Hepatocyte nuclear factor 4-mediated lipotoxicity provokes mitochondrial damage in peroxisome-deficient pex19 mutants

Abstract

Peroxisomes are important metabolic organelles involved in the catabolism of several lipid classes, e.g. very-long-chain fatty acids. Malfunction or absence of peroxisomes leads to accumulation of educts for peroxisomal {beta}-oxidation and mitochondrial damage, resulting in fatal perturbation of metabolism. The impact of peroxisome deficiency on mitochondria is not elucidated yet. Here we present a model of Hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of non-esterified fatty acids (NEFA) as the cause for mitochondrial damage in consequence of peroxisome loss in a Peroxin19 (pex19) mutant. Hyperactive Hnf4 signaling leads to upregulation of lipase 3 and enzymes for mitochondrial {beta}-oxidation. This results in enhanced lipolysis, elevated concentrations of NEFA, maximal {beta}-oxidation and mitochondrial swelling. NEFA are ligands for Hnf4 and further enhance its activity. By genetic removal of Hnf4 in pex19 mutants, lipotoxicity and mitochondrial swelling are reduced and their survival is rescued.\n\nAuthor summaryPeroxisomes are cell organelles which play a major role in lipid metabolism. They interact with mitochondria, the organelles which are responsible for cellular energy production. Loss of peroxisomes, as it occurs in the rare, inheritable human disease class of Peroxisome Biogenesis Disorders, is lethal. Over the past couple of years, a number of studies showed that peroxisome loss leads to mitochondrial damage as a secondary consequence, but the underlying mechanism has not been understood yet. In our study, we use a mutant of the fruitfly Drosophila melanogaster as a model for Peroxisome Biogenesis Disorders and find that a protein called Hepatocyte nuclear factor 4 is hyperactive upon peroxisome loss, which provokes the mobilization of storage fat and, as a consequence, the accumulation of toxic free fatty acids. These enter the mitochondria, but cannot be used for energy gain. Free fatty acids are then trapped in the mitochondria and lead to their swelling and damage, which provides an explanation for mitochondrial defects in Peroxisomal Biogenesis Disorders. Genetic reduction of Hepatocyte nuclear factor 4 activity rescues the viability of the peroxisome mutant by reducing the accumulation of free fatty acids and the subsequent mitochondrial damage, which might provide a novel target for therapy development.