FIGURE 9.

IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis. (A) Loss of function of IGFBP-3: knockdown of IGFBP-3 using siRNA oligonucleotides abrogated cytoplasmic expression. This was associated with (1) a decrease in MFN2 that coincided with the appearance of numerous small mitochondria and potential release of mtDNA; (2) an increase in sBNIP3L/NIX that activated mitophagy through mTOR; and (3) residual IGFBP-3 protein accumulation in the nucleus and increased oxidative phosphorylation. (B) Gain of function of IGFBP-3: Co-treatment with exogenous IGFBP-3 in cells subject to IGFBP-3 knockdown resulted in opposite effects with (1) an increase in MFN2 that coincided with an enhancement in lamellar cristae morphology; (2) a decrease in sBNIP3L/NIX that inhibited mitophagy through activation of mTOR; and (3) robust accumulation of IGFBP-3 in the nucleus and further increase in oxidative phosphorylation. Dotted lines highlight the pathways identified in this study. Further experiments are required to define the molecular mechanisms responsible for the observed phenotypes