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Credit seminar

Mitochondria: Role in Signaling and Innate Immunity

Speaker : Sandeep Kumar Ph.D Ist Year Animal Biochemistry

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Introduction

Mitochondrial Regulation of Apoptosis

Role of Mitochondria in Antiviral Immunity

Role of Mitochondria in Antibacterial

Immunity

Mitochondrial Response to Cellular Damage

Summary

Contents

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STRUCTURE OF MITOCHONDRIA

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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

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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

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MOMP

Intrinsic Pathway (DNA Damage)BH3 only protein activation

BAX, BAK

Cytochrome C

Caspase activation

Apoptosis

Mitochondrial Regulation of Apoptosis

(Stephen et.al.,2012)

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ROLE IN INNATE IMMUNITY

Antiviral Immunity

Antibacterial Immunity

Response to Cellular Damage

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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)

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TLR4

TIRAPMyD8

8

(Takeda et.al.,2005)

SIGNALING PATHWAY MEDIATED BY ENDOSOMAL TOLL LIKE RECEPTORS

(Takeda et.al.,2005)

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Mitochondrial Antiviral Signaling Protein (MAVS)

540 amino acids

N- Terminal CardProline Rich RegionC-Terminal Transmembrane Domain

Present on Outer Mitochondrial Membrane (OMM)

The RIG-I – MAVS signaling pathway

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MAVS STRUCTURE

(Koshiba et.al.,2011)

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The RIG-I – MAVS signaling pathway

MAVS MAVS

TRAF5

TRAF6

TRADD

Cytoplasm

Nucleus

Mitochondria

(Phillip West et.al.,2011)

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MAVS inhibition

MAVS MAVS

HCVHAVGBVHBV

X-protein

Proteases

NS3-4A

NLRX 1

_ _ _ _ _ _

Nucleus

cytoplasm

(Tattoli et.al., 2008)

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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)

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mROS and Antiviral Signaling

(Phillip West et.al.2011)

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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 fusionMitochondrial fission protein 1 (FIS1) and dynamin-related protein 1 (DRP1) control fission

Mitochondrial Dynamics in Antiviral Signalling

(Okamoto et.al., 2005)

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Mitochondrial Dynamics in Antiviral Signaling

(Lenz et.al., 2010)

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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

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(Emre et.al.,2007)

mROS and Anti- bacterial Signaling

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Mitochondrial DAMPs

(Phillip West et.al.,2011)

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(Tschopp et.al.,2010)

Mitochondrial DAMPs

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

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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

ConclusionN

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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 innate immunity. EMBO reports. 12, 901-911 (2011).

References

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Thank You…