Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42

Abstract

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 Aβ42 (the main biomarker of AD), eGFP-Aβ42, Aβ40, and eGFP-Aβ40 were constructed and examined. In contrast to the cells expressing eGFP and eGFP-Aβ40, retaining “normal” mitochondrial reticulum, eGFP-Aβ42 cells possessed a disturbed mitochondrial reticulum with fragmented mitochondria; this was partially restored by preincubation with a mitochondria-targeted antioxidant SkQThy. Aβ42 expression also elevated ROS production and cell death; low concentrations of SkQThy mitigated these effects. Aβ42 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.

SkQ3 Exhibits the Most Pronounced Antioxidant Effect on Isolated Rat Liver Mitochondria and Yeast Cells

“…Cells were incubated with 10 µM DHE for 30 min at room temperature in the dark. The fluorescence of DHE was measured via flow cytometry as described in [58], via flow cytometry with a FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA).…”

Potential benefits of medium chain fatty acids in aging and neurodegenerative disease

“…Reduced PGC-1 activation and downregulation of SIRT1 also promote amyloid-beta (Aβ) production, impaired Aβ clearance and tau hyperphosphorylation, resulting in the formation of Aβ plaques and neurofibrillary tangles ( Qin et al, 2006 ; Min et al, 2010 ). The accumulation of Aβ has been shown to affect mitochondrial bioenergetics, dynamics, distribution and clearance in human cell cultures, yeast, fruit fly and mice ( Iijima-Ando et al, 2009 ; Sinclair et al, 2021 ; Lee et al, 2022 ; Epremyan et al, 2023 ; Zyśk et al, 2023 ). Altered glucose metabolism is one of the hallmarks of AD ( Hoyer, 1991 ; Schubert, 2005 ; Calsolaro and Edison, 2016 ).…”

“…The accumulation of Aβ has been shown to affect mitochondrial bioenergetics, dynamics, distribution and clearance in human cell cultures, yeast, fruit fly and mice (Iijima-Ando et al, 2009;Sinclair et al, 2021;Lee et al, 2022;Epremyan et al, 2023;Zyśk et al, 2023). Altered glucose metabolism is one of the hallmarks of AD (Hoyer, 1991;Schubert, 2005;Calsolaro and Edison, 2016).…”

Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models

“…Thus, the facultative aerobic yeast S. cerevisiae , with its few, small, and poorly structured mitochondria, cannot be considered the bioenergetic equivalent of neurons. Therefore, in addition to well-established S. cerevisiae models, new, upcoming, so-called non-convential yeasts Schizosaccharomyces pombe , Candida glabrata , Kluyveromyces lactis , and Yarrowia lipolytica yeast models for AD were described [ 70 , 71 ]. Y. lipolytica , an aerobic “multitalented” yeast species with a well-described genome, has GRAS (generally regarded as safe) status; the versatile substrate utilization profile, rapid utilization rates, metabolic diversity and flexibility, unique biosynthetic and secreting capacities, and energy metabolism that are closely reminiscent of that in mammals, susceptible to molecular genetic engineering tools, and having a long history of using heterologically expressed proteins due to unique biosynthesis and secreting capacities (reviewed by [ 72 ]) may be an extremely promising alternative model for deciphering mitochondria-associated AD pathogenesis.…”

“…It is therefore essential to deepen our understanding of AD by detecting new risk factors and biomarkers and developing therapeutic strategies to treat or prevent the disease. Research reviewed above clearly indicates that yeast models, together with other more simple eukaryotic models including animal models, C. elegans and Drosophila (reviewed in [ 70 ]), significantly contributed to understanding Aβ and tau biology. These models combined with an enhanced suite of technologies allowed for high-throughput screening of drugs affecting Aβ oligomerization, aggregation and toxicity, as well as tau hyperphosphorylation.…”