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

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 bodies. Transcription of the nuclear-encoded gene for mHMG-CoAS is stimulated by peroxisome proliferator-activated receptor (PPAR) alpha, a fatty acid-activated nuclear hormone receptor. Here we show that the mHMG-CoAS protein physically interacts with PPAR alpha in vitro, and potentiates PPAR alpha-dependent 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 translocated into the nucleus. Binding to PPAR alpha, stimulation of PPAR alpha activity and nuclear penetration require the integrity of the sequence LXXLL in mHMG-CoAS, a motif known to mediate the interaction between nuclear hormone receptors and coactivators. These findings reveal a novel mechanism of gene regulation whereby the product of a PPAR alpha-responsive gene, normally resident in the mitochondria, directly interacts with this nuclear hormone receptor to autoregulate its own nuclear transcription.