Orlandi Ivan, Stamerra Giulia, Vai Marina
SYSBIO Centre for Systems Biology, Milan, Italy.
Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
Front Genet. 2018 Dec 19;9:676. doi: 10.3389/fgene.2018.00676. eCollection 2018.
Nicotinamide adenine dinucleotide (NAD) represents an essential cofactor in sustaining cellular bioenergetics and maintaining cellular fitness, and has emerged as a therapeutic target to counteract aging and age-related diseases. Besides NAD involvement in multiple redox reactions, it is also required as co-substrate for the activity of Sirtuins, a family of evolutionary conserved NAD-dependent deacetylases that regulate both metabolism and aging. The founding member of this family is Sir2 of , a well-established model system for studying aging of post-mitotic mammalian cells. In this context, it refers to chronological aging, in which the chronological lifespan (CLS) is measured. In this paper, we investigated the effects of changes in the cellular content of NAD on CLS by altering the expression of mitochondrial NAD carriers, namely Ndt1 and Ndt2. We found that the deletion or overexpression of these carriers alters the intracellular levels of NAD with opposite outcomes on CLS. In particular, lack of both carriers decreases NAD content and extends CLS, whereas overexpression increases NAD content and reduces CLS. This correlates with opposite cytosolic and mitochondrial metabolic assets shown by the two types of mutants. In the former, an increase in the efficiency of oxidative phosphorylation is observed together with an enhancement of a pro-longevity anabolic metabolism toward gluconeogenesis and trehalose storage. On the contrary, overexpression brings about on the one hand, a decrease in the respiratory efficiency generating harmful superoxide anions, and on the other, a decrease in gluconeogenesis and trehalose stores: all this is reflected into a time-dependent loss of mitochondrial functionality during chronological aging.
烟酰胺腺嘌呤二核苷酸（NAD）是维持细胞生物能量和保持细胞健康的必需辅因子，并已成为对抗衰老和与年龄相关疾病的治疗靶点。除了参与多种氧化还原反应外，NAD还是Sirtuins活性的共底物，Sirtuins是一类进化保守的NAD依赖性脱乙酰酶家族，可调节代谢和衰老。该家族的创始成员是酵母的Sir2，是研究有丝分裂后哺乳动物细胞衰老的成熟模型系统。在这种情况下，它指的是时序衰老，其中测量时序寿命（CLS）。在本文中，我们通过改变线粒体NAD载体Ndt1和Ndt2的表达来研究NAD细胞含量变化对CLS的影响。我们发现这些载体的缺失或过表达会改变NAD的细胞内水平，对CLS产生相反的结果。特别是，两种载体的缺失都会降低NAD含量并延长CLS，而过表达则会增加NAD含量并缩短CLS。这与两种类型突变体所显示的相反的胞质和线粒体代谢特征相关。在前者中，观察到氧化磷酸化效率增加，同时向糖异生和海藻糖储存的促长寿合成代谢增强。相反，过表达一方面导致产生有害超氧阴离子的呼吸效率降低，另一方面导致糖异生和海藻糖储存减少：所有这些都反映在时序衰老过程中线粒体功能随时间的丧失。
