Nuclear factor erythroid 2-related factor 2 induction abrogates mitochondrial stress through parkin regulation

Mitochondrial stress (MS) is a hallmark of a number of aging-associated neurodegenerative diseases, including Parkinson's disease (PD). Chronic MS in PD disrupts neuronal proteostasis, causing dopaminergic neurodegeneration through inactivation of an E3 ubiquitin ligase, parkin, although the mechanism of its inactivation is not understood. Here, we elucidate a mechanistic framework linking progressive changes in mitochondrial mass with MS-induced alterations in parkin activity. We showed that acute and chronic MS differentially modulate parkin activity and regulate mitochondrial biogenesis by transcriptional control of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), through parkin substrate PARIS (parkin-interacting substrate). Acute exposure to the PD neurotoxin, 1-methyl-4-phenylpyridinium (MPP⁺), activates the parkin-PARIS-PGC1α pathway, transiently facilitating mitochondrial biogenesis. However, sustained and repetitive MS leads to parkin mis localisation, inactivation, and aggregation, resulting in PARIS accumulation, repression of PGC1α activity, and loss of mitochondrial mass. Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2 or NRF2) activation by methylene blue (MB) transcriptionally upregulates parkin expression by enhancing its binding to NRF2/antioxidant responsive element (ARE) within the PARK2 promoter. MB treatment in cells exposed to chronic MPP ⁺ reduces PARIS levels, restores PGC1α activity, and rejuvenates mitochondria. These findings underscore the impact of chronic mitochondrial damage on parkin dysfunction in PD and suggest a promising role for MB in protecting against mitochondrial and proteostatic failure in PD by targeting the NRF2-parkin axis.