Mitochondria role in signaling and innate immunity
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Mitochondria role in signaling and innate immunity

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Mitochondria role in signaling and innate immunity Mitochondria role in signaling and innate immunity Presentation Transcript

  • NationalDairyResearchInstitute Credit seminar Mitochondria: Role in Signaling and Innate Immunity Speaker : Sandeep Kumar Ph.D Ist Year Animal Biochemistry
  • NationalDairyResearchInstitute Introduction Mitochondrial Regulation of Apoptosis Role of Mitochondria in Antiviral Immunity Role of Mitochondria in Antibacterial Immunity Mitochondrial Response to Cellular Damage Summary Contents
  • NationalDairyResearchInstitute STRUCTURE OF MITOCHONDRIA
  • NationalDairyResearchInstitute ATP SYNTHESIS BIOGENESIS OF HEME IRON- SULPHUR PROTEIN ASSEMBLY AND BIOGENESIS Ca2+ STORAGE LIPID METABOLISM CARBOHYDRATE METABOLISM AMINO ACID METABOLISM PROGRAMMED CELL DEATH IN INNATE IMMUNITY KEY ROLES OF MITOCHONDRIA
  • NationalDairyResearchInstitute In the intrinsic or mitochondrial pathway of apoptosis, proapoptotic insults such as DNA damage lead to the activation of two key proteins, BAX and BAK that cause mitochondrial outer membrane permeabilisation (MOMP),enabling the release of cytochrome c into the cytoplasm where they promote activation of caspases Mitochondrial Regulation of Apoptosis Signaling
  • NationalDairyResearchInstitute MOMP Intrinsic Pathway (DNA Damage) BH3 only protein activation BAX, BAK Cytochrome C Caspase activation Apoptosis Mitochondrial Regulation of Apoptosis (Stephen et.al.,2012)
  • NationalDairyResearchInstitute ROLE IN INNATE IMMUNITY Antiviral Immunity Antibacterial Immunity Response to Cellular Damage
  • NationalDairyResearchInstitute RNA viral infection of host cells is sensed by PRR recognition of PAMPs such as ssRNA, dsRNA, DNA etc. that initiate two distinct signaling pathways. 1.Mediated by endosomal Toll like receptor 3 2. Mediated by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) ROLE IN ANTIVIRAL IMMUNITY (Koshiba et.al.,2011)
  • NationalDairyResearchInstitute TLR4 TIRAP MyD88 (Takeda et.al.,2005) SIGNALING PATHWAY MEDIATED BY ENDOSOMAL TOLL LIKE RECEPTORS (Takeda et.al.,2005)
  • NationalDairyResearchInstitute Mitochondrial Antiviral Signaling Protein (MAVS) 540 amino acids N- Terminal Card Proline Rich Region C-Terminal Transmembrane Domain Present on Outer Mitochondrial Membrane (OMM) The RIG-I – MAVS signaling pathway
  • NationalDairyResearchInstitute MAVS STRUCTURE (Koshiba et.al.,2011)
  • NationalDairyResearchInstitute The RIG-I – MAVS signaling pathway MAVS MAVS TRAF5 TRAF6 TRADD Cytoplasm Nucleus Mitochondria (Phillip West et.al.,2011)
  • NationalDairyResearchInstitute MAVS inhibition MAVS MAVS HCV HAV GBV HBV X-protein Proteases NS3-4A ______ Nucleus cytoplasm (Tattoli et.al., 2008)
  • NationalDairyResearchInstitute Play central role in RLR-MAVS signaling during viral infection NLRX1 and gC1qR increase mROS generation Uncoupling protein 2 (UCP2) decrease RLR-MAVS signaling mROS and Antiviral Signaling (Junai et.al.,2007)
  • NationalDairyResearchInstitute mROS and Antivira l Signalin (Phillip West et.al.2011)
  • NationalDairyResearchInstitute Mitochondrial dynamics play role in apoptosis and neurodegeneration  Mitofusin:MFN1 and MFN2 are dynamin-related GTPases expressed on the OMM that tether mitochondria together during fusion Mitochondrial fission protein 1 (FIS1) and dynamin- related protein 1 (DRP1) control fission Mitochondrial Dynamics in Antiviral Signalling (Okamoto et.al., 2005)
  • NationalDairyResearchInstitute Mitochondrial Dynamics in Antiviral Signaling (Lenz et.al., 2010)
  • NationalDairyResearchInstitute Reactive oxygen species(ROS) production Signaling via TLR’s ( TLR1, TLR2 & TLR4) augments mROS generation NADPH oxidase - derived ROS & mROS both play role in innate immunity Role in Antibacterial Immunity
  • NationalDairyResearchInstitute (Emre et.al.,2007) mROS and Anti- bacterial Signaling
  • NationalDairyResearchInstitute Mitochondrial DAMPs (Phillip West et.al.,2011)
  • NationalDairyResearchInstitute (Tschopp et.al.,2010)
  • DAMP Location of action Receptor Inflammatory action Mt.DNA Endosomal and Intracellular TLR9 & AIM2 Macrophage & caspase 1 activation N-formyl peptides Extracellular FPR1 Monocyte activation Mitochondrial TFAM Extracellular Uncharacterized Monocyte activation Mitochondrial ATP Extracellular P2RX7 & NLRP3 inflammasome Caspase 1 activation mROS Intracellular NLRP3 inflammasome Caspase 1 activation
  • NationalDairyResearchInstitute Mitochondria have signaling role in Apoptosis MAVS present on outer mitochondrial membrane plays an important role in Antiviral immunity TLR’s enhance the production of mROS in Antibacterial immunity Mitochondrial DAMPs activate innate immune response Summary
  • Mitochondria appear to function as centrally positioned hubs for innate immune signaling and the subsequent generation of effectors' responses ConclusionNationalDairyResearchInstitute
  • NationalDairyResearchInstitute Stephen,W. , & Douglas, R. Mitochondria and cell signaling. J of Cell Science 125, 807-815 (2012) Khoo, J., Nagley, P., & Mansell. Mitochondria: an Unexpected Force in Innate Immunity. Australian Biochemist. 44, 17-20 (2013). Seth, R.B., Sun, L., & Chen, Z. Antiviral innate immunity pathways. Annu. Rev. Cell Research. 16, 141-147 (2006). Koshiba, T., Bashiruddin, N., & Kawabata. Mitochondria and antiviral innate immunity. J Biochem Mol Bio. 3, 257-262 (2011). Phillip, A., Shadel, S. & Ghose,S. Mitochondria in innate Immune responses. Nat. Rev. Imm. 11,389-402 (2011). Arnoult, D., Soares, F., & Tattoli, I. Mitochondria in References
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