Cellular quality control during gametogenesis

Abstract

A hallmark of aging is the progressive accumulation of cellular damage. Age-induced damage arises due to a decrease in organelle function along with a decline in protein quality control. Although somatic tissues deteriorate with age, the germline must maintain cellular homeostasis in order to ensure the production of healthy progeny. While germline quality control has been primarily studied in multicellular organisms, recent evidence suggests the existence of gametogenesis-specific quality control mechanisms in unicellular eukaryotes, highlighting the evolutionary conservation of meiotic events beyond chromosome morphogenesis. Notably, budding yeast eliminates age-induced damage during meiotic differentiation, employing novel organelle and protein quality control mechanisms to produce young and healthy gametes. Similarly, organelle and protein quality control is present in metazoan gametogenesis; however, whether and how these mechanisms contribute to cellular rejuvenation requires further investigation. Here, we summarize recent findings that describe organelle and protein quality control in budding yeast gametogenesis, examine similar quality control mechanisms in metazoan development, and identify research directions that will improve our understanding of meiotic cellular rejuvenation.

Figure 1:. Organelle and protein quality control in budding yeast gametogenesis.

(A) Protein aggregates, rDNA circles, abnormal nucleolar material, and misorganized nuclear pore complexes (NPCs) accumulate in mother cells during replicative aging (Rempel et al., 2019; Saarikangas et al., 2017; Denoth-Lippuner et al., 2014; Erjavec et al., 2007; Sinclair et al., 1997; Sinclair and Guarente, 1997). Nuclear damage along with a subpopulation of mitochondria is not inherited by the nascent gametes during anaphase II. This process is coupled to a nuclear remodeling event that generates the GUNC (Gametogenesis Uninherited Nuclear Compartment), which is subsequently eliminated late in gametogenesis via vacuolar lysis (Eastwood ane Meneghini, 2015; Eastwood et al., 2012). Adapted from King and Goodman et al., 2019. (B) Summary of quality control events that take place hours post yeast gametogenesis induction. Timing of UPR induction was estimated by assessing ribosome footprint levels of HAC1 (Brar et al., 2012).

Figure 2:. The Balbiani body facilitates mitochondrial inheritance during D. melanogaster oogenesis.

Nurse cells, which are derived from cystoblasts, transfer cytoplasmic material to the developing oocyte. Mitochondria, along with other organelle components, are encapsulated by Balbiani bodies and are transferred to the oocyte along the fusomes of nurse cells (Cox and Spradling, 2006; Cox and Spradling, 2003). Balbiani bodies initially localize to the perinuclear region before distributing organelle contents throughout the oocyte cytoplasm (Lei and Spradling, 2016).

Figure 3:. Age-induced protein aggregates are eliminated during C. elegans oogenesis.

Protein aggregates accumulate in oocytes prior to fertilization (David et al., 2010; Goudeau and Aguilaniu, 2010). Male sperm protein (MSP) signaling enhances Vacuolar-type H⁺ ATPase (V-ATPase) activity in oocyte lysosomes, leading to protein aggregate clearance (Goudeau et al., 2020; Bohnert and Kenyon, 2017).