Spermidine toxicity in Saccharomyces cerevisiae due to mitochondrial complex III deficiency

Area of Science:

• Cellular biology
• Aging research
• Mitochondrial function

Background:

• Spermidine, a natural polyamine, declines with age and extends lifespan in various organisms.
• Autophagy induction is a proposed mechanism for spermidine's lifespan-extending effects.
• Mitochondrial dysfunction is a key factor in aging.

Purpose of the Study:

• To investigate spermidine's effect on mitochondrial dysfunction in yeast lacking mitochondrial DNA (ρ0 cells).
• To determine if spermidine can rescue or exacerbate mitochondrial dysfunction and aging phenotypes.

Main Methods:

• Utilized Saccharomyces cerevisiae ρ0 cells as a model system.
• Assessed spermidine's impact on cell survival and lifespan.
• Investigated the roles of mitochondrial complex III, autophagy (ATG8), and mitochondrial complex II (SDH2) in spermidine toxicity.
• Compared responses across different yeast strains (BY4741, W303, D273-10B).

Main Results:

• Spermidine exhibited toxicity in ρ0 cells, shortening lifespan, rather than rescuing dysfunction.
• Toxicity was not linked to impaired respiration, oxidative stress, or ATP depletion.
• Spermidine toxicity was mimicked by inhibiting mitochondrial complex III and prevented by impairing autophagy or inhibiting mitochondrial complex II.
• A strain-dependent genetic variation in spermidine toxicity was observed.

Conclusions:

• Spermidine can be toxic in cells with mitochondrial dysfunction, challenging its universal anti-aging benefits.
• The observed toxicity is associated with specific mitochondrial pathways and autophagy.
• Genetic background influences spermidine's effect, suggesting caution in human applications for aging.
• Further research is needed to understand the complex interplay between spermidine, mitochondria, and aging.