**6. Acknowledgments**

324 Etiology and Pathophysiology of Parkinson's Disease

decreased malate/glutamate-supported mitochondrial respiration, reduced complex I (NADH-dehydrogenase) activity, increased phospholipid and protein oxidation products, increased protein nitration products, and increased O2- and H2O2 production rates (Boveris et al., 2010). Interestingly, high doses of vitamin E are able to restore to normal the agedependent complex I syndrome in hippocampus and brain cortex (Navarro et al., 2010).This "complex I syndrome" has been observed in PD and in other neurodegenerative diseases (Schapira et al., 1990a; Schapira et al., 1990b; Cooper et al., 1992; Schapira, 2008; Carreras et al., 2004; Navarro & Boveris, 2007; Navarro et al., 2009), as well as in aging (Boveris& Navarro, 2008) and in ischemia-reperfusion (Gonzalez-Flecha et al., 1993; Valdez et al.,

The molecular mechanisms responsible for complex I syndrome are likely accounted for a series of processes and reactions that lead synergistically to complex I inactivation. The involved processes and reactions are, in the first place, the lipid peroxidation process and

second place, the reactions of the aldehydes produced in the lipid peroxidation process (4- HO-nonenal and malonaldehyde) with amino groups of the polypeptide chain of the complex I proteins. In the third place, nitration of complex I proteins following to the increased formation of ONOO-, the chemical species produced by the intramitochondrial reaction of NO and O2-at the vicinity of NADH-dehydrogenase active center (Turrens & Boveris, 1980). The three mentioned processes provide synergistically pathways leading to complex I inactivation. Interestingly, complex I inactivation is accompanied by increased auto-oxidation and O2- production rate and subsequently an enlarged generation of H2O2 (Hensley et al., 2000; Navarro et al., 2011). It is understood that the reactions that inactivate

covalent intermolecular forces bonding and synergistically promote covalent cross linking

Parkinson's disease is characterized by persistent, coordinated, nuclear-encoded cellular energy defects to which nigral dopamine neurons are intrinsically more susceptible than others cells. Complex I dysfunction in PD may be a biochemically detectable "tip of the iceberg" of a deeper molecular defect comprising the entire nuclear-encoded electron transfer chain. Under expression of PGC-1α-controlled genes involved in cellular energetic might represent a common link for these diverse manifestations of defects in mitochondrial biogenesis, and abnormal glucose utilization. One of the basic postulates of the mitochondrial theory of aging and neurodegenerative diseases is that there is a significant reduction in the capacity for ATP production in the brain and other organs of old mammals. The concept of a decrease in the effectiveness of the mitochondrial process of energy transduction (or oxidative phosphorylation) is expressed as an under function of "the mitochondrial redox-energy axis" (Yap et al., 2010). Although mitochondrial complexes, complex I (Valdez et al., 2004; Boveris & Navarro, 2008; Navarro et al., 2009), complex IV (Valdez et al., 2004; Boveris & Navarro, 2008), and complex V (Lam et al., 2009), are considered the main targets in neurodegeneration and aging, there are also cytosolic enzymes whose activities are simultaneously decreased, such as succinyl-CoA-transferase (Lam et al. 2009) and as 6-phosphofructo-2-kinase (Herrero-Mendez et al., 2009). The cytosolic-mitochondrial interaction is certainly affected and there is recognition of a

), aldehydes and ONOO-

) with complex I. In the

, change the native non-

the reactions of the reactive free radical intermediates (mainly ROO•

complex I, mediated by free radicals (ROO•

with protein inactivation (Liu et al., 2003).

**5. Conclusions** 

2011).

This work was supported by research grants from the University of Buenos Aires (B005), Agencia Nacional de Promoción Científica y Tecnológica (PICT 38326, PICT 1138), and Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 688) in Argentina; and from Ministerio de Ciencia e Innovación (SAF2008-03690) and Plan Andaluz de Investigación 2007-2008 (CTS-194) in Spain.
