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ACCEPTED MANUSCRIPT encephalomyopathy at 5 weeks of age leading to death at 7 weeks. The abundance of intact complex I and complex I-driven oxygen consumption were significantly reduced, indicating that NDUFS4 may help to assemble and/or stabilize complex I. Remarkably, ATP levels were in the normal range and total oxygen consumption was unaffected in NDUFS4 knockout mice. Moreover, the authors of this sudy reported that they did not observe increased ROS formation in neuronal cultures derived from these mice. To add another layer of complexity, primary mesencephalic cultures from NDUFS4 knockout mice did not show an increased rate of cell death. Moreover, they were not protected from cell death induced by MPP + and rotenone [85]. These findings are surprising as they do not support the link between complex I deficiency, ATP depletion, oxidative stress and dopaminergic neuron death, which has been put forward to explain pathophysiological events leading to PD. A plausible explanation would be that these mice do not reflect the gradual decline in complex I activity which may persist over decades during the pathogenesis of PD in an aging individual. However, it might well be that complex I inhibition is not primarily responsible for the toxicitiy of MPP + and rotenone in dopaminergic neurons. Clearly, more in vivo models are needed to address the role of complex I deficiency in PD. ACCEPTED MANUSCRIPT Mitochondrial DNA mutations MtDNA is a double-stranded circular genome of about 16.6 kb, which replicates independently from the cell cycle and nuclear DNA replication. It encodes 13 proteins, all of which are subunits of respiratory chain complexes: seven subunits of complex I, one subunit of complex III, three subunits of complex IV and two of ATP synthase. In addition, mtDNA codes for 22 tRNAs and two rRNAs that are necessary for mitochondrial protein synthesis (rev. in [86]). Mitochondria contain 11
ACCEPTED MANUSCRIPT about 1500 different proteins, thus the majority of mitochondrial proteins is encoded by nuclear DNA, translated in the cytoplasm and imported into mitochondria by an elaborate import machinery (for review see [87-89]). The multiple copies of mitochondrial DNA (1,000 - 10,000 per mitochondrion) are arranged in nucleoids, which consist of several mtDNA molecules together with proteins necessary for mitochondrial replication and transcription, such as the mitochondrial transcription factor A (TFAM). MtDNA is characterized by an increased vulnerability to mutations, based on less efficient DNA repair mechanisms and the absence of protective histones. In addition, the proximity of the respiratory chain has been suggested to favor mtDNA damage by ROS. MtDNA mutations are inherited maternally or acquired. The high copy number confers some protective genetic redundancy, and usually, point mutations or large-scale deletions of the mtDNA co- exist together with wildtype mtDNA within a single mitochondrion, a condition which is known as heteroplasmy (rev. in [70, 86, 90]). By a process called clonal expansion the mtDNA mutations can spread to daughter mitochondria and daughter cells (in mitotic tissue), leading to respiratory deficiency when a certain threshold of mutant mtDNA is exceeded [91]. Typically, mutations in the mitochondrial genome ACCEPTED MANUSCRIPT cause symptoms in postmitotic cell with high energy demands, in particular neurons and skeletal and cardiac muscle cells, resulting in encephalomyopathies (rev. in [86, 90, 92]). However, accumulation of somatic mtDNA mutations occur also during aging in various tissues, such as brain and muscle (rev. in [70, 71]). An age-dependent increase in somatic mtDNA deletions associated with a respiratory chain defect has been identified in dopaminergic neurons from the substantia nigra by using long-range PCR and quantitative real time or single molecule PCR [93, 94]. Different neurons from the same individual showed unique 12
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Page 47 and 48: ACCEPTED MANUSCRIPT [47] B. Janetzk
Page 49 and 50: 486-517. ACCEPTED MANUSCRIPT [63] B
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Page 55 and 56: ACCEPTED MANUSCRIPT causes of Parki
Page 57 and 58: ACCEPTED MANUSCRIPT [125] A. Grunew
Page 59 and 60: ACCEPTED MANUSCRIPT [136] G.B. John
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ACCEPTED MANUSCRIPT (2004) 1328-133
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