Two different phospholipases C, Isc1 and Pgc1, cooperate to regulate mitochondrial function

Absence of inositolphosphosphingolipid phospholipase C, Isc1, a yeast homologue of mammalian neutral sphingomyelinase type 2, leads to severe mitochondrial dysfunction. We show that the defect can be largely rescued by deletion of another type-C phospholipase, the phosphatidylglycerol (PG)-specific Pgc1. The reduced phosphatidylethanolamine (PE) levels, as well as reduced cytochrome c oxidase activity, observed in isc1Δ cells were restored to wild-type levels in the pgc1Δisc1Δ mutant. We found that Pgc1 substrate, PG, inhibits in vitro activity of Isc1 and phosphatidylserine decarboxylase Psd1, an enzyme crucial for PE biosynthesis. We also identified 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.