000 Leuven, Belgium; eCell Death Research & Therapy Laboratory, Department for Cellular and Molecular Medicine, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; fVIB Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium; gVIB Proteomics Core, VIB, 9000 Ghent, Belgium; hDepartment for Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; iInstituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; jCentro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas-Junta de Andalucía, 41013 Seville, Spain; kCentro de Investigaciones Biomédicas en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28029 Madrid, Spain; and lUK Dementia Research Institute, University College London, WC1E 6BT London, United Kingdom Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved November 21, 2018 (received for review July 11, 2018) The mitochondrial intramembrane rhomboid protease PARL has been proposed that PARL exerts proapoptotic effects via misprocessing implicated in diverse functions in vitro, but its physiological role in of the mitochondrial Diablo homolog (hereafter DIABLO) (10).
    [Show full text]