Activity of NADH‐ and FADH2‐linked mitochondrial respiration are significantly decreased in two mice models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a complex neurodegenerative disorder, which etiology is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we tested the hypothesis that the activity of complex I and II (NADH‐and FADH2‐linked mitochondrial respiration, respectively) in the substantia nigra are significantly decreased in PD. To test this hypothesis, we used two different mice models of PD: Mice that received a single unilateral intrastriatal injection of 1) 6‐OHDA (9μg ‐ a selective catecholaminergic neurotoxin), or 2) A53T‐α‐synuclein (5.62E12 GC/ml – a molecule that attenuates synaptic vesicle recycling and neurotransmitter release). Control groups were injected with vehicle (fluorescent protein). Mitochondrial oxygen consumption was evaluated by using our oxygraph‐2K system (O2k‐OROBOROS), in 2 mg weight of tissue permeabilized with saponin. Measurements were performed one week after treatment with 6‐OHDA, and five weeks after treatment with A53T‐α‐synuclein. Our preliminary results show that, compared to control animals, substrates of complex I (Pyruvate/Glutamate/Malate), in the presence of ADP (state 3 complex I), induced a reduced oxygen consumption in mice treated with 6‐OHDA,(50.65 ± 2 vs 78 ±3 pmol O2/s/mg tissue, p<0.001). Inline, compared to control animals, oxygen consumption in state 3 complex I, was significantly reduced in mice treated with α‐synuclein (31.05 ± 5 vs 43.56 ± 2 pmol O2/s/mg tissue, p<0.05). Moreover, oxygen consumption in the presence of substrates of the mitochondrial complex II (succinate – state 3‐complex II), was also significantly reduced after treatment with α‐synuclein (30.8 ± 4.5 vs 46.5 ± 5 pmol O2/s/mg tissue, p<0.05). No differences of oxygen consumption were found in the presence of PMG, but the absence of ADP (state 4 – mitochondrial membrane leak) with none of the treatments. We concluded that 6‐OHDA and α‐synuclein, two reliable models of PD, induce mitochondrial dysfunction by decreasing the activity of mitochondrial complexes I and II. Our results contribute to a better understanding of the mitochondrial dysfunction induced by PD, and open the avenue for alternative treatments aiming to avoid the degeneration of dopaminergic neurons in the substantia nigra.Support or Funding InformationJorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S; FQ121919)