**5. Concluding comments**

**4. The interplay between mitochondria and innate immunity**

150 Mitochondrial Diseases

released to trigger sterile proinflammatory immune responses.

In response to microbial infection, the mammalian innate immune system recognizes invading microorganisms and orchestrates a proinflammatory immune response to eliminate the undesired pathogens and infected cells. The sensing of the infection by the innate immune system is mediated by a variety of pattern recognition receptors (PRRs), which recognize molecular patterns conserved among microbial species known as PAMPs. For detailed information regarding the different families of receptors, respective PAMPs recognition, and the intracellular signaling cascades triggered, see reference [288]. Interestingly, even in the absence of microbial infection, PRRs sense and orchestrate inflammatory responses through recognition of intracellular molecules known as DAMPs. DAMPs are endogenous molecules sequestered within cellular compartments of healthy cells, which, upon injury or stress, are

Recent insights revealed that mitochondria are an important source of DAMPs. Interestingly, upon injury, both mtDNA and N-formylated peptides can act as DAMPs. This is due to the fact that mitochondria and bacteria display some similarities in that both possess circular DNA, N-formylated proteins and are double-membrane structures—evidence used in support of the endosymbiotic theory. mtDNA is similar to bacterial DNA in that it contains CpG motifs, which activate the TLR9 [289, 290]. Moreover, mitochondrial protein synthesis is initiated with the residue N-formyl methionine, similar to bacterial protein synthesis [291]. The resulting bacterial N-formylated peptides are known to act as PAMPs by binding and activating G protein-coupled formyl peptide receptors (FPRs) [292], while the mitochondrial N-formylated peptides act as DAMPs through activation of the formyl peptide receptor 1 [290]. Therefore, upon injury, release of these mitochondrial DAMPs activates the innate immune system, much like bacterial PAMPs, to promote sterile inflammatory responses [290]. Several studies have now described a crucial role for mitochondria in the regulation and activation of the inflammasome, specifically the NLRP3 inflammasome [293]. The inflammasomes are intracellular molecular platforms activated upon cellular infection or sterile stressors, which activate the proinflammatory cytokines, interleukin-1β (IL-1β) and IL-18, to trigger pyroptotic cell death (reviewed in [294, 295]). A variety of insults, resulting from cellular infection or stress, can promote mitochondrial dysfunction and activate the NLRP3 inflammasome [293]; however, the molecular mechanisms underlying the contribution of mitochondria to the activation of the NLRP3 inflammasome have only recently been described. While initial studies showed that mitochondrial dysfunction and mtROS production are required for NLRP3 inflammasome activation [296, 297], further evidence has shown that mtDNA translocation to the cytosol plays an active role in this process [297, 298], where it can directly bind to and activate the NRLP3 inflammasome [298]. In addition, the mitochondrial lipid cardiolipin—a phospholipid located exclusively in mitochondrial inner and bacterial membranes, regarded as evidence for symbiogenesis [299, 300]—is also required for NLRP3 inflammasome activation, by directly binding to NLRP3, downstream of mitochondrial dysfunction [301]. Altogether, mitochondria and mitochondrial DAMPs (such as mtDNA and cardiolipin) play a critical role in NLRP3 inflammasome activation and regulation. Moreover, by sensing mitochondrial DAMPs, the NLRP3 inflammasome plays a critical role in integrating mitochondrial dysfunction in a proinflammatory signaling response, thus explaining the association of mitochondrial damage with inflammatory diseases.

Although the innate immune system has specialized in the recognition of molecular patterns foreign to the host cells, cellular injury or stress may result in the release of endogenous molecular patterns, which trigger sterile inflammatory responses. Given its bacterial origin, mitochondria display some similarities with bacteria and represent an important source of DAMPs (including lipids, nucleic acids and proteins) with immunostimulatory potential. While under healthy conditions these DAMPs are sequestered within mitochondria, pathological insults resulting in mitochondrial and cellular damage promote the release of these danger signals to cause inflammation mediated by the innate immune system. Recent studies have shown that mitochondrial DAMPs have the potential to mediate inflammatory signaling in the brain; therefore, its contribution to the neuroinflammatory process in neurodegenerative disorders characterized by impaired mitochondrial function represents an emerging and promising field of research (**Figure 1**).

**Acknowledgements**

**Author details**

Coimbra, Portugal

2016;**9**:1-11

Research. 2011;**8**:563-572

Disorders Drug Targets. 2010;**9**:105-119

**References**

and Sandra M. Cardoso1,2,3\*

Work in our laboratories is supported by Fundação para a Ciência e a Tecnologia (FCT) and by EU-FEDER funding through the Operational Competitiveness Programme—COMPETE grant UID/NEU/04539/2013 and by Prémio Santa Casa Neurociências Mantero Belard MB-40-2016.

Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer's and Parkinson's Diseases

http://dx.doi.org/10.5772/intechopen.72612

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A. Raquel Esteves1,2, Diana F. Silva1,2, Daniel Santos1,2, Emanuel Candeias1,2, Filipa Filipe1,2

1 CNC–Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

3 Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra,

[1] Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Mitochondrial fragmentation in neurodegeneration. Nature Reviews Neuroscience. 2008;**9**:505-518. DOI: 10.1038/nrn2417

[2] Lobet E, Letesson JJ, Arnould T. Mitochondria: A target for bacteria. Biochemical Phar-

[3] Hawking ZL. Alzheimer's disease: The role of mitochondrial dysfunction and potential new therapies. Bioscience Horizons: The International Journal of Student Research.

[4] Lionaki E, Markaki M, Palikaras K, Tavernarakis N. Mitochondria, autophagy and age-associated neurodegenerative diseases: New insights into a complex interplay. Biochimica et Biophysica Acta. 2015;**1847**:1412-1423. DOI: 10.1016/j.bbabio.2015.04.010 [5] Silva DF, Esteves AR, Oliveira CR, Cardoso SM. Mitochondria: The common upstream driver of amyloid-beta and tau pathology in Alzheimer's disease. Current Alzheimer

[6] Arduino DM, Esteves AR, Oliveira CR, Cardoso SM. Mitochondrial metabolism modulation: A new therapeutic approach for Parkinson's disease. CNS & Neurological

[7] Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Wang KZQ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayir H, Kagan VE. Cardiolipin

\*Address all correspondence to: cardoso.sandra.m@gmail.com

macology. 2015;**94**:173-185. DOI: 10.1016/j.bcp.2015.02.007

2 CNC-IBILI, University of Coimbra, Coimbra, Portugal

Further understanding of neuronal innate immunity-induced chronic mild neuroinflammation and its impact on age-related neurodegenerative disorders should focus on new studies addressing not only mitochondrial dysfunction and protein oligomerization but also mild inflammation, nutritional states, among others. The development of new biomarkers focusing on the inflammatory process and the identification of protective inflammatory processes should be pursuit. Additionally, exploiting the effect of mutations, epigenetic and the microbiome on immune-related modifications affecting the AD and PD phenotypes will be of paramount relevance to understand etiology of both diseases.

**Figure 1.** Mitochondria are primary targets of cellular peptides, such as Aβ, tau and SNCA, overproduced during AD and PD pathogenesis. Damaged mitochondria are a source of DAMPs that activate the NLRP3 inflammasome and TLRs leading to the intraneuronal production of cytokines. These proinflammatory cytokines are released and activate innate immune response through microglia and astrocytes. This chronic inflammation impacts neurons exacerbating peptides formation and mitochondrial damage.
