S-allyl-L-cysteine and isoliquiritigenin improve mitochondrial function in cellular models of oxidative and nitrosative stress.

Oxidative and nitrosative stress resulting in mitochondrial dysfunction are an early event in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid-2-related factor 2 (Nrf2) is a key transcription factor and regulator of the cellular response to oxidative stress. Thus known Nrf2 activators from food materials were tested for improvement of mitochondrial membrane potential (MMP) and ATP level in neuronal pheochromocytoma cell (PC12) models of oxidative and nitrosative stress. The effects of rotenone and sodium nitroprusside (complex inhibitors of the respiratory chain) on mitochondrial function were also studied. Furthermore, Nrf2 activators were tested in human embryonic kidney cells bearing the Swedish mutation of amyloid precursor protein (APP(sw) HEK cells) as a cellular model of familial AD. Preincubation with S-allyl-l-cysteine and isoliquiritigenin increased MMP in both PC12 cell models in a similar range as the positive control l-sulforaphane. None of the test compounds, however, improved MMP and ATP level in APP(sw) HEK cells.

Modulation of mitochondrial dysfunction in neurodegenerative diseases via activation of nuclear factor erythroid-2-related factor 2 by food-derived compounds.

Oxidative stress and mitochondrial dysfunction are early events in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Mitochondria are important key players in cellular function based on mitochondrial energy production and their major role in cell physiology. Since neurons are highly depending on mitochondrial energy production due to their high energy demand and their reduced glycolytic capacity mitochondrial dysfunction has fatal consequences for neuronal function and survival. The transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2) is the major regulator of cellular response to oxidative stress. Activation of Nrf2 induces the transcriptional regulation of antioxidant response element (ARE)-dependent expression of a battery of cytoprotective and antioxidant enzymes and proteins. Moreover, activation of Nrf2 protects mitochondria from dysfunction and promotes mitochondrial biogenesis. Therefore, the Nrf2/ARE pathway has become an attractive target for the prevention and treatment of oxidative stress-related neurodegenerative diseases. Small food-derived inducers of the Nrf2/ARE pathway including l-sulforaphane from broccoli and isoliquiritigenin from licorice displayed promising protection of mitochondrial function in models of oxidative stress and neurodegenerative diseases and represent a novel approach to prevent and treat aging-associated neurodegenerative diseases.

Mitochondrial dysfunction: cause and consequence of Alzheimer's disease.

The etiology of common, nonfamiliar late-onset Alzheimer's disease (LOAD) is only partly understood and seems to be extremely complex including many genetic and environmental factors. The most important environmental risk factor to develop LOAD is aging itself. Aging and LOAD are considered to be strongly linked to mitochondrial dysfunction and enhanced oxidative stress. In this review, we focus on the interaction between mitochondrial dysfunction in aging especially on defects of the respiratory chain of the oxidative phosphorylation system resulting in enhanced oxidative stress and the interplay between aging-associated mitochondrial defects and LOAD-associated mitochondrial failure. The deleterious effects of the two hallmarks of LOAD, amyloid beta, and hyperphosphorylated tau, on mitochondrial function, movement, and morphology are described as well as the toxic effects of the most relevant genetic risk factor of LOAD, the apolipoprotein E4 allele. Finally, the review provides an overview about drugs and nutritional ingredients which improve mitochondrial function or/and act as antioxidants and discusses their potential role in the treatment of LOAD.