TY - JOUR
T1 - Prolyl-hydroxylase PHD3 interacts with pyruvate dehydrogenase (PDH)-E1β and regulates the cellular PDH activity
AU - Kikuchi, Daisuke
AU - Minamishima, Yoji Andrew
AU - Nakayama, Koh
N1 - Funding Information:
We thank Dr. Hiroshi Nishina and members of his laboratory for helpful discussions during the course of the study. We also thank Dr. Noriyo Hayakawa and Ms. Makiko Nawa for technical assistance. K.N. was supported by the Takeda Science Foundation , the Tokyo Biochemical Research Foundation and the Kato Memorial Bioscience Foundation . This study was also supported by a Grant-in-Aid for Scientific Research C ( JSPS ).
PY - 2014/8/22
Y1 - 2014/8/22
N2 - Cells are frequently exposed to hypoxia in physiological and pathophysiological conditions in organisms. Control of energy metabolism is one of the critical functions of the hypoxic response. Hypoxia-Inducible Factor (HIF) is a central transcription factor that regulates the hypoxic response. HIF prolyl-hydroxylase PHDs are the enzymes that hydroxylate the α subunit of HIF and negatively regulate its expression. To further understand the physiological role of PHD3, proteomics were used to identify PHD3-interacting proteins, and pyruvate dehydrogenase (PDH)-E1β was identified as such a protein. PDH catalyzes the conversion of pyruvate to acetyl-coA, thus playing a key role in cellular energy metabolism. PDH activity was significantly decreased in PHD3-depleted MCF7 breast cancer cells and PHD3-/- MEFs. PHD3 depletion did not affect the expression of the PDH-E1α, E1β, and E2 subunits, or the phosphorylation status of E1α, but destabilized the PDH complex (PDC), resulting in less functional PDC. Finally, PHD3-/- cells were resistant to cell death in prolonged hypoxia with decreased production of ROS. Taken together, the study reveals that PHD3 regulates PDH activity in cells by physically interacting with PDC.
AB - Cells are frequently exposed to hypoxia in physiological and pathophysiological conditions in organisms. Control of energy metabolism is one of the critical functions of the hypoxic response. Hypoxia-Inducible Factor (HIF) is a central transcription factor that regulates the hypoxic response. HIF prolyl-hydroxylase PHDs are the enzymes that hydroxylate the α subunit of HIF and negatively regulate its expression. To further understand the physiological role of PHD3, proteomics were used to identify PHD3-interacting proteins, and pyruvate dehydrogenase (PDH)-E1β was identified as such a protein. PDH catalyzes the conversion of pyruvate to acetyl-coA, thus playing a key role in cellular energy metabolism. PDH activity was significantly decreased in PHD3-depleted MCF7 breast cancer cells and PHD3-/- MEFs. PHD3 depletion did not affect the expression of the PDH-E1α, E1β, and E2 subunits, or the phosphorylation status of E1α, but destabilized the PDH complex (PDC), resulting in less functional PDC. Finally, PHD3-/- cells were resistant to cell death in prolonged hypoxia with decreased production of ROS. Taken together, the study reveals that PHD3 regulates PDH activity in cells by physically interacting with PDC.
KW - Hypoxia
KW - PDH-E1β
KW - PHD3
KW - Prolyl-hydroxylase
KW - Pyruvate dehydrogenase complex
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U2 - 10.1016/j.bbrc.2014.07.114
DO - 10.1016/j.bbrc.2014.07.114
M3 - Article
C2 - 25088999
AN - SCOPUS:84906936812
SN - 0006-291X
VL - 451
SP - 288
EP - 294
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -
