A pathological consequence of damage in mitochondria and in mitochondrial DNA (mtDNA) is the release of free mtDNA fragments into cytoplasm, and later to extracellular spaces. These mtDNA fragments function as danger-associated molecular patterns to induce inflammation via toll-like receptor 9 (TLR9). Further, a complex formed by the receptor for advanced glycation end-products and mitochondrial transcription factor A is a critical component to facilitate the signal transduction.
Our current investigation indicates that this signaling pathway is dependent on mitochondrial reactive oxygen species, and is used in cardiac inflammation in response to sepsis.
Future studies will determine how cardiac inflammation is regulated via different TLR pathways, spatially and temporally, or by their crosstalk. These studies will help clarify the pathological mechanisms underlying sepsis-induced cardiac dysfunction.