Impact of aging and permethrin on mitochondrial protein abundance and protein aggregation in Nothobranchius furzeri

Details

Supervisors

Page, Melissa ; Debier, Cathy

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en sciences agronomiques, à finalité spécialisée

Abstract

Aging is associated with various molecular and cellular defects that can accumulate, leading to age-related pathologies. The decline in proteostasis and mitochondrial dysfunction are prominent features of normal brain aging and can contribute to neurodegenerative diseases such as Alzheimer's and Parkinson's. Proteostasis is vital for maintaining protein homeostasis and regulating protein turnover, but it can be disrupted by chronic stress and aging, leading to protein aggregation, a common feature of neurodegenerative diseases. Mitochondria are crucial for energy production, calcium regulation, cellular signalling, apoptosis control, and biosynthesis pathways. Aging cells exhibit a decreased mitochondrial biogenesis and some mitochondrial dysfunction such as increased ROS levels, particularly in high-energy-demand tissues like the brain, heart, muscles, and liver. Mitochondria are increasingly recognized as key contributors to the aging process, and consequently, most neurodegenerative diseases involve mitochondrial dysfunction. The primary goal of this research is to evaluate the effects of aging on mitochondrial abundance and function in the liver and brain of N. furzeri by quantifying the levels of mitochondrial proteins. Three proteins—TIM23, VDAC2, and SOD2—located in different mitochondrial compartments were chosen for semi-quantitative analysis across different ages (6, 12 and 19-week old) and treatments (permethrin as a pro-aging chemical and DMSO as the vehicle control). The secondary objective is to investigate the presence of protein aggresomes in the brain of the GRZ strain of N. furzeri in response to aging. Our results reveal that aging affected the abundance of mitochondrial proteins and the formation of potential aggresomes. However, we do not find evidence that permethrin acts in a pro-aging manner. Our measurements within the permethrin treated fishes did not differ from those treated with the DMSO control. VDAC2 levels measured within brain samples isolated from older fish were reduced compared to those measured within younger brains. VDAC2 is a mitochondrial protein that is located within the outer mitochondrial membrane and has been used as a marker for mitochondrial abundance. Therefore, these results suggest that the number of brain mitochondria is reduced with increased age. In contrast, SOD2, which is an antioxidant only found within mitochondria increased in both brain and liver. Whether this is a response to heightened oxidative stress with aging remains to be determined. The levels of TIM23, which is localized to the inner mitochondrial membrane did not change with age in both brain and liver. Higher levels of protein aggresomes appeared in the brains of 19-week old fish compared to those at 6-week of age. However, as there were limitations using this detection method, further investigation is required to confirm this.