1. NationalDairyResearchInstitute
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
TIRAP
MyD88
(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 Card
Proline Rich Region
C-Terminal Transmembrane Domain
Present on Outer Mitochondrial Membrane (OMM)
The RIG-I – MAVS signaling pathway

11. NationalDairyResearchInstitute 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)

13. NationalDairyResearchInstitute MAVS inhibition
MAVS MAVS
HCV
HAV
GBV
HBV
X-protein
Proteases
NS3-4A
______
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
Antivira
l
Signalin (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 fusion
Mitochondrial fission protein 1 (FIS1) and dynamin-
related protein 1 (DRP1) control fission
Mitochondrial Dynamics in Antiviral Signalling
(Okamoto et.al., 2005)

17. NationalDairyResearchInstitute 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

20. NationalDairyResearchInstitute Mitochondrial DAMPs
(Phillip West et.al.,2011)

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(Tschopp et.al.,2010)

22. 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

24. Mitochondria appear to function as centrally
positioned hubs for innate immune signaling and
the subsequent generation of effectors' responses
ConclusionNationalDairyResearchInstitute

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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
References

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