LRP130 protein remodels mitochondria and stimulates fatty acid oxidation.

Impaired oxidative phosphorylation (OXPHOS) is implicated in several metabolic disorders. Even though mitochondrial DNA encodes several subunits critical for OXPHOS, the metabolic consequence of activating mitochondrial transcription remains unclear. We show here that LRP130, a protein involved in Leigh syndrome, increases hepatic β-fatty acid oxidation. Using convergent genetic and biochemical approaches, we demonstrate LRP130 complexes with the mitochondrial RNA polymerase to activate mitochondrial transcription. Activation of mitochondrial transcription is associated with increased OXPHOS activity, increased supercomplexes, and denser cristae, independent of mitochondrial biogenesis. Consistent with increased oxidative phosphorylation, ATP levels are increased in both cells and mouse liver, whereas coupled respiration is increased in cells. We propose activation of mitochondrial transcription remodels mitochondria and enhances oxidative metabolism.