Abstract
Absence of Isc1, the yeast homologue of mammalian neutral sphingomyelinase type 2, leads to severe mitochondrial dysfunction. We show that deletion of another type-C phospholipase, the phosphatidylglycerol (PG)-specific Pgc1, rescues this defect. Phosphatidylethanolamine (PE) levels and cytochrome c oxidase activity, reduced in isc1Δ cells, were restored to wild-type levels in the pgc1Δisc1Δ mutant. Pgc1 substrate, PG, inhibited in vitro activity of Isc1 and phosphatidylserine decarboxylase Psd1, an enzyme crucial for PE biosynthesis. We also identify a mechanism by which the balance between the current demand for PG and its consumption is controlled. We document that the product of PG hydrolysis, diacylglycerol, competes with the substrate of PG-phosphate synthase, Pgs1, and thereby inhibits the biosynthesis of excess PG. This feedback loop does not work in the absence of Pgc1, which catalyzes PG degradation. Finally, Pgc1 activity is partially inhibited by products of Isc1-mediated hydrolysis. The described functional interconnection of the two phospholipases contributes significantly to lipid homeostasis throughout the cellular architecture.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Figures 2 and 4, as well as Supplemental Figure S1 have been revised after the addition of new experiments documenting the effect of added ethanolamine (Fig. 2), comparing the Pgc1 activities and total DAG amounts in relevant mutant strains (Fig. 4), and Isc1 activities under conditions of different concentrations of PG in situ (Fig. S1). Scheme in Fig. 5 has been updated to reflect two fades of PG.
