Laboratório de Biologia Molecular de Leveduras, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Av. Carlos Chagas Filho 373, Ilha do Fundão, Rio de Janeiro, 21941-590, Brazil.
Laboratório de Bioenergética e Fisiologia Mitocondrial, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Av. Carlos Chagas Filho 373, Ilha do Fundão, Rio de Janeiro, 21941-590, Brazil.
Free Radic Biol Med. 2023 Nov 20;209(Pt 1):29-39. doi: 10.1016/j.freeradbiomed.2023.09.035. Epub 2023 Sep 28.
Aging is a time-related functional decline that affects many species. One of the hallmarks of aging is mitochondrial dysfunction, which leads to metabolic decline. The NAD decline during aging, in several tissues, correlates with increase in NADase activity of CD38. Knock out or pharmacological inhibition of CD38 activity can rescue mitochondrial function in several tissues, however, the role of CD38 in controlling NAD levels and metabolic function in the aging brain is unknown. In this work, we investigated CD38 NADase activity controlling NAD levels and mitochondrial function in mice brain with aging. We demonstrate that NADase activity of CD38 does not dictate NAD total levels in brain of aging mice and does not control mitochondrial oxygen consumption nor other oxygen parameters markers of mitochondrial dysfunction. However, for the first time we show that CD38 regulates hydrogen peroxide (HO) generation, one of the reactive oxygen species (ROS) in aging brain, through regulation of pyruvate dehydrogenase and alfa-ketoglutarate dehydrogenase, as mitochondria HO leakage sites. The effect may be related to mitochondrial calcium handling differences in CD38 absence. Our study highlights a novel role of CD38 in brain energy metabolism and aging.
衰老是一种与时间相关的功能衰退，影响许多物种。衰老的标志之一是线粒体功能障碍，导致代谢下降。在几种组织中，衰老过程中 NAD 的下降与 CD38 的 NAD 酶活性的增加相关。敲除或药理学抑制 CD38 的活性可以挽救几种组织中的线粒体功能，然而，CD38 在控制衰老大脑中的 NAD 水平和代谢功能方面的作用尚不清楚。在这项工作中，我们研究了 CD38 NAD 酶活性在衰老小鼠大脑中控制 NAD 水平和线粒体功能的作用。我们证明，CD38 的 NAD 酶活性并不能决定衰老小鼠大脑中 NAD 的总水平，也不能控制线粒体耗氧量或其他线粒体功能障碍的氧参数标志物。然而，我们首次表明，CD38 通过调节丙酮酸脱氢酶和阿尔法-酮戊二酸脱氢酶来调节活性氧（ROS）之一的过氧化氢（HO）的产生，作为线粒体 HO 泄漏的部位。这种影响可能与 CD38 缺失时线粒体钙处理的差异有关。我们的研究强调了 CD38 在大脑能量代谢和衰老中的新作用。
