The sensing of mitochondrial DAMPs by non-immune cells

Abstract

Mitochondria are the source of damage-associated molecular patterns (DAMPs), which are molecules that play a key modulatory role in immune cells. These molecules include proteins and peptides, such as N-formyl peptides and TFAM, as well as lipids, and metabolites such as cardiolipin, succinate and ATP, and also mitochondrial DNA (mtDNA). Recent data indicate that somatic cells sense mitochondrial DAMPs and trigger protective mechanisms in response to these signals. In this review we focus on the well-described effects of mitochondrial DAMPs on immune cells and also how these molecules induce immunogenic responses in non-immune cells. Special attention will be paid to the response to mtDNA.

Keywords: DAMP; TLR9; cGAS; immunity; mitochondria; mitochondrial DNA.

Figure 1. FIGURE 1: Mitochondria-derived DAMPs.

Mitochondria generate immunogenic molecules, named damage associated molecular patters (DAMPS). The scheme represents the localization of the different DAMPs in their non-immunogenic state, as well as a brief description of their immunogenic capacity when misplaced.

Figure 2. FIGURE 2: cGAS and TLR9 activation by mtDNA.

Under conditions of impaired mitophagy initiation (green background), thus accumulation of dysfunctional mitochondria, there is mtDNA leakage to the cytosol. cGAS homodimers recognize double stranded DNA as mtDNA and produce c-GAMP, which interacts with STING, triggering IRF3 or NF-κB, and in turn the expression of type I IFNs or cytokines, respectively. Under conditions in which mitophagosomal formation occurs normally but resolution is defective (orange background), mtDNA instability can lead to its recognition by TLR9 in different endosomal compartments. TLR9 is recruited from the ER to the endo-lysosomal system, guided by UNC93B1. Engagement of TLR9 in early endosomes or lysosomes results in type I IFN expression through various IRFs. Interaction of mtDNA with TLR9 in late endosomes results in NF-κB activation. Given the resemblance of amphisomes to late endosomes, TLR9 engagement in amphisomes could result in cytokine production.