TY - JOUR
T1 - Insulin receptor preserves mitochondrial function by binding VDAC1 in insulin insensitive mucosal epithelial cells
AU - Titone, Rossella
AU - Robertson, Danielle M.
N1 - Funding Information:
This study was funded by NIH grants R01 EY029258 (DMR), R01 EY024546 (DMR), P30 EY030413, and S10 OD021685, an unrestricted grant from Research to Prevent Blindness, New York, NY, and a Fight for Sight postdoctoral award (RT).
Publisher Copyright:
© 2019 Federation of American Societies for Experimental Biology
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Unlike many epithelial tissues, the corneal epithelium is insulin insensitive, meaning it does not require insulin for glucose uptake. In this study, we show that insulin differentially regulates mitochondrial respiration in two human mucosal epithelial cell types: insulin-insensitive corneal epithelial cells and insulin-sensitive bronchial epithelial cells. In both cell types, insulin blocks glycogen synthase kinase beta (GSK3β) activity. In the corneal epithelium however, insulin selectively regulates PTEN-induced kinase 1 (PINK-1)-mediated mitophagy and mitochondrial accumulation of insulin receptor (INSR). While insulin blocked basal levels of PINK-1-mediated mitophagy in bronchial epithelial cells, mitochondrial trafficking of INSR was not detectable. We further show that in corneal epithelia, INSR interacts with the voltage-dependent anion channel-1 (VDAC1) in mitochondria and that INSR knockdown triggers robust mitochondrial fragmentation, alterations in mitochondrial polarization, and blocks the induction of PINK-1-mediated mitophagy. Collectively, these data demonstrate that INSR interacts with VDAC1 to mediate mitochondrial stability. We also demonstrate unique interactions between VDAC1 and other receptor tyrosine kinases, indicating a novel role for this family of receptors in mitochondria.
AB - Unlike many epithelial tissues, the corneal epithelium is insulin insensitive, meaning it does not require insulin for glucose uptake. In this study, we show that insulin differentially regulates mitochondrial respiration in two human mucosal epithelial cell types: insulin-insensitive corneal epithelial cells and insulin-sensitive bronchial epithelial cells. In both cell types, insulin blocks glycogen synthase kinase beta (GSK3β) activity. In the corneal epithelium however, insulin selectively regulates PTEN-induced kinase 1 (PINK-1)-mediated mitophagy and mitochondrial accumulation of insulin receptor (INSR). While insulin blocked basal levels of PINK-1-mediated mitophagy in bronchial epithelial cells, mitochondrial trafficking of INSR was not detectable. We further show that in corneal epithelia, INSR interacts with the voltage-dependent anion channel-1 (VDAC1) in mitochondria and that INSR knockdown triggers robust mitochondrial fragmentation, alterations in mitochondrial polarization, and blocks the induction of PINK-1-mediated mitophagy. Collectively, these data demonstrate that INSR interacts with VDAC1 to mediate mitochondrial stability. We also demonstrate unique interactions between VDAC1 and other receptor tyrosine kinases, indicating a novel role for this family of receptors in mitochondria.
KW - VDAC1
KW - bronchial epithelial cells
KW - corneal epithelial cells
KW - insulin
KW - mitochondria
KW - receptor tyrosine kinases
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U2 - 10.1096/fj.201901316RR
DO - 10.1096/fj.201901316RR
M3 - Article
C2 - 31914671
AN - SCOPUS:85077749281
SN - 0892-6638
VL - 34
SP - 754
EP - 775
JO - FASEB Journal
JF - FASEB Journal
IS - 1
ER -