Mitochondria have a vital role in respiration-coupled energy production, amino acid and fatty acid metabolism, Fe2+/Ca2+ homeostasis and the integration of apoptotic signals that regulate cellular life and death (Babcock et al., 1997; Loeb et al., 2005; Taylor & Turnbull, 2005; Kroemer et al., 2007). Given the importance of these cellular functions regulated by the mitochondria with implications for aging, degenerative diseases and carcinogenesis, it is not surprising that this organelle has been the subject of intensive investigation for decades and continues to challenge investigators. Mitochondria produce nearly 90% of all the energy made in the body by oxidative phosphorylation that occurs via the electron transport chain (ETC). Mitochondria are the major cellular site of reactive oxygen species (ROS) production. It is estimated that 1–5% of the oxygen consumed in the mitochondrial ETC is converted to ROS (Kroemer et al., 2007). Mammalian mitochondria have a covalently closed round mitochondrial DNA (mtDNA) that is replicated and expressed within the mitochondria in close proximity to the ETC and potentially damaging ROS (Clayton 1982; Clayton 1984; Kroemer et al., 2007). Mammalian mtDNA contains 37 genes that encode 13 proteins (all of which are involved in the ETC), 22 tRNAs, and 2 rRNAs (Anderson et al., 1981). The remaining mitochondrial ETC proteins, the metabolic enzymes, the DNA and RNA polymerases and the ribosomal proteins are all encoded by nuclear genome. Oxidative stress-induced mtDNA damage is implicated in a wide range of pathologic processes including carcinogenesis, aging and degenerative diseases of various organs and tissues (Bohr et al., 2002; Van Houten et al., 2006; Kroemer et al., 2007; Gredilla et al., 2010). In this review, we summarize the evidence that mtDNA damage augments mitochondriaregulated (intrinsic) apoptosis; an event that underlies the pathophysiologic mechanisms of diverse diseases. We focus our attention on one form of oxidative stress, exposure to asbestos fibers, which are well known to cause pulmonary fibrosis (asbestosis) and malignancies (e.g. mesothelioma and lung cancer). Specifically, we examine the role of a mitochondrial oxidative DNA repair enzyme (8-oxoguanine DNA glycosylase; Ogg1) and a recently described novel mechanism whereby mitochondrial Ogg1 acts as a mitochondrial aconitase chaperone protein to prevent oxidant-induced alveolar epithelial cell (AEC) mitochondrial dysfunction and intrinsic apoptosis. We discuss studies showing that