Treatment of Saccharomyces cerevisiae with cigarette smoke extract causes vacuolar fragmentation to combat cigarette smoke-induced cellular toxicity.

Exposure to cigarette smoke is one of the major risk factors for developing various diseases, such as chronic obstructive pulmonary disease (COPD), cardiovascular disorders, and cancer mediated via cellular oxidative stress and organelle dysfunction. To this end, the current study investigated how cigarette smoke extract (CSE) affects the vacuole structure and function in Saccharomyces cerevisiae as the vacuole plays a crucial role in handling oxidative stress-induced misfolded proteins. Our results indicated that CSE exposure causes transient vacuolar fragmentation peaking at 0.5 h, which correlates with reduced protein misfolding and improved cell survival. However, excessive fragmentation or vacuolar fusion sensitizes cells toward CSE-mediated cellular toxicity. To understand the underlying mechanism, this study provides the evidence of the involvement of PI(3,5)P2-Mediated signaling and phospholipase-driven remodeling of lipid moieties and suggests a role for mitochondrial function in CSE-mediated vacuolar fragmentation. Prolonged exposure to CSE impairs mitochondrial function and thus disrupts fragmentation, the adaptive survival strategy against cigarette smoke (CS). It results in proteostasis collapse, a characteristic shared by many inflammatory and degenerative disorders. Together, this study reveals a previously unrecognized cellular protection mechanism induced by CS and suggests avenues for further investigation for mitigating CS-mediated diseases.