Mitochondrial amidoxime‐reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome

• DOI: 10.1111/liv.15857
• Publication Date: 2024-02-20T12:39:00Z
• Authors: Tanmoy Dutta; Kavitha Sasidharan; Ester Ciociola; Grazia Pennisi; Francesca R. Noto; Lohitesh Kovooru; Tobias Kroon; Anna Lindblom; Yue Du; Mohammad Pirmoradian; Simonetta Wallin; Rosellina M. Mancina; Daniel Lindén; Stefano Romeo
• Keywords: Protein Degradation; Mutant protein; Alanine; Wild type

Abstract Objective Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime‐reducing component 1 ( MARC1 ) results an aminoacidic substitution (p.Ala165Thr) associates protection against MASLD. However, the mechanisms behind this protective effect are unknown. In study, we examined consequences of on protein stability subcellular localization. Methods We overexpressed human A165 (wild‐type) or 165T (mutant) vivo mice vitro hepatoma cells (HepG2 HuH‐7), generated several mutants at position 165 by situ mutagenesis then levels. also HepG2 stably overexpressing to test Results overexpression resulted lower levels than both vitro. Similarly, any mutant showed compared wild‐type protein. that polyubiquitinated its degradation accelerated through lysine‐48 ubiquitin‐mediated proteasomal degradation. does not affect Conclusions This study shows alanine crucial for stability, threonine leads hypomorphic variant due Our result supports notion lowering hepatic level may be successful therapeutic strategy treating