Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing A beta 42

Alzheimer's disease (AD) is an incurable, age-related neurological disorder, the most common form of dementia. Considering that AD is a multifactorial complex disease, simplified experimental models are required for its analysis. For this purpose, genetically modified Yarrowia lipolytica yeast strains expressing A beta 42 (the main biomarker of AD), eGFP-A beta 42, A beta 40, and eGFP-A beta 40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-A beta 40, retaining "normal " mitochondrial reticulum, eGFP-A beta 42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. A beta 42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. A beta 42 expression caused mitochondrial dysfunction as inferred from a loose coupling of respiration and phosphorylation, the decreased level of ATP production, and the enhanced rate of hydrogen peroxide formation. Therefore, we have obtained the same results described for other AD models. Based on an analysis of these and earlier data, we suggest that the mitochondrial fragmentation might be a biomarker of the earliest preclinical stage of AD with an effective therapy based on mitochondria- targeted antioxidants. The simple yeast model constructed can be a useful platform for the rapid screening of such compounds.