A role for selective autophagy of the ER in gametogenic rejuvenation revealed by microfluidics-based lifespan profiling

Abstract

During mitotic growth, Saccharomyces cerevisiae cells age by dividing asymmetrically producing young daughter cells while retaining age-associated damage in the mother cell, which will eventually become senescent. Gametogenesis naturally and fully resets precursor cell lifespan, even for replicatively aged cells. However, the mechanisms responsible for gametogenic rejuvenation remain elusive. This is, in part, due to the existing methods to quantify replicative lifespan resetting in this context, which are limited to low-throughput and labor-intensive approaches. Here, we introduce a high-throughput microfluidic-based assay that allows systematic characterization of factors required for gametogenic rejuvenation in S. cerevisiae. With this technique, we show that we can sensitively measure a wide range of gamete replicative lifespans that are consistent with known short and long-lived mutants. Excitingly, using this technique, we report Atg39 and Atg40, receptors involved in selective autophagy of the ER, as the first identified molecular determinants of gametogenic rejuvenation. We anticipate that this novel technique will enable systematic identification of additional molecular factors that drive gametogenic rejuvenation.