Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease

Search for a definitive cure for neurodegenerative disorders like Parkinson's disease (PD) has met with little success. Mitochondrial dysfunction and elevated oxidative stress precede characteristic loss of dopamine-producing neurons from the midbrain in PD. The majority of PD cases are classified as sporadic (sPD) with an unknown etiology, whereas mutations in a handful of genes cause monogenic form called familial (fPD). Both sPD and fPD is characterized by proteinopathy and mitochondrial dysfunction leading to increased oxidative stress. These pathophysiological mechanisms create a vicious cycle feeding into each other, ultimately tipping the neurons to its demise. Effect of iron accumulation and dopamine oxidation adds an additional dimension to mitochondrial oxidative stress and apoptotic pathways affected. Nrf2 is a redox-sensitive transcription factor which regulates basal as well as inducible expression of antioxidant enzymes and proteins involved in xenobiotic detoxification. Recent advances, however, shows a multifaceted role for Nrf2 in the regulation of genes connected with inflammatory response, metabolic pathways, protein homeostasis, iron management, and mitochondrial bioenergetics. Here we review the role of mitochondria and oxidative stress in the PD etiology and the potential crosstalk between Nrf2 signaling and mitochondrial function in PD. We also make a case for the development of therapeutics that safely activates Nrf2 pathway in halting the progression of neurodegeneration in PD patients.