Mitochondrial Complex I Reversible S-Nitrosation Improves Bioenergetics and Is Protective in Parkinson's Disease

Abstract

Aims: This study was designed to explore the neuroprotective potential of inorganic nitrite as a new therapeutic avenue in Parkinson's disease (PD).

Results: Administration of inorganic nitrite ameliorates neuropathology in phylogenetically distinct animal models of PD. Beneficial effects are not confined to prophylactic treatment and also occur if nitrite is administered when the pathogenic cascade is already active. Mechanistically, the effect is mediated by both complex I S-nitrosation, which under nitrite administration is favored over formation of other forms of oxidation, and down-stream activation of the antioxidant Nrf2 pathway. Nitrite also rescues respiratory reserve capacity and increases proton leakage in LRRK2 PD patients' dermal fibroblasts.

Innovation: The study proposes an unprecedented approach based on the administration of the nitrosonium donor nitrite to contrast complex I and redox anomalies in PD. Dysfunctional mitochondrial complex I propagates oxidative stress in PD, and treatments mitigating this defect may, therefore, limit disease progression. Therapeutic complex I targeting has been successfully achieved in ischemia/reperfusion by using nitrosonium donors such as nitrite to reversibly modify its subunits and protect from oxidative damage after reperfusion. This evidence led to the innovative hypothesis that nitrite could exert protective effects also in pathological conditions where complex I dysfunction occurs in normoxia, such as in PD.

Conclusions: Overall, these results demonstrate that administration of inorganic nitrite improves mitochondrial function in PD, and it, therefore, represents an amenable intervention to hamper disease progression.