ABSTRACT
In addition to supplying most of the adenosine triphosphate (ATP) demand of the cell, mitochondria are central to metabolism and are also involved in both apoptotic and necrotic cell death (Kroemer, Zamzami, and Susin 1997; Lemasters et al. 1998; Saraste 1999; Wallace 1999; Murphy and Smith 2000; Szewczyk and Wojtczak 2002; Duchen 2004; Yousif, Stewart, and Kelley 2009). Because of these vital roles, mitochondrial dysfunction contributes to a wide range of diseases and pathologies, and some of these are due to mutations to mitochondrial or nuclear genomes. However, many others occur because of cumulative damage to mitochondria over the lifetime of the organism or acute alterations to mitochondrial function (Kroemer et al. 1997; Lemasters et al. 1998; Wallace 1999; Murphy and Smith 2000; Duchen 2004). Therefore mitochondrial dysfunction is a contributing factor in a diverse range of disorders ranging from neurodegenerative diseases such as Parkinson’s disease (PD), to metabolic disorders, such as diabetes and metabolic syndrome to acute injury in heart attack and in organ preservation. A major factor in all these
6.1 Introduction .................................................................................................. 111 6.2 Targeting Antioxidants to Mitochondria ...................................................... 112
6.2.1 Targeting by Conjugation to a Lipophilic Cation ............................. 112 6.2.1.1 Uptake of TPP Antioxidants by Mitochondria in vivo ...... 114 6.2.1.2 Concerns about Using Lipophilic Cations to Target
Antioxidants to Mitochondria ............................................ 116 6.2.2 Use of Peptides to Target Antioxidants to Mitochondria ................. 117
6.3 Therapeutic Efcacy of Mitochondria-Targeted Antioxidants ..................... 119 6.3.1 Antioxidants Based on Lipophilic Cations ....................................... 119 6.3.2 Antioxidants Based on Mitochondria-Targeted Peptides ................. 121
6.4 Conclusions ................................................................................................... 121 Acknowledgments .................................................................................................. 121 Conicts of Interest ................................................................................................ 121 References .............................................................................................................. 122
disorders is oxidative damage to mitochondria. This type of damage occurs because mitochondria are a major source of the reactive oxygen species (ROS) superoxide that in turn forms hydrogen peroxide, which, in the presence of ferrous or cuprous ions, can lead to the very damaging hydroxyl radical. In addition, superoxide can damage iron-sulfur centers directly and also react with nitric oxide to form peroxynitrite, a far more damaging species than either superoxide or nitric oxide (Balaban, Nemoto, and Finkel 2005; Murphy 2009a, 2009b). Mitochondria have a number of components that are particularly susceptible to oxidative damage, including an extensive inner membrane that contains a large proportion of unsaturated fatty acids, a number of vulnerable proteins, and its own genome. In many pathologies, superoxide and nitric oxide production increases, or antioxidant defenses are compromised; consequently, mitochondria accumulate oxidative damage that contributes to dysfunction and cell death in many pathologies (Balaban et al. 2005; Miller et al. 2007; Murphy 2009a, 2009b). There is considerable interest in developing therapies to decrease this oxidative damage to mitochondria (Murphy and Smith 2000; Szewczyk and Wojtczak 2002; Balaban et al. 2005; Murphy 2009a, 2009b).
