Organelle-Based Aggregation and Retention of Damaged Proteins in Asymmetrically Dividing Cells

Abstract

Aggregation of damaged or misfolded proteins is a protective mechanism against proteotoxic stress, abnormalities of which underlie many aging-related diseases. Here, we show that in asymmetrically dividing yeast cells, aggregation of cytosolic misfolded proteins does not occur spontaneously but requires new polypeptide synthesis and is restricted to the surface of ER, which harbors the majority of active translation sites. Protein aggregates formed on ER are frequently also associated with or are later captured by mitochondria, greatly constraining aggregate mobility. During mitosis, aggregates are tethered to well-anchored maternal mitochondria, whereas mitochondria acquired by the bud are largely free of aggregates. Disruption of aggregate-mitochondria association resulted in increased mobility and leakage of mother-accumulated aggregates into the bud. Cells with advanced replicative age exhibit gradual decline of aggregates-mitochondria association, likely contributing to their diminished ability to rejuvenate through asymmetric cell division.

Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

“…We thus conjecture that a substructure of mitochondria that is tethered to the ER is not equally transmitted to the daughter cell. Consistent with this conjecture is a recent observation showing that aggregated proteins in the ER are captured by mitochondria and preferentially retained in the mother cells (18).…”

“…One example is extrachromosomal rDNA circles, which are known to be a limiting factor for lifespan (12,13) and are retained in mother cells (14)(15)(16). Protein aggregates, carbonylated proteins, and reactive oxygen species have also been reported to distribute asymmetrically between old mothers and their daughters (17)(18)(19)(20)(21)(22). Preferential retention of membrane transporters in the mother cells has also been associated with lifespan asymmetry (23,24).…”

The endosomal trafficking factors CORVET and ESCRT suppress plasma membrane residence of the renal outer medullary potassium channel (ROMK)

“…To this end, we expressed Venustagged ROMKK80M (Vn-ROMK) in an ESCRT (snf7Δ) and CORVET (vps8Δ) deficient yeast strain, in the pep4Δ mutant, and in an isogenic wild -type strain (BY4742). In wild-type yeast, Vn-ROMK partially colocalized with both an mCherrytagged ER-resident marker, Scs2-mCh (69), and the dye FM4-64 (70), which binds lipids on the cell surface, passes through the endocytic pathway, and accumulates on the vacuolar limiting membrane ( Figure 7A,B). These results are consistent with passage of the protein through the secretory pathway and into a pre-degradative compartment.…”

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…In yeast, aggregated and damaged proteins can be retained in mother cells during division 74 . In this mechanism, protein aggregates are captured by maternal mitochondria, whereas mitochondria acquired by the daughter cells are free of aggregates 75 . This asymmetric division enables the generation of a rejuvenated, germ-like, daughter cell lineage 76 .…”