Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Behav Brain Res. 2023 Apr 27;444:114335. doi: 10.1016/j.bbr.2023.114335. Epub 2023 Feb 15.
The NAD(+)-dependent deacetylase SIRT3 is a proven mitochondrial metabolic stress sensor. It has been linked to the regulation of the mitochondrial acetylome and activation of several metabolic enzymes (e.g., manganese superoxide dismutase [MnSOD]) to protect mitochondrial function and redox homeostasis, which are vital for survival, excitability, and synaptic signaling of neurons mediating short- and long-term memory formation as well as retention. Eighteen-month-old male and female wild-type (WT) and Sirt3 mice were behaviorally tested for hippocampus-dependent cognitive performance in a Morris water maze paradigm. Cognitive impairment was displayed during the probe trial by female and male Sirt3 mice but not WT mice. Upon sacrifice, brains were fixed, and morphological assessments were conducted on hippocampal tissues. Both female and male Sirt3 mice demonstrated impaired spatial memory retention implying that SIRT3 plays a role in long-term memory function. Golgi-staining studies revealed decreased dendritic arborization and dendritic length in the hippocampi of male Sirt3 compared to WT animals. Sirt3 deletion significantly increased NR1, NR2A, and NR2B expression in the hippocampus of female mice only. Enzymatic activity of MnSOD, a major mitochondrial deacetylation target of SIRT3, was significantly decreased in both female and male Sirt3 mice. Similarly, both female and male Sirt3 mice demonstrated a significant decrease in their respiratory control ratio during Complex I-driven respiration, which was apparent only in female Sirt3 mice during Complex II-driven respiration.
NAD(+)-依赖性去乙酰化酶 SIRT3 是一种已被证实的线粒体代谢应激传感器。它与线粒体乙酰基组的调节和几种代谢酶的激活有关（例如锰过氧化物歧化酶 [MnSOD]），以保护线粒体功能和氧化还原稳态，这对于神经元的生存、兴奋和突触信号传导至关重要，神经元介导短期和长期记忆的形成和保留。在 Morris 水迷宫范式中对 18 个月大的雄性和雌性野生型（WT）和 Sirt3 小鼠进行了海马依赖性认知表现的行为测试。雌性和雄性 Sirt3 小鼠在探针试验中表现出认知障碍，但 WT 小鼠没有。处死时，固定大脑，并对海马组织进行形态评估。雌性和雄性 Sirt3 小鼠均表现出空间记忆保留受损，表明 SIRT3 在长期记忆功能中发挥作用。高尔基染色研究显示，与 WT 动物相比，雄性 Sirt3 小鼠的海马中的树突分支和树突长度减少。Sirt3 缺失仅显著增加了雌性小鼠海马中的 NR1、NR2A 和 NR2B 表达。MnSOD 的酶活性，SIRT3 的主要线粒体去乙酰化靶标，在雌性和雄性 Sirt3 小鼠中均显著降低。同样，雌性和雄性 Sirt3 小鼠在复合物 I 驱动的呼吸过程中的呼吸控制比都显著降低，而在复合物 II 驱动的呼吸过程中仅在雌性 Sirt3 小鼠中明显。
