A mitochondrial ketogenic enzyme regulates its gene expression by association with the nuclear hormone receptor PPAR alpha

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMG-CoAS) is a key enzyme in ketogenesis, catalyzing the condensation of acetyl-CoA and aceto- acetyl-CoA to generate HMG-CoA, which is eventually converted to ketone bod ies. Transcription of the nuclear-encoded gene for mHMG-CoAS is stimulated by peroxisome proliferator-activated receptor (PPAR) alpha, a fatty acid-ac tivated nuclear hormone receptor. Here we show that the mHMG-CoAS protein p hysically interacts with PPAR alpha in vitro, and potentiates PPAR alpha-de pendent transcriptional activation via the cognate PPAR response element of the mHMG-CoAS gene in vivo. Immunofluorescence of transiently transfected cells demonstrated that in the presence of PPAR alpha, mHMG-CoAS is translo cated into the nucleus. Binding to PPAR alpha, stimulation of PPAR alpha ac tivity and nuclear penetration require the integrity of the sequence LXXLL in mHMG-CoAS, a motif known to mediate the interaction between nuclear horm one receptors and coactivators. These findings reveal a novel mechanism of gene regulation whereby the product of a PPAR alpha-responsive gene, normal ly resident in the mitochondria, directly interacts with this nuclear hormo ne receptor to autoregulate its own nuclear transcription.