Modulation of autophagy by the novel mitochondrial complex I inhibitor Authipyrin. Issue 12 (15th June 2019)

• Record Type: Journal Article
• Authors: Kaiser, Nadine; Corkery, Dale; Wu, Yaowen; Laraia, Luca; Waldmann, Herbert
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 12(2019)
• Page Start: 2444
• Page End: 2448
• Publication Date: 2019-06-15
• Subjects: Thienopyrimidines -- Autophagy -- Mitochondrial respiration -- Complex I -- Inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.02.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Autophagy ensures cellular homeostasis by the degradation of long-lived proteins, damaged organelles and pathogens. This catabolic process provides essential cellular building blocks upon nutrient deprivation. Cellular metabolism, especially mitochondrial respiration, has a significant influence on autophagic flux, and complex I function is required for maximal autophagy. In Parkinson's disease mitochondrial function is frequently impaired and autophagic flux is altered. Thus, dysfunctional organelles and protein aggregates accumulate and cause cellular damage. In order to investigate the interdependency between mitochondrial function and autophagy, novel tool compounds are required. Herein, we report the discovery of a structurally novel autophagy inhibitor (Authipyrin) using a high content screening approach. Target identification and validation led to the discovery that Authipyrin targets mitochondrial complex I directly, leading to the potent inhibition of mitochondrial respiration as well as autophagy.