title: CCN6 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 investigated whether 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 using siRNA results in altered mitochondrial electron transport and respiration. Enhanced electron transport chain (ETC) activity of CCN6-depleted cells was reflected by increased mitochondrial ROS levels in association with augmented mitochondrial ATP synthesis, mitochondrial membrane potential and Ca(2+) Additionally, CCN6-depleted cells display ROS-dependent PGC1α (also known as PPARGC1A) induction, which correlates with increased mitochondrial mass and volume density, together with altered mitochondrial morphology. Interestingly, transcription factor Nrf2 (also known as NFE2L2) repressed CCN6 expression. Taken together, our results suggest that CCN6 acts as a molecular brake, which is appropriately balanced by Nrf2, in regulating mitochondrial function.
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian institute of Chemical Biology, 4-Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Milan
authors.identifier: 0000-0001-6870-9938
authors.initials: M
authors.lastname: Patra
authors.affiliation: Metabolic Physiology and Ultrastructure Biology Laboratory, University of California, San Diego, CA 92093-0732, USA Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian institute of Chemical Biology, 4-Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
authors.forename: Deepesh K
authors.identifier: 0000-0003-2159-5800
authors.initials: DK
authors.lastname: Padhan
authors.affiliation: Cancer Biology and Inflammatory Disorder Division, CSIR-Indian institute of Chemical Biology, 4-Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India msen@iicb.res.in senmalini@yahoo.com.
authors.forename: Malini
authors.identifier: 0000-0001-5903-5943
authors.initials: M
authors.lastname: Sen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001483:Base Sequence; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004579:Electron Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: CCN6; Mitochondria; Nrf2; PGC1α