Regulated intramembrane proteolysis of the leptin receptor prevents mitochondrial depolarization and mitophagy Joris Wauman1, Jan Tavernier1 1 Center for Medical Biotechnology, Cytokine Receptor Laboratory, VIB and Ghent University, Belgium * Corresponding author: joris.wauman@vib-ugent.be
In the hypothalamus, leptin and the leptin receptor (LR) regulate body weight by balancing food intake and energy expenditure and therefore act as a metabolic switch connecting the body's nutritional status to high energy consuming processes. It is well established that the human LR undergoes ectodomain shedding, resulting in the release of its extracellular domain. We therefore investigated whether this also acts an initiating step towards the release of its intracellular domain (ICD) as shown for other cytokine receptors such as the interleukin-6 receptor and the growth hormone receptor. The present study demonstrates how the LR undergoes regulated intramembrane proteolysis (R.I.P.), resulting in the release of a soluble LR fragment and an ICD, which translocates to the mitochondria where it interacts with SOCS6. The ICD-SOCS6 association stabilizes both proteins on the mitochondrial outer membrane and requires a functional SOCS box in SOCS6 (required for mitochondrial association) and a central motif in the ICD (required for SOCS6 binding). The LR ICD prevents CCCP-induced mitochondrial depolarization and mitophagy as shown by lowered Parkin translocation and p62 accumulation. It is demonstrated that tight regulation of mitochondrial dynamics in the hypothalamus is essential for the control of body weight. This is the first study demonstrating how a receptor fragment (originating from a key receptor involved in body weight homeostasis) can modulate mitochondrial biology.
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