Mitochondrial generation of reactive oxygen species in the presence of a partial complex I inhibition: Effect of different metabolic states

• Grant number: 11/14229-4
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2012
• End date: February 28, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Roger Frigério Castilho
• Grantee: Luiz Guilherme Michelini Bueno
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The aim of this project is to improve the understanding of the neurodegenerative process of Parkinson´s disease (PD). The major neuropathological alteration of PD is a progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, with cytoplasmatic inclusions enriched with alpha-synuclein and ubiquitin proteins, also known as Lewy´s bodies. Postmortem studies in PD patients evidenced a partial inhibition of mitochondrial respiratory chain complex I activity. This dysfunction in respiratory chain may lead to impairment in ATP production, increased generation of reactive oxygen species (ROS) and increased susceptibility to redox imbalance. Interestingly, the chronic and systemic treatment of rats with rotenone (a classical complex I inhibitor) results in nigrostriatal dopaminergic degeneration and intracellular inclusions enriched with alpha-synuclein and ubiquitin in substantia nigra neurons, thus comprising an interesting experimental model for PD. We seek to evaluate the effects of a partial inhibition of the mitochondrial complex I by rotenone on ROS production under different mitochondrial metabolic states, ranging from resting to maximal ADP-stimulated oxidative phosphorylation. We will use different approaches to accomplish our aim, such as synaptic and nonsynaptic mitochondria (in vitro), synaptosomes (in situ) and rotenone-treated rats (in vivo).

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MICHELINI, LUIZ G. B.; FIGUEIRA, TIAGO R.; SIQUEIRA-SANTOS, EDILERIE S.; CASTILHO, ROGER F.. Rotenone exerts similar stimulatory effects on H2O2 production by isolated brain mitochondria from young-adult and old rats. Neuroscience Letters, v. 589, p. 25-30, MAR 4 2015. (11/50400-0, 11/51800-1, 11/14229-4)

MICHELINI, LUIZ G. B.; BENEVENTO, CARLOS E.; ROSSATO, FRANCO A.; SIQUEIRA-SANTOS, EDILENE S.; CASTILHO, ROGER F.. Effects of Partial Inhibition of Respiratory Complex I on H2O2 Production by Isolated Brain Mitochondria in Different Respiratory States. Neurochemical Research, v. 39, n. 12, p. 2419-2430, DEC 2014. (11/50400-0, 11/14229-4)