Project Summary Our research aims to understand the role of serotonin modulated mitochondrial biogenesis in diabetes, depression, and dementia (Alzheimer's disease, AD). Diabetes and depression are independent risk factors for dementia and worsen the dementia pathology and therapeutic response. Depression comorbidity impaired metabolic function such as hyperglycemia, insulin resistance, inflammation, and oxidative stress results in physical depression and cognitive impairment. Serotonin is an essential neurotransmitter that performs synaptic transmission, plasticity, energy homeostasis in aging and dementia. For a long time, it is known that the brainstem harbors unique neurons to synthesize and project serotonin to the entire central nervous system. However, molecular links between serotonin levels and mitochondrial biogenesis, mitochondrial dynamics, mitophagy/autophagy in dementia, diabetes, and depression are not entirely understood. It is established that serotonin synthesis in dorsal raphe is protective and essential for cell homeostasis and energy metabolism. It has been hypothesized that low serotonin levels induce defective mitochondrial biogenesis, impaired mitochondrial dynamics, mitochondrial dysfunction and defective mitophagy/autophagy in depression, diabetes, and dementia, and selective serotonin reuptake inhibitors, such as citalopram treatment reverses defective mitochondrial biogenesis and all mitochondrial defective aspects. We have conceptualized the study in rodents focusing on the transgenic models of 3Ds focusing hippocampus (APP, Tau, HT22 cells), hypothalamus (DbDb, mHypo cells), and raphe (TPH2/ko, RN46A-B14 cells). Therefore, the current study proposes to understand the pathologies and the protective effects of citalopram (SSRI) against defective mitochondrial biogenesis, impaired mitochondrial dynamics, and defective mitophagy/autophagy. The outcome of our proposed experiments will provide new insights into the role of serotonin in depression, diabetes, and dementia concerning mitochondrial biogenesis, mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy. The outcome will also provide beneficial effects of citalopram against common serotonin-induced defects of mitochondrial dynamics, mitochondrial function, and mitophagy/autophagy.