have shown that inhibition of complex I of the electron transport chain by exposure to rotenone triggers mitotic catastrophe and makes cells more susceptible to death by inhibition of autophagy [20]

have shown that inhibition of complex I of the electron transport chain by exposure to rotenone triggers mitotic catastrophe and makes cells more susceptible to death by inhibition of autophagy [20]. damage and that autophagy is an important survival mechanism for ENMD-2076 cells suffering from mitochondrial damage. 1. Introduction Mitochondria are vital cell organelles that not only produce the majority of cellular ATP but also control cellular calcium homeostasis and regulate Rabbit Polyclonal to MYT1 apoptotic pathways, among many other ENMD-2076 key functions [1]. They are also the primary source of intracellular reactive oxygen species (ROS) [2]. During normal cellular metabolism, ROS can function as important secondary messengers and there is a balance between ROS production and their detoxification by cellular antioxidant systems [2, 3]. However, dysfunctional mitochondria, marked by reduced ATP production and an increased generation of ROS, disturb this balance and have been speculated to contribute to ageing and the development of age-related diseases [1, 3, 4]. In a vicious cycle, aberrant mitochondrial ROS cause further damage to mitochondrial DNA (mtDNA), membrane lipids, and proteins, increasing mitochondrial damage and further augmenting ROS leakage. ROS generation and mtDNA damage have been found to increase with age, while there is a corresponding decline in mitochondrial function and ATP generation [4]. mtDNA is usually a 16569?bp loop of super-coiled, double-stranded DNA, encoding 37 genes that translate 22 tRNAs, 2 ribosomal RNAs, and 13 proteins [1, 5]. All of the proteins encoded by the mtDNA are components of the electron transport chain (ETC) and vital for cellular energy production by oxidative phosphorylation (OXPHOS). Due to a lack of protective histones and its close proximity to the ROS produced by the ETC, mtDNA is usually susceptible to mutations; it has been estimated to have a mutation rate 10 times more than that of nuclear DNA [5, 6]. Furthermore, the relative lack of noncoding regions and an absence of introns in mtDNA [5] mean that mtDNA mutations almost invariably cause dysfunction in ETC protein expression and, consequently, lead to a loss of mitochondrial function, i.e., energy generation declines while ROS production increases. Heteroplasmy prevents immediate consequences of mtDNA damage to cells, but as the number of mutated mtDNA molecules and ROS production increase with age, cells are at an increased risk of dying [1]. Postmitotic tissues, such as the brain, muscle, and retinal pigment epithelium (RPE), are especially vulnerable to the accumulation of mtDNA damage, as the mitochondrial genome replicates independently of the cell cycle, allowing the clonal growth of mutated mtDNA [1, 5]. Consequently, mitochondrial dysfunction has been linked to many age-related neurodegenerative diseases, such as Parkinson’s disease [7, 8] ENMD-2076 and Alzheimer’s [9, 10]. There is evidence that dysfunctional mitochondria are a key factor also in the development of age-related macular degeneration (AMD), the leading cause of blindness among the elderly [11, 12]. Mitochondrial number and size, as well as the mitochondrial matrix density, are reduced in the RPE of AMD patients [13]. Mitochondrial DNA damage was found to be elevated in the retina and RPE layer of AMD patients when compared to healthy controls [14, 15] whereas the protein expression levels of several subunits of the ATP synthase as well as cytochrome c oxidase were reduced in AMD patients suffering from advanced AMD [16]. Cells can employ a specific form of macroautophagy, called mitophagy, to remove damaged mitochondria. Excessive production of the superoxide anion by the ETC is usually a known trigger for the induction of autophagy [17, 18], and dysfunction of.

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