Pathological mitochondrial dysfunction mimics an aging pathway in budding yeast

ABSTRACT Mitochondrial dysfunction has long been associated with aging and linked to lifespan limitation across many species, including the budding yeast Saccharomyces cerevisiae . However, the widely used S288C laboratory background carries several polymorphisms that impair mitochondrial genome stability and function. Here, using a three-color reporter and single-cell microfluidics, we demonstrate how these mutations cause spontaneous transition to a state with severe mitochondrial deficiency characterized by low membrane potential, loss of heme biosynthesis, activation of iron regulon and morphological changes. Equally affecting young and old cells, this condition-dependent transition creates an apparent split in aging trajectories mimicking an age-dependent pathway. We further identify the mkt1-30D allele as a key genetic modifier of this pathological mitochondrial state. Together, these results suggest that mitochondrial dysfunction in this system reflects a genetic abnormality rather than an intrinsic aging process, calling for a reassessment of its role as a conserved hallmark. Our study also highlights how genetic defects can distort aging progression, potentially obscuring genuine age-associated phenotypes.