PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity

Themis Thoudam, Chae Myeong Ha, Jaechan Leem, Dipanjan Chanda, Jong Seok Park, Hyo Jeong Kim, Jae Han Jeon, Yeon Kyung Choi, Suthat Liangpunsakul, Yang Hoon Huh, Tae Hwan Kwon, Keun Gyu Park, Robert A. Harris, Kyusang Park, Hyun Woo Rhee, In Kyu Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca 2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca 2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca 2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4 2 / 2 mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

Original languageEnglish
Pages (from-to)571-586
Number of pages16
JournalDiabetes
Volume68
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

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Endoplasmic Reticulum
Mitochondria
Skeletal Muscle
Obesity
Insulin
Insulin Resistance
Endoplasmic Reticulum Stress
Diet
Membranes
glucose-regulated proteins

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Thoudam, T., Ha, C. M., Leem, J., Chanda, D., Park, J. S., Kim, H. J., ... Lee, I. K. (2019). PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity. Diabetes, 68(3), 571-586. https://doi.org/10.2337/db18-0363
Thoudam, Themis ; Ha, Chae Myeong ; Leem, Jaechan ; Chanda, Dipanjan ; Park, Jong Seok ; Kim, Hyo Jeong ; Jeon, Jae Han ; Choi, Yeon Kyung ; Liangpunsakul, Suthat ; Huh, Yang Hoon ; Kwon, Tae Hwan ; Park, Keun Gyu ; Harris, Robert A. ; Park, Kyusang ; Rhee, Hyun Woo ; Lee, In Kyu. / PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity. In: Diabetes. 2019 ; Vol. 68, No. 3. pp. 571-586.
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abstract = "Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca 2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca 2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca 2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4 2 / 2 mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.",
author = "Themis Thoudam and Ha, {Chae Myeong} and Jaechan Leem and Dipanjan Chanda and Park, {Jong Seok} and Kim, {Hyo Jeong} and Jeon, {Jae Han} and Choi, {Yeon Kyung} and Suthat Liangpunsakul and Huh, {Yang Hoon} and Kwon, {Tae Hwan} and Park, {Keun Gyu} and Harris, {Robert A.} and Kyusang Park and Rhee, {Hyun Woo} and Lee, {In Kyu}",
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Thoudam, T, Ha, CM, Leem, J, Chanda, D, Park, JS, Kim, HJ, Jeon, JH, Choi, YK, Liangpunsakul, S, Huh, YH, Kwon, TH, Park, KG, Harris, RA, Park, K, Rhee, HW & Lee, IK 2019, 'PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity', Diabetes, vol. 68, no. 3, pp. 571-586. https://doi.org/10.2337/db18-0363

PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity. / Thoudam, Themis; Ha, Chae Myeong; Leem, Jaechan; Chanda, Dipanjan; Park, Jong Seok; Kim, Hyo Jeong; Jeon, Jae Han; Choi, Yeon Kyung; Liangpunsakul, Suthat; Huh, Yang Hoon; Kwon, Tae Hwan; Park, Keun Gyu; Harris, Robert A.; Park, Kyusang; Rhee, Hyun Woo; Lee, In Kyu.

In: Diabetes, Vol. 68, No. 3, 01.03.2019, p. 571-586.

Research output: Contribution to journalArticle

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T1 - PDK4 augments ER–mitochondria contact to dampen skeletal muscle insulin signaling during obesity

AU - Thoudam, Themis

AU - Ha, Chae Myeong

AU - Leem, Jaechan

AU - Chanda, Dipanjan

AU - Park, Jong Seok

AU - Kim, Hyo Jeong

AU - Jeon, Jae Han

AU - Choi, Yeon Kyung

AU - Liangpunsakul, Suthat

AU - Huh, Yang Hoon

AU - Kwon, Tae Hwan

AU - Park, Keun Gyu

AU - Harris, Robert A.

AU - Park, Kyusang

AU - Rhee, Hyun Woo

AU - Lee, In Kyu

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca 2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca 2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca 2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4 2 / 2 mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

AB - Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca 2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca 2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca 2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4 2 / 2 mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

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