The role of inflammation in promoting CVD is increasingly recognised. Recent discoveries have demonstrated that mitochondria are key elements that stimulate innate immune signalling cascades which trigger inflammation and promote pathology in an expanding list of diseases, including cardiac pathologies. Many investigations have revealed that, when mitochondrial integrity is compromised, mtROS and mtDNA act as damage-associated molecular patterns (DAMPs), endogenous molecules that are isolated within intracellular compartments and discharged to the extracellular space in response to damaged or dying cells, promoting pathological inflammatory responses by binding with pattern-recognition receptors (PRRs).
For example, a study on mice found that mtDNA released by dying ischemic cells during MI activates the Interferon regulatory factor 3 (IRF3)-dependent innate immune response, which has a harmful effect on ventricular remodelling after MI. The Stimulator of interferon genes (STING)-IRF3 pathway might also facilitate chronic inflammation and dysfunction in endothelial cells via sensing mtDNA which are key events in the development of atherosclerosis and are associated with an elevated risk of many cardiovascular events . Furthermore, cytoplasmic mtDNA which escapes from autophagy-mediated degradation cell-autonomously has been linked with the activation of the immune system via Toll-like receptor 9 (TLR9), which has been associated with elevated arterial pressure and vascular dysfunction in spontaneously hypertensive rats, and with exacerbated HF in mice .
Accumulating evidence has also shown that mtROS and mtDNA contribute to molecular inflammation events during the pathogenesis of CVDs, activating the Nod-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome , although how this unfolds remains unknown. For example, excessive mtROS and dysfunctional mitochondria are considered critical drivers responsible for NLRP3 activation during the progression of atherosclerosis, and the level of the inflammasome has been found to be highly associated with the severity of disease. Upon activation, NLRP3 inflammasome activates caspase-1, which cleaves and matures the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which contribute to cardiac fibrosis and HF . Elevated IL-1β levels have been also correlated with age-related CVD .
Furthermore, the suppression of NLRP3 extends the lifespan of obese adult mice by reducing liver steatosis and cardiac damage. In turn, PRRs might also modulate mitochondrial dysfunction and apoptosis, protecting against mortality as occurs with the receptor NLR family member X1 (NLRX1) during IR injury.