Acetyl-CoA is a central metabolite crucial for energy production, neuroprotection, and the activity of the citric acid cycle to support oxidative phosphorylation in brain cells. Alzheimer’s disease (AD) is a neurodegenerative disorder that affects more than 7 million Americans characterized by metabolic dysfunction, synaptic degeneration, and alterations in mitochondrial function in early-stage disease mechanisms. One prominent characteristic of the disease is a reduction in glucose uptake, resulting in a diminished level of acetyl-CoA. Along with decreased acetyl-CoA levels, AD also presents reduced histone acetylation, one of the main downstream targets of acetyl-CoA, subsequently resulting in a downregulation of gene transcription. Previous studies demonstrated that mild inhibition of mitochondrial complex I (mtCI) with tricyclic pyrone compound CP2 induces the adaptive stress response, activating multiple neuroprotective mechanisms in brain cells, including increased glucose uptake and utilization. C273 is a small molecule with similar dynamics to that of CP2. It binds to the same site of mtCI as CP2 with differing efficacy and concentration. Optimized for clinical applications, C273 shows greater promise as an alternative therapeutic approach to treating AD. The aim of this project is to assess whether the inhibition of mtCI with C273 affect to the abundance of acetyl-CoA and improves transcription of genes involved in cognition. Neuroblastoma SH-SY5Y cells that express mutant human APP protein (APPswe) and control cells were treated with C273 (50 nM or 500 nM) and CP2 (2.5 μM) for 24 hours. Mass spectrometry was used to measure the acetyl-coA level. The change in acetyl-CoA–sensitive targets (H3K27 acetylation and total histone H3) were analyzed by Western blot. At 24 hours of treatment with C273 or CP2, acetyl-coA levels increased significantly in both control and APPswe cells. Confirmation of acetyl-CoA level changes by assessing downstream effects on H3K27 acetylation. Importantly, C273 induced a similar percentage increase acetyl-coA as CP2, but at a 50-fold-lower concentration. These findings suggest that C273-dependent activation of multiple mechanisms essential for improved energy homeostasis in APPswe cells results in an increase of whole cell acetyl-CoA levels enhanced gene expression associated with cognition via histone acetylation. These preliminary results will be validated in future studies.
