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Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases

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Abstract

Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1β and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-κB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases.

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Abbreviations

AIM2:

Absent in melanoma 2

ASC:

Apoptosis-associated speck-like protein containing CARD domain

CARD:

Caspase recruitment domain

CSF:

Cerebrospinal fluid

DAMP:

Damage-associated molecular pattern

dsDNA:

Double-stranded DNA

ER:

Endoplasmic reticulum

FPR:

Formyl peptide receptor

HMGB1:

High-mobility group protein B1

IAPP:

Islet amyloid polypeptide

IFNβ:

Interferon β

IKK:

Inhibitory-κB kinase

IL:

Interleukin

LPS:

Lipopolysaccharide

LRR:

Leucine-rich repeat

MAM:

Mitochondria-associated ER membrane

MAVS:

Mitochondrial antiviral signaling protein

MnSOD:

Mitochondrial manganese superoxide dismutase

mtDNA:

Mitochondrial DNA

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor-κB

NAIP5:

NLR family, apoptosis inhibitory protein

NLR:

Nucleotide-binding domain leucine-rich repeat-containing receptor family

NLRC4:

NLR family, CARD-containing 4

NLRP3:

NLR family, pyrin domain-containing 3

NOD1:

Nucleotide-binding oligomerization domain-containing protein 1

NOS:

Nitric-oxide synthase

Nox1-4:

NADPH oxidases 1–4

NRF2:

Nuclear factor E2-related factor 2

P2X7:

P2X purinoceptor 7

PMN:

Polymorphonuclear neutrophil

PYD:

Pyrin domain

RIG-1:

Retinoic acid inducible gene-1

ROS:

Reactive oxygen species

SAMP:

Senescence-accelerated prone mouse

STAT1:

Signal transducer and activator of transcription 1

TLR:

Toll-like receptors

TNF:

Tumour necrosis factor

TRAF:

TNF receptor-associated factor

TRIM30:

Tripartite-motif protein 30

TRX:

Thioredoxin

TXNIP:

Thioredoxin-interacting protein

UCP:

Uncoupling protein

UPRmt :

Mitochondrial unfolded protein response

UVB:

Ultraviolet B

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Acknowledgments

This study was financially supported by Grants from the Academy of Finland and the University of Eastern Finland, Kuopio, Finland. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

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Authors and Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Antero Salminen & Johanna Ojala

  2. Department of Neurology, University Hospital of Kuopio, P.O. Box 1777, FIN-70211, Kuopio, Finland

    Antero Salminen

  3. Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Kai Kaarniranta & Anu Kauppinen

  4. Department of Ophthalmology, University Hospital of Kuopio, P.O. Box 1777, FIN-70211, Kuopio, Finland

    Kai Kaarniranta

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  1. Antero Salminen
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  4. Anu Kauppinen
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Correspondence to Antero Salminen.

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Salminen, A., Ojala, J., Kaarniranta, K. et al. Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. Cell. Mol. Life Sci. 69, 2999–3013 (2012). https://doi.org/10.1007/s00018-012-0962-0

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