Caffeine improves mitochondrial function in PINK1B9-null mutant Drosophila melanogaster.

Mitochondrial dysfunction plays a central role in Parkinson's disease (PD) and can be triggered by xenobiotics and mutations in mitochondrial quality control genes, such as the PINK1 gene. Caffeine has been proposed as a secondary treatment to relieve PD symptoms mainly by its antagonistic effects on adenosine receptors (ARs). Nonetheless, the potential protective effects of caffeine on mitochondrial dysfunction could be a strategy in PD treatment but need further investigation. In this study, we used high-resolution respirometry (HRR) to test caffeine's effects on mitochondrial dysfunction in PINK1B9-null mutants of Drosophila melanogaster. PINK1 loss-of-function induced mitochondrial dysfunction in PINK1B9-null flies observed by a decrease in O2 flux related to oxidative phosphorylation (OXPHOS) and electron transfer system (ETS), respiratory control ratio (RCR) and ATP synthesis compared to control flies. Caffeine treatment improved OXPHOS and ETS in PINKB9-null mutant flies, increasing the mitochondrial O2 flux compared to untreated PINKB9-null mutant flies. Moreover, caffeine treatment increased O2 flux coupled to ATP synthesis and mitochondrial respiratory control ratio (RCR) in PINK 1B9-null mutant flies. The effects of caffeine on respiratory parameters were abolished by rotenone co-treatment, suggesting that caffeine exerts its beneficial effects mainly by stimulating the mitochondrial complex I (CI). In conclusion, we demonstrate that caffeine may improve mitochondrial function by increasing mitochondrial OXPHOS and ETS respiration in the PD model using PINK1 loss-of-function mutant flies.

Mitochondrial function and cellular energy maintenance during aging in a Drosophila melanogaster model of Parkinson disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by movement disorders as well as loss of dopaminergic neurons. Moreover, genes affecting mitochondrial function, such as SNCA, Parkin, PINK1, DJ-1 and LRRK2, were demonstrated to be associated with PD and other neurodegenerative disease. Additionally, mitochondrial dysfunction and cellular energy imbalance are common markers found in PD. In this study, we used the pink1 null mutants of Drosophila melanogaster as a Parkinson's disease model to investigate how the energetic pathways and mitochondrial functions change during aging in a PD model. In our study, the loss of the pink1 gene decreased the survival percent and the decreased climbing index during aging in pink1-/- flies. Furthermore, there was an impairment in mitochondrial function demonstrated by a decrease in OXPHOS CI&CII-Linked and ETS CI&CII-Linked in pink1-/- flies at 3, 15 and 30 days of life. Interestingly, OXPHOS CII-Linked and ETS CII-Linked presented decreases only at 15 days of life in pink1-/- flies. Moreover, there was an increase in peroxide (H2O2) levels in pink1-/- flies at 15 and 30 days of life. Loss of the pink1 gene also decreased the activity of citrate synthase (CS) and increased the activity of lactate dehydrogenase (LDH) in pink1-/- flies head. Our results demonstrate a metabolic shift in ATP production in pink1-/- flies, which changed from oxidative to glycolytic pathways from 15 days of age, and is apparently more pronounced in the central nervous system.