Regulatory role of mitochondria in oxidative stress and atherosclerosis

Figure 1 The molecular regulation of nuclear and mitochondrial cross-talk signaling on ROS-triggered AST/VCD development. ROS activate PARP-1 and cause AST primarily by increasing endothelial and smooth muscle cell death (mitochondria-dependent or not) and triggering inflammatory reactions. In addition, proinflammatory cytokines and chemokines induce plaque formation and plaque vulnerability that leads to deterioration in the later stages of AST. However, PARP-1 can also participate in NRF-1 regulation or indirectly activate PGC-1 to improve mitochondrial biofunctions such as biogenesis and fusion. This mechanism defends against ROS-induced progression of AST by inhibiting mitochondrial-mediated apoptosis and against the occurrence of AST at an early stage. ROS: Reactive oxygen species; PARP-1: Poly(ADP-ribose) polymerase-1; NRF-1: Nuclear respiratory factor 1; PGC-1: Peroxisome proliferator-activated receptor γ coactivator-1; mtDNA: Mitochondrial DNA; AIF: Apoptosis-inducing-factor; NF-κB: Nuclear factor κ-light-chain-enhancer of activated B cells; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; AST: Atherosclerosis; CVD: Cardiovascular diseases; N: Nucleus.

Figure 2 Proposed facilitation of AST progression via the opening of mitoK_ATP channels. Decreased NO production by eNOS and increased expression of ROS induce AST. Excessive ROS with affinity for NO bind with it to produce the peroxynitrite anion (ONOO.) which inhibits tetrahydrobiopterin (BH4), an essential cofactor of eNOS, leading to further reduction of NO. Significantly reduced NO not only increases ROS production, but also induces the opening of mitoK_ATP channels, followed by activation of the permeability transition pore (PTP), leading to mtROS release and AST development. mtROS: Mitochondrial ROS; NO: Nitric oxide; mitoK_ATP: Mitochondrial ATP-sensitive K⁺; eNOS: Endothelial nitric oxide synthase.