PDK4 augments ER-mitochondria contact to dampen skeletal muscle insulin signaling during obesity
Open accessAbstract
Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ 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 Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4−/− 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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The role of mitochondria-SR interactions in promoting insulin signalling in skeletal muscle is a matter of contention.
“Nonetheless, the role of mitochondria-SR interactions in promoting insulin signalling in skeletal muscle is emerging as a matter of contention”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Thoudam et al., 2019
The downstream event responsible for the deleterious metabolic effect of augmented mitochondria-SR interactions is accumulation of Ca2+ in mitochondria.
“The downstream event being held responsible for the deleterious metabolic effect of augmented mitochondria-SR interactions is the accumulation of Ca2+ in the mitochondria (Thoudam et al., 2019).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Thoudam et al., 2019
Interaction between mitochondria and the sarcoplasmic reticulum has been confirmed in skeletal muscle.
“Remarkably, the interaction between mitochondria and the sarcoplasmic reticulum (SR) has been confirmed in skeletal muscle (Tubbs et al., 2018; Thoudam et al., 2019).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Thoudam et al., 2019
Dysregulation of MAMs may contribute to skeletal muscle insulin resistance in mice and humans.
“Not surprisingly, also in consideration of the pivotal role of skeletal muscle in the regulation of glucose homeostasis, the dysregulation of MAMs may contribute to skeletal muscle insulin resistance in mice and humans (Tubbs et al., 2018; Thoudam et al., 2019).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Thoudam et al., 2019
The deleterious effect of augmented mitochondria-SR interactions relies on mitochondrial Ca2+ accumulation, underpinned by activation of PDK4 and subsequent stabilisation of key proteins involved in mitochondria-SR interactions.
“This relies on mitochondrial Ca2+ accumulation, which is underpinned by the activation of pyruvate dehydrogenase kinase 4 (PDK4) and the subsequent stabilisation of key proteins involved in mitochondria-SR interactions”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Thoudam et al., 2019
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References 52 · Cited by 207
- Authors
- Thoudam, T., Ha, C.-M., Leem, J., Chanda, D., Park, J.-S., Kim, H.-J., Jeon, J.-H., Choi, Y.-K., Liangpunsakul, S., Huh, Y. H., Kwon, T.-H., Park, K.-G., Harris, R. A., Park, K.-S., Rhee, H.-W., & Lee, I.-K.
- Affiliations
- Kyungpook National University (KR)
- Daegu Catholic University (KR)
- Kyungpook National University Hospital (KR)
- Ulsan National Institute of Science and Technology (KR)
- Korea Basic Science Institute (KR)
- Richard L. Roudebush VA Medical Center (US)
- Yonsei University (KR)
- Indiana University School of Medicine (US)
- Seoul National University (KR)
- Corresponding author
- Lee, In-Kyu
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2018-12-06
- Volume
- 68
- Issue
- 3
- Pages
- 571-586
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC6385748
- OpenAlex
- W2903416559
- Cited by
- 207
- References
- 52
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 43 · 2023: 24 · 2022: 27 · 2021: 18 · 2020: 32 · 2019: 7
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Ministry of Science, ICT and Future Planning (NRF-2016M3A9B6902872, NRF-2017R1A2B3006406, NRF-2016R1E1A2020567, NRF-2017R1E1A2A02023467)
- Ministry of Health & Welfare (HI16C1501)
- Korea Basic Science Institute (T38210)
- VA Merit Award (1I01CX000361)
- National Institutes of Health (U01-AA-021840, R01-DK-107682, R01-AA-025208, R21-AA-024935-01)
- U.S. Department of Defense (W81XWH-12-1-0497)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PDK4, mitochondria-associated endoplasmic reticulum membranes, ER-mitochondria contact sites, skeletal muscle insulin resistance, obesity, mitochondrial calcium overload, mitochondrial dysfunction, endoplasmic reticulum stress, diet-induced obesity, insulin signaling
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Calcium, Cell Line, Insulin, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Oxygen Consumption, Immunoblotting, Signal Transduction, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, Knockout, Muscle, Skeletal, Microscopy, Electron, Transmission, Immunoprecipitation, Mice, Membrane Potential, Mitochondrial, Endoplasmic Reticulum Stress
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