To gain insight into the genetic regulation of lipid metabolism in tomato, we conducted metabolic trait loci (mQTL) analysis following the lipidomic profiling of fruit pericarp and leaf tissue of the Solanum pennellii introgression lines (IL). To enhance mapping resolution for selected fruit-specific mQTL, we profiled the lipids in a subset of independently derived S. pennellii backcross inbred lines, as well as in a near-isogenic sub-IL population. We identified a putative lecithin:cholesterol acyltransferase that controls the levels of several lipids, and two members of the class III lipase family, LIP1 and LIP2, that were associated with decreased levels of diacylglycerols (DAGs) and triacylglycerols (TAGs). Lipases of this class cleave fatty acids from the glycerol backbone of acylglycerols. The released fatty acids serve as precursors of flavor volatiles. We show that LIP1 expression correlates with fatty acid-derived volatile levels. We further confirm the function of LIP1 in TAG and DAG breakdown and volatile synthesis using transgenic plants. Taken together, our study extensively characterized the genetic architecture of lipophilic compounds in tomato and demonstrated at molecular level that release of free fatty acids from the glycerol backbone can have a major impact on downstream volatile synthesis.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

The phenylpropanoid pathway of flavonoid biosynthesis has been the subject of considerable research attention. By contrast, the proposed polyketide pathway, also known as the acetate pathway, which provides malonyl-CoA moieties for the C2 elongation reaction catalyzed by chalcone synthase, is less well studied. Here, we identified four genes as candidates for involvement in the supply of cytosolic malonyl-CoA from the catabolism of acyl-CoA, based on coexpression analysis with other flavonoid-related genes. Two of these genes, ACC and KAT5, have been previously characterized with respect to their involvement in lipid metabolism, but no information concerning their relationship to flavonoid biosynthesis is available. To assess the occurrence and importance of the acetate pathway, we characterized the metabolomes of two mutant or transgenic Arabidopsis lines for each of the four enzymes of this putative pathway using a hierarchical approach covering primary and secondary metabolites as well as lipids. Intriguingly, not only flavonoid content but also glucosinolate content was altered in lines deficient in the acetate pathway, as were levels of lipids and most primary metabolites. We discuss these data in the context of our current understanding of flavonoids and lipid metabolism as well as with regard to improving human nutrition.