CCN6 (Wnt induced signaling protein – 3) regulates mitochondrial function

Abstract

Despite established links of CCN6 or Wnt Induced Signaling Protein -3 (WISP3) with Progressive Pseudo Rheumatoid Dysplasia, functional characterization of CCN6 remains incomplete. In light of the documented negative correlation between accumulation of reactive oxygen species (ROS) and CCN6 expression, we deciphered if CCN6 regulates ROS accumulation through its influence on mitochondrial function. We found that CCN6 localizes to mitochondria, and depletion of CCN6 in the chondrocyte cell line C-28/I2 by siRNA results in altered mitochondrial electron transport and respiration. Enhanced Electron Transport Chain (ETC) activity of CCN6 depleted cells is reflected by increased mitochondrial ROS in association with augmented mitochondrial ATP synthesis, mitochondrial membrane potential and calcium. Additionally, CCN6 depleted cells display ROS dependent PGC1-α induction that correlates with increased mitochondrial mass / volume density together with altered mitochondrial morphology. Interestingly, transcription factor Nrf2 represses CCN6 expression. Taken together, our results suggest that CCN6 acts as a molecular brake appropriately balanced by Nrf2 in regulating mitochondrial function.