Mitochondrial dysfunction is one contributor to aging, and it is implicated in many neurodegenerative diseases, including Alzheimer’s Disease (AD). Additionally, age-related vascular and neuronal pathologies may precede AD development. Studies showed that aging correlated with alterations in mitochondrial function and structure. However, how mitochondrial dysfunction affects cellular decline in the brain is still unclear. The mitochondria are regulated by the cristae organizing system (MICOS) complex and mitochondria–ER contact sites (MERCSs) in various organs. In the hippocampus of an AD mice model, researchers have also observed decreases in a MICOS protein, CHCHD6. Therefore, in other vulnerable regions of AD, such as the hypothalamus, dysregulation of the MICOS and MERCSs may lead to mitochondrial dysfunction in the aging process and eventually accelerate AD. Using quantitative polymerase chain reaction, serial block-face scanning electron microscopy, light microscopy, and 3D reconstruction, we found that the gene expression of the MICOS and MERCSs decreased in the aged amygdala and hypothalamus. The mitochondria also had significant morphological changes in the aged hypothalamus. Understanding the importance of the MICOS complex, we investigated mitochondrial homeostasis and observed that the inactivation of MICOS genes disrupted the synaptic transmission in crucial hypothalamic circuits. These results suggested that aging abates mitochondrial dynamics and physiology in the amygdala and the hypothalamus, and the MICOS is necessary for mitochondrial calcium regulation. This study provides targetable therapeutic strategies for aging in the brain, preventing the progression of AD at the early stages.