Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Universidad San Sebastián, Chile.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Redox Biol. 2020 Jul;34:101558. doi: 10.1016/j.redox.2020.101558. Epub 2020 May 5.
Aging is a process characterized by cognitive impairment and mitochondrial dysfunction. In neurons, these organelles are classified as synaptic and non-synaptic mitochondria depending on their localization. Interestingly, synaptic mitochondria from the cerebral cortex accumulate more damage and are more sensitive to swelling than non-synaptic mitochondria. The hippocampus is fundamental for learning and memory, synaptic processes with high energy demand. However, it is unknown if functional differences are found in synaptic and non-synaptic hippocampal mitochondria; and whether this could contribute to memory loss during aging. In this study, we used 3, 6, 12 and 18 month-old (mo) mice to evaluate hippocampal memory and the function of both synaptic and non-synaptic mitochondria. Our results indicate that recognition memory is impaired from 12mo, whereas spatial memory is impaired at 18mo. This was accompanied by a differential function of synaptic and non-synaptic mitochondria. Interestingly, we observed premature dysfunction of synaptic mitochondria at 12mo, indicated by increased ROS generation, reduced ATP production and higher sensitivity to calcium overload, an effect that is not observed in non-synaptic mitochondria. In addition, at 18mo both mitochondrial populations showed bioenergetic defects, but synaptic mitochondria were prone to swelling than non-synaptic mitochondria. Finally, we treated 2, 11, and 17mo mice with MitoQ or Curcumin (Cc) for 5 weeks, to determine if the prevention of synaptic mitochondrial dysfunction could attenuate memory loss. Our results indicate that reducing synaptic mitochondrial dysfunction is sufficient to decrease age-associated cognitive impairment. In conclusion, our results indicate that age-related alterations in ATP produced by synaptic mitochondria are correlated with decreases in spatial and object recognition memory and propose that the maintenance of functional synaptic mitochondria is critical to prevent memory loss during aging.
衰老是一个以认知障碍和线粒体功能障碍为特征的过程。在神经元中，这些细胞器根据其定位分为突触和非突触线粒体。有趣的是，大脑皮层的突触线粒体积累的损伤更多，对肿胀更敏感。海马体对学习和记忆至关重要，因为这些过程需要高能量。然而，目前尚不清楚突触和非突触海马体线粒体是否存在功能差异；以及这是否会导致衰老过程中的记忆丧失。在这项研究中，我们使用 3、6、12 和 18 月龄（mo）的小鼠来评估海马体记忆以及突触和非突触线粒体的功能。我们的结果表明，识别记忆从 12mo 开始受损，而空间记忆在 18mo 受损。这伴随着突触和非突触线粒体的功能差异。有趣的是，我们观察到 12mo 时突触线粒体过早出现功能障碍，表现为 ROS 生成增加、ATP 产生减少以及对钙超载的敏感性增加，而非突触线粒体则没有观察到这种现象。此外，在 18mo 时，两种线粒体群都表现出生物能量缺陷，但与非突触线粒体相比，突触线粒体更容易肿胀。最后，我们用 MitoQ 或姜黄素（Cc）处理 2、11 和 17mo 的小鼠 5 周，以确定预防突触线粒体功能障碍是否可以减轻记忆丧失。我们的结果表明，减少突触线粒体功能障碍足以降低与年龄相关的认知障碍。总之，我们的结果表明，与年龄相关的突触线粒体产生的 ATP 变化与空间和物体识别记忆的下降相关，并提出维持功能性突触线粒体对于防止衰老过程中的记忆丧失至关重要。
