Unraveling the peroxisome-associated mechanisms counteracting ferroptosis during quiescence

ongoing

Quiescence, a temporary cellular state of non-proliferation, is widespread in nature. Quiescent fungi often cause persistent infections resistant to conventional treatments. Quiescence is maintained via the consorted action of several regulatory pathways. In yeast, these include stabilization of the eisosome-localized, ubiquinol-generating Flavodoxin-like proteins (FLPs), recently shown by my host labs to counteract ferroptosis, a form of iron-dependent cell death promoted by peroxidised phospholipid (PL) accumulation at the plasma membrane. Importantly, new results suggest that lack of eisosomes or FLPs disrupts peroxisome biogenesis and function, i.e. fatty acid β-oxidation. PEROXISCENCE focuses on the data-driven hypothesis that increased PL peroxidation rewires certain Membrane Contact Sites (MCSs), leading to channeling of fatty acids towards PL remodeling instead of β-oxidation, to compensate for defective repair. I will investigate this model by employing a multidisciplinary approach, including genetics, a split-Venus-based screening of peroxisomal MCSs, lipidomics and a secondment for training in STED microscopy, with the goals to 1) identify the enzymes involved in PL remodeling and determine their role in counteracting ferroptosis, 2) determine if eisosomes and PL peroxidation regulate fatty acid flux by affecting MCSs, and 3) elucidate the role of Pex11, a protein implicated in the formation of tethers at peroxisomal MCSs. The outputs of PEROXISCENCE are expected to provide novel scientific knowledge with an impact on the fields of cell biology, ferroptosis, aging, and fungal pathogenicity. Furthermore, understanding the mechanisms of lipid homeostasis in quiescence could lead to the identification of innovative ways to tackle persistent fungal infections. With a strong background in molecular microbiology and microbial biotechnology, PEROXISCENCE is the ideal project for expanding my expertise in the field of cell and molecular biology of S. cerevisiae.