Investigating Mitochondrial Stress Response Mechanisms in Aging

Mitochondrial dysfunction is widely recognized as a key contributor to aging and age-related diseases. The concept of mitohormesis suggests that low levels of ROS can activate stress-responsive transcription factors, promoting adaptive mechanisms that enhance longevity. We hypothesized that changes in protein abundance under conditions of mild mitochondrial stress reflect an adaptive response, and that commonly altered proteins across diverse genetic backgrounds of mitochondrial stress can help identify key regulators of stress resilience and aging. Our study identified conserved mitochondrial stress response pathways and highlighted candidate regulators for further investigation. These regulators appear to impair mitochondrial energy production by downregulating ATP synthesis and components of the electron transport chain. In turn, cells compensate by activating alternative metabolic pathways, modulating transcriptional programs, and initiating stress response mechanisms. Phenotypic analysis revealed specific genes whose overexpression enhanced cellular stress resilience and overexpression of proteins commonly altered in mitochondrial genome maintenance mutants generally extended chronological lifespan. These findings support our hypothesis that protein abundance changes under mild mitochondrial stress reflect an adaptive, pro-survival response.