Asbestos induces apoptosis in alveolar epithelial cells (AEC) via the mitochondria-regulated (intrinsic) death pathway. We previously showed that asbestos induces AEC mitochondria-derived reactive oxygen species (ROS) production that causes DNA damage, decreased mitochondrial membrane potential (Δψm), increased caspase-9 activity and apoptosis (AJRCMB 2003, AJP Lung 2004). The human 8-oxoguanine-DNA glycosylase 1 (hOgg-1) is a DNA repair enzyme implicated in preventing mitochondrial DNA damage by ROS. We hypothesized that over-expression of a mitochondria-targeted hOgg-1 (kind gift of Dr. M. Gillespie) would protect AEC cells from asbestos-induced apoptosis. As compared to empty vector (EV) transfected A549 cells, cells transfected with an adenoviral vector encoding mitochondria-targeted hOgg-1 significantly increased hOgg-1 in the mitochondria rather than the cytosol as assessed by Western blot analysis. Compared to EV-controls, mitochondria hOgg-1 overexpressing A549 cells completely blocked asbestos-induced reduction in Δψm (-39 ± 6% vs. +19 ± 6%, respectively; n = 4) and caspase 9 activation (Table). Mitochondria-targeted hOgg-1 also prevented asbestos-induced apoptosis as assessed by DNA fragmentation (see Table). We conclude that mitochondria-targeted hOgg-1 inhibits asbestos-induced AEC mitochondrial dysfunction and apoptosis. These data implicate an important role of AEC mitochondrial DNA in the pathogenesis of asbestos-induced pulmonary toxicity. Funding: VA Merit Award.
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