In aging and neurodegenerative diseases, loss of distinct type of neurons characterizes disease-specific pathological and clinical features, and mitochondria play a pivotal role in neuronal survival and death. Mitochondria are now considered as the organelle to modulate cellular signal pathways and functions, not only to produce energy and reactive oxygen species. Oxidative stress, deficit of neurotrophic factors, and multiple other factors impair mitochondrial function and induce cell death. Multi-functional plant polyphenols, major groups of phytochemicals, are proposed as one of most promising mitochondria-targeting medicine to preserve the activity and structure of mitochondria and neurons. Polyphenols can scavenge reactive oxygen and nitrogen species and activate redox-responsible transcription factors to regulate expression of genes, coding antioxidants, anti-apoptotic Bcl-2 protein family, and pro-survival neurotrophic factors. In mitochondria, polyphenols can directly regulate the mitochondrial apoptosis system either in preventing or promoting way. Polyphenols also modulate mitochondrial biogenesis, dynamics (fission and fusion), and autophagic degradation to keep the quality and number. This review presents the role of polyphenols in regulation of mitochondrial redox state, death signal system, and homeostasis. The dualistic redox properties of polyphenols are associated with controversial regulation of mitochondrial apoptosis system involved in the neuroprotective and anti-carcinogenic functions. Mitochondria-targeted phytochemical derivatives were synthesized based on the phenolic structure to develop a novel series of neuroprotective and anticancer compounds, which promote the bioavailability and effectiveness. Phytochemicals have shown the multiple beneficial effects in mitochondria, but further investigation is required for the clinical application.

In neurodegenerative disorders, including Alzheimer's and Parkinson's disease, neuroprotection by diet and natural bioactive compounds has been proposed to prevent the onset and progress of neurodegeneration by modification of pathogenic factors. Plant food-derived phytochemicals protect neurons via targeting oxidative stress, mitochondrial dysfunction, neurotrophic factor deficit, apoptosis and abnormal protein accumulation. This review presents the molecular mechanism of neuroprotection by phytochemicals: direct regulation of mitochondrial apoptotic machinery, modification of cellular signal pathways, induction of antiapoptotic Bcl-2 protein family and prosurvival neurotrophic factors, such as brain- and glial cell line-derived neurotrophic factor, and prevention of protein aggregation. Multitargeted neuroprotective agents are under development based on the structure of blood–brain barrier-permeable phytochemicals to ameliorate brain dysfunction and prevent neurodegeneration.