Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

Abstract

Inflammation represents a comprehensive host response to external stimuli for the purpose of eliminating the offending agent, minimizing injury to host tissues and fostering repair of damaged tissues back to homeostatic levels. In normal physiologic context, inflammatory response culminates with the resolution of infection and tissue damage response. However, in a pathologic context, persistent or inappropriately regulated inflammation occurs that can lead to chronic inflammatory diseases. Recent scientific advances have integrated the role of innate immune response to be an important arm of the inflammatory process. Accordingly, the dysregulation of innate immunity has been increasingly recognized as a driving force of chronic inflammatory diseases. Mitochondria have recently emerged as organelles which govern fundamental cellular functions including cell proliferation or differentiation, cell death, metabolism and cellular signaling that are important in innate immunity and inflammation-mediated diseases. As a natural consequence, mitochondrial dysfunction has been highlighted in a myriad of chronic inflammatory diseases. Moreover, the similarities between mitochondrial and bacterial constituents highlight the intrinsic links in the innate immune mechanisms that control chronic inflammation in diseases where mitochondrial damage associated molecular patterns (DAMPs) have been involved. Here in this review, the role of mitochondria in innate immune responses is discussed and how it pertains to the mitochondrial dysfunction or DAMPs seen in chronic inflammatory diseases is reviewed.

Mitochondrial dysfunction in pathophysiology of heart failure

“…Mitochondrial DAMPs retain at least two unique molecular features that are evolutionary endosymbionts derived from bacteria: mtDNA rich in unmethylated CpG motifs and N-formyl peptides. Emerging evidence suggests that mtDNA and N-formyl peptides act on TLR9 and formyl peptide receptors, respectively, to induce inflammatory responses through the assembly of the NLRP3 inflammasome (143)(144)(145)(146).…”

The role of mitochondria in aging

“…In that context, the mitochondria, derived several billions of years ago from the endosymbiosis of α-proteobacteria into a eukaryotic cell, represent a smorgasbord of potential immune-stimulating DAMPs. Putative mitochondrial DAMPs include the release of mitochondrial DNA (mtDNA), N-formyl peptides generated by translation of mitochondrial-encoded protein, and unique lipid species such as cardiolipin, a unique phospholipid enriched on the inner mitochondrial membrane (25). In the case of circulating mtDNA, immune activation occurs, in part, by activation of Toll-like receptor 9 (TLR9) signaling, while for mitochondrial proteins, activation occurs through binding to formyl peptide receptor-1.…”

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

“…It is currently clear that mitochondrial dysfunction and damage is involved in NLRP3 inflammasomes activation [60]. Dysfunctional mitochondria serve as an important source of DAMPs and as the inducers of cells oxidative damage and death implicated in several chronic human pathologies [63].…”