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ACCEPTED MANUSCRIPT been observed [207]. Curiously, an increase of extracellular striatal dopamine occured in some parkin knockout mice (Δexon3; [208, 209]. Gautier et al. reported a subtle increase in larger, but ultrastructurally normal mitochondria, a mild reduction in mitochondrial respiration in the striatum of young (3-4 months) and in the cortex of aged (22-24 months) PINK1 knockout mice, which, however, did not lead to reduced ATP levels [122]. Even in aged PINK1 knockout mice levels of oxidative stress markers were unchanged. In a different PINK1 knockout mouse line Gispert et al. observed progressive reduction of body weight and spontaneous locomotor activity in the absence of nigrostriatal degeneration [124]. Whether locomotor deficits in these mice were L-dopa responsive has not been reported. Furthermore, import of pre- proteins in liver mitochondria from these PINK1-deficient mice was impaired in an age-dependent manner [124]. This is an interesting observation which raises the question whether PINK1 per se has an effect on mitochondrial import or whether the defective import observed in PINK1-deficient mice is a consequence of the reduced mitochondrial membrane potential. In contrast to parkin and PINK1 knockout mice, Drosophila null mutants show a striking and remarkably similar phenotype, characterized by reduced life span, ACCEPTED MANUSCRIPT male sterility, and locomotor defects due to apoptotic flight muscle degeneration [210-214]. The earliest manifestation of muscle degeneration and defective spermatogenesis was mitochondrial pathology, exemplified by swollen mitochondria and disintegrated cristae. [210]. Strikingly, parkin could compensate for the PINK1 loss-of-function phenotype, but not vice versa, implying that PINK1 and parkin function in a common genetic pathway with parkin acting downstream of PINK1 [211-213]. Subsequent studies in Drosophila suggested that parkin and PINK1 may have a possible role in modulating mitochondrial morphology and dynamics [215- 25
ACCEPTED MANUSCRIPT 218] (see Fig. 1 for an overview of mitochondrial dynamics). In flies, the parkin or PINK1 flight muscle phenotype was suppressed by an increase in mitochondrial fission or a decrease in fusion, leading to the conclusion that the PINK1/parkin pathway promotes mitochondrial fission. In parallel, we performed studies in cultured human cells and confirmed that parkin can compensate for the alterations in mitochondrial morphology induced by siRNA-mediated downregulation of PINK1 [134]. Notably, transient silencing of parkin in dopaminergic SH-SY5Y showed a mitochondrial phenotype remarkably similar to that of PINK1 deficiency, characterized by a marked increase in mitochondrial fragmentation and a decrease in overall ATP production [135]. Both the morphological and functional deficits could be prevented by the enhanced expression of the fusion-promoting proteins Mfn2 or OPA1. Likewise, a dominant negative mutant of the fission-promoting protein Drp1 was protective, suggesting that a decrease in mitochondrial fusion or an increase in fission is associated with a loss of parkin or PINK1 function. The following findings established that an increase in mitochondrial fragmentation is responsible for the alterations observed in parkin- or PINK1-deficient cells. First, the mitochondrial phenotype in parkin- or PINK1 deficient cells was not observed in Drp1-deficient ACCEPTED MANUSCRIPT cells. Second, parkin as well as PINK1 suppressed mitochondrial fission induced by Drp1. At the same time Sandebring et al. reported very similar findings for a stable PINK1 knockdown in human dopaminergic M17 cells [130]. These authors used fluorescence recovery after photobleaching (FRAP) to show that PINK1 can reduce mitochondrial fragmentation induced by rotenone in a kinase-dependent fashion, whereas PINK1-deficient cells displayed a lower mitochondrial connectivity. In line with a study by Dagda et al. and our observations, knockdown of Drp1 prevented mitochondrial fragmentation caused by PINK1 loss of function [129, 135]. Of note, 26
Page 1 and 2: ÔØ ÅÒÙ× ÖÔØ Mitochondrial
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Page 19 and 20: 2.1.2. PINK1 substrates ACCEPTED MA
Page 21 and 22: 2.2. Parkin ACCEPTED MANUSCRIPT 2.2
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Page 39 and 40: Acknowledgements ACCEPTED MANUSCRIP
Page 41 and 42: References ACCEPTED MANUSCRIPT [1]
Page 43 and 44: ACCEPTED MANUSCRIPT Sciences of the
Page 45 and 46: ACCEPTED MANUSCRIPT biological chem
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Page 51 and 52: ACCEPTED MANUSCRIPT Parkinson's dis
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Page 69 and 70: ACCEPTED MANUSCRIPT Dalkara, N. Oze
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