Department of Biology and Biotechnology, University of Pavia, Milan, Italy.
Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse, Toulouse, France.
ACS Chem Biol. 2020 Jul 17;15(7):1795-1800. doi: 10.1021/acschembio.0c00366. Epub 2020 Jun 30.
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 reactivity leading to HO production. The K305Q variant is as active as the wild-type enzyme, whereas K305M and K305S have 200-fold and 100-fold lower values and similar . Under anaerobic conditions, K305M MAO A was normally reduced by substrate, whereas reoxidation by O was much slower but could be accomplished by quinone electron acceptors. When overexpressed in cardiomyoblasts 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.
心脏衰老（Cardiac senescence）是老年人群中一种典型的慢性虚弱状态，细胞衰老通常与氧化应激有关。线粒体膜黄素酶单胺氧化酶 A（MAO A）催化神经递质的氧化脱氨，其在衰老心脏中的表达增加。我们产生了在赖氨酸 305 处发挥关键作用的重组人 MAO A 变体，该变体导致 HO 生成的 O 反应性。K305Q 变体与野生型酶一样活跃，而 K305M 和 K305S 的 值低 200 倍和 100 倍，且相似。在厌氧条件下，K305M MAO A 可被底物正常还原，但 O 的再氧化要慢得多，但可以通过醌电子受体完成。当通过腺病毒载体在心肌细胞中过表达时，K305M 变体显示出与野生型相似的酶周转率，但显示出降低的 ROS 水平和衰老标志物。这些结果可能转化为药物治疗，因为 MAO 抑制剂可能会减轻心肌细胞衰老。
