[Frontiers in Bioscience 12, 1238-1246, January 1, 2007]

Impairment of mitochondrial function by particulate matter (PM) and their toxic components: implications for PM-induced cardiovascular and lung disease

Tian Xia, Michael Kovochich, and Andre E. Nel

Division of Clinical Immunology and Allergy, Department of Medicine; Southern California Particle Center and Supersite, University of California, Los Angeles, CA

FIGURES

Figure 1. Sources of PM-induced ROS production and their cellular effects. Quinones, under the catalytic influence of NADPH-cytochrome P450 reductase, can redox cycle to produce ROS in the endoplasmic reticulum. Phagocytosis can induce the assembly and activation of NADPH oxidase to produce superoxide. PM can interfere in electron transduction in the mitochondrial inner membrane as well as perturb the PT pore to generate ROS. ROS induce lipid peroxidation in the cell membrane, crosslinking of protein SH groups, and DNA damage. ROS can also deplete GSH, resulting in redox dysequilibrium in the cell. Depending on the level of oxidative stress this could induce Nrf2 release to the nucleus, activation of MAPK and NF-kappaB signaling cascades or cytotoxicity. According to the hierarchical oxidative stress hypothesis, Nrf2 interaction with the ARE leads to heme oxygenase 1 and other phase II enzyme expression at lower levels of oxidative stress (Tier 1), while at a higher level of oxidative stress, activation of the MAPK and NF-kappaB signaling cascades can induce pro-inflammatory responses (e.g., cytokine and chemokine production) (Tier 2). At the highest oxidative stress level (Tier 3), ROS can induce the opening of the mitochondrial PT pore, followed by cytochrome c release, caspase-3 activation and induction of programmed cell death.

Figure 2. Putative structure of the PT pore and the electron transfer chain in the mitochondrial inner membrane. The PT pore is comprised of VDAC in the outer membrane, ANT in the inner membrane, and cyclophilin D (Cyp-D) in the matrix. Apart from the Ca2+-dependent function of Cyp-D, the pore also contains putative quinone binding sites and vicinal thiol groups on ANT protein which can regulate the open/close status of the pore. Bcl-2 family proteins such as Bcl-2, Bax, Bak, and Bcl-xL also regulate PT pore function. PT pore opening leads to cytochrome c release from inter membrane space. Cytochrome c binding to APAF-1 leads to the formation of an apoptosome that leads to the sequential caspase 9 and caspase 3 activation, which can induce apoptosis. The electron transfer chain is composed of 4 complexes, along which electrons donated by NADH and FADH2 are transferred along a decreasing redox potential gradient from complex I to complex IV. Energy dissipation along this gradient is used to pump protons from the matrix into the intermembrane space, thereby leading to the formation of the mitochondrial membrane potential. ATP synthase utilizes the proton motive force to produce ATP from ADP. During electron transfer, ubiquinone (Q) can accept an electron to form ubisemiquinone (Q.- ), which can transfer an electron to O2 to form superoxide. Mn-SOD in the matrix catalyzes O2.- dismutation to H2O2. H2O2 freely diffuses through the mitochondrial inner and outer membranes, which could lead to mitochondrial ROS to exert wider spread effects in the cell or cellular ROS to affect mitochondrial function. Transition metals can also catalyze .OH production through Fenton reaction and could also regulate the open/close status of the PT pore. ROS react and deplete GSH pool in the matrix. Ambient UFP can lodge in mitochondria with the possibility of releasing their chemical components to promote ROS production, PT pore opening and mitochondrial destruction. It is also possible, however, that the mitochondria can be damaged because of chemical release and ROS production elsewhere in the cell and that the particles enter the already damaged mitochondria. One mechanism by which this takes place is the increase in [Ca2+]i that occurs as a result of ROS generation extra-mitochondrially. This increase in [Ca2+]i is buffered by Ca2+ uptake into the mitochondria. If this uptake leads to saturation of the mitochondrial Ca2+ retention capacity, large scale PT transition leads to structural mitochondrial damage. The extent to which Ca2+-dependent and -independent processes contribute to PM-induced mitochondrial perturbation is difficult to quantify at this stage. It is apparent that the effects of aromatic PM chemicals proceed Ca2+-independently and that the effects of polar compounds and redox cycling quinones are mostly Ca2+-dependent.