Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

• Published in: Cell death & disease Vol. 12; no. 7; p. 671
• Main Authors: Gumeni, Sentiljana, Papanagnou, Eleni-Dimitra, Manola, Maria S., Trougakos, Ioannis P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/89; 14; 14/19; 45; 45/77; 631/80/304; 631/80/39/2348; 631/80/474/2085; 64; 64/24; 96; 96/109; Adapter proteins; Age; Antibodies; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Cell Biology; Cell Culture; Degeneration; Degenerative diseases; Disease; Gene expression; Homeostasis; Immunology; Insects; Kinases; Life Sciences; Mitochondria; Mitophagy; Neurodegeneration; Oxidative stress; Parkin protein; Phenotypes; Proteomes; PTEN-induced putative kinase; Quality control
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03952-w

The balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.