γ-Terpinene from citrus peel enhances mitochondrial bioenergetics and protects neuronal cells from glutamate-induced injury

Citrus processing generates substantial peel residues, which are increasingly recognized as a sustainable source of bioactive compounds. Citrus peel essential oils are rich in monoterpenes with reported antioxidant and neuroregulatory activities; however, their effects on neuronal energy metabolism and mitochondrial function remain unclear. Glutamate serves as the primary excitatory neurotransmitter in the central nervous system, and glutamate-induced mitochondrial dysfunction and oxidative stress are major contributors to neurodegenerative disorders. In this study, essential oils from lemon ( Citrus limon ), lime ( Citrus aurantifolia ), sweet orange ( Citrus sinensis ), ponkan ( Citrus reticulata ), and hirami lemon ( Citrus reticulata var. depressa ) were evaluated, with a focus on γ -terpinene. A glutamate-induced PC12 cell toxicity model was employed to evaluate the neuroprotective effects of γ -terpinene and to elucidate its potential pharmacological mechanisms. The results demonstrated that glutamate exposure significantly impaired cell viability and mitochondrial function, while increasing oxidative stress and cellular damage. γ -Terpinene significantly alleviated glutamate-induced cytotoxicity, restored mitochondrial function and ATP levels, and partially reversed reductions in dopamine and norepinephrine synthesis. Mechanistically, γ -terpinene activated the AMPK-SIRT1-PGC-1 α -TFAM signaling pathway, promoting mitochondrial biogenesis and improving cellular energy metabolism. Notably, this study is the first to demonstrate that γ -terpinene regulates mitochondrial bioenergetics and neurotransmitter homeostasis under glutamate-induced neuronal stress. From a functional food perspective, this study highlights citrus peel-derived monoterpenes as promising bioactive compounds and provides a scientific basis for the sustainable valorization of citrus processing by-products.