Comparative analysis of vitamin C derivatives on ATP homeostasis across diverse cell types

Cellular energy homeostasis is tightly regulated by mitochondrial function and substrate availability. Vitamin C is a redox-active molecule with emerging roles in cellular metabolism; however, the metabolic impacts of structurally distinct vitamin C derivatives remain incompletely defined. In this study, we systematically compared l-ascorbic acid, dehydroascorbic acid, 6-O-palmitoyl-l-ascorbate, and mineral ascorbates (calcium, magnesium, sodium, and potassium salts) across multiple mammalian cell types. Cells were exposed to concentrations ranging from 60 to 500 µM, encompassing physiologically and pharmacologically relevant levels. The vitamin C derivatives induced cell type- and concentration-dependent modulation of intracellular ATP levels. Notably, HepG2 and renal epithelial cells exhibited robust ATP increases, whereas fibroblasts, myocytes, microglia, and skeletal muscle models displayed variable responses depending on the derivative and dose. Moreover, in skeletal muscle cells, co-treatment of standard l-ascorbic acid with select fatty acids did not yield additive bioenergetic effects, suggesting a localized, substrate-specific plateau or shared regulatory step in this specific cell model. Exposure to l-ascorbic acid induced selective increases in COX-1 without changes in SDH-A, consistent with rapid functional modulation of mitochondrial activity in myocytes and microglial cells only. Collectively, these findings demonstrate that vitamin C derivatives modulate cellular ATP levels within existing metabolic networks in a context-dependent manner, consistent with the modulation of mitochondrial-associated energy metabolism.