期刊
ACS CHEMICAL BIOLOGY
卷 15, 期 7, 页码 1795-1800出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00366
关键词
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资金
- Fondazione Cariplo [2014-0672]
- Italian Ministry of Education, University and Research (MIUR, Dipartimenti di Eccellenza Program 2018-2022 - Dept. of Biology and Biotechnology L. Spallanzani, University of Pavia)
- Agence Nationale pour la Recherche [ANR-19-CE14-00384-01]
- Fondation pour la Recherche Medicale (equipe FRM2016) [DEQ20160334892]
- Region Occitanie
- Federation Francaise de Cardiologie (FFC)
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [IG19808]
Cardiac senescence is a typical chronic frailty condition in the elderly population, and cellular aging is often associated with oxidative stress. The mitochondrial-membrane flavoenzyme monoamine oxidase A (MAO A) catalyzes the oxidative deamination of neurotransmitters, and its expression increases in aged hearts. We produced recombinant human MAO A variants at Lys305 that play a key role in O-2 reactivity leading to H2O2 production. The K305Q variant is as active as the wild-type enzyme, whereas K305M and K305S have 200-fold and 100-fold lower k(cat) values and similar K-m. Under anaerobic conditions, K305M MAO A was normally reduced by substrate, whereas reoxidation by O-2 was much slower but could be accomplished by quinone electron acceptors. When overexpressed in cardiomyo-blasts by adenoviral vectors, the K305M variant showed enzymatic turnover similar to that of the wild-type but displayed decreased ROS levels and senescence markers. These results might translate into pharmacological treatments as MAO inhibitors may attenuate cardiomyocytes aging.
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