Open AccessReprograming of proteasomal degradation by branched chain amino acid metabolism
Author(s) -
Ravanelli Sonia,
Li Qiaochu,
Annibal Andrea,
Trifunovic Aleksandra,
Antebi Adam,
Hoppe Thorsten
Publication year - 2022
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13725
Subject(s) - catabolism , transamination , proteasome , branched chain amino acid , biology , metabolism , amino acid , ubiquitin , caenorhabditis elegans , function (biology) , biochemistry , protein degradation , enzyme , microbiology and biotechnology , leucine , gene
Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans , we identified adaptive regulation of the ubiquitin‐proteasome system (UPS) in response to defective BCAA catabolic reactions after the initial transamination step. Worms with impaired BCAA metabolism show a slower turnover of a GFP‐based proteasome substrate, which is suppressed by loss‐of‐function of the first BCAA catabolic enzyme, the branched‐chain aminotransferase BCAT‐1. The exogenous supply of BCAA‐derived carboxylic acids, which are known to accumulate in the body fluid of patients with BCAA metabolic disorders, is sufficient to regulate the UPS. The link between BCAA intermediates and UPS function presented here sheds light on the unexplained role of BCAAs in the aging process and opens future possibilities for therapeutic interventions.