Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
Departamento de Fisiopatología, Hospital de Clínicas, Montevideo, Uruguay.
Am J Physiol Cell Physiol. 2022 Mar 1;322(3):C521-C545. doi: 10.1152/ajpcell.00451.2021. Epub 2022 Feb 9.
Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.
烟酰胺腺嘌呤二核苷酸（NAD）作为几种氧化还原（还原）反应的辅助因子，也是许多非还原酶的底物。NAD 对多种细胞过程至关重要，包括能量代谢、细胞信号转导和表观遗传学。NAD 动态平衡似乎对健康寿命和长寿至关重要，其失调与多种疾病有关。NAD 代谢是动态的，通过合成和降解来维持。酶 CD38 是主要的 NAD 消耗酶之一，是 NAD 动态平衡的关键组成部分。大多数 CD38 位于质膜上，其催化结构域面向细胞外环境，可能是为了控制 NAD 的全身水平。几种细胞类型表达 CD38，但在能够渗透器官和组织的内皮细胞和免疫细胞中表达更为突出。在这里，我们回顾了 CD38 在健康和疾病中的潜在作用，并假设 CD38 失调如何导致 NAD 动态平衡的变化，并促进多种疾病的病理生理学。事实上，在动物模型中，传染病、自身免疫性疾病、纤维化、代谢疾病以及与年龄相关的疾病（包括癌症、心脏病和神经退行性疾病）的发展与改变的 CD38 酶活性有关。在 CD38 缺乏的小鼠或通过阻断 CD38 NADase 活性可以改变这些疾病中的许多疾病。在 CD38 似乎起作用的疾病中，CD38 依赖性 NAD 下降通常是病理生理学的共同特征。因此，了解 CD38 对 NAD 动态平衡的失调可能为人类疾病的治疗开辟新途径。
