Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes

Zhangsen Zhou; Mauricio Torres; Haibo Sha; Christopher J. Halbrook; Françoise van den Bergh; Rachel B. Reinert; Tatsuya Yamada; Siwen Wang; Yingying Luo; Allen H. Hunter; Chunqing Wang; Thomas H. Sanderson; Meilian Liu; Aaron Taylor; Hiromi Sesaki; Costas A. Lyssiotis; Jun Wu; Sander Kersten; Daniel A. Beard; Ling Qi

doi:10.1126/science.aay2494

Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes

Zhangsen Zhou, Mauricio Torres, Haibo Sha, Christopher J. Halbrook, Françoise van den Bergh, Rachel B. Reinert, Tatsuya Yamada, Siwen Wang, Yingying Luo, Allen H. Hunter, Chunqing Wang, Thomas H. Sanderson, Meilian Liu, Aaron Taylor, Hiromi Sesaki, Costas A. Lyssiotis, Jun Wu, Sander Kersten, Daniel A. Beard, Ling Qi

School of Medicine

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic “megamitochondria” with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

Original language	English (US)
Article number	aay2494
Journal	Science
Volume	368
Issue number	6486
DOIs	https://doi.org/10.1126/science.aay2494
State	Published - Apr 3 2020

ASJC Scopus subject areas

General

Access to Document

10.1126/science.aay2494

Cite this

Zhou, Z., Torres, M., Sha, H., Halbrook, C. J., van den Bergh, F., Reinert, R. B., Yamada, T., Wang, S., Luo, Y., Hunter, A. H., Wang, C., Sanderson, T. H., Liu, M., Taylor, A., Sesaki, H., Lyssiotis, C. A., Wu, J., Kersten, S., Beard, D. A., & Qi, L. (2020). Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes. Science, 368(6486), [aay2494]. https://doi.org/10.1126/science.aay2494

Zhou, Z, Torres, M, Sha, H, Halbrook, CJ, van den Bergh, F, Reinert, RB, Yamada, T, Wang, S, Luo, Y, Hunter, AH, Wang, C, Sanderson, TH, Liu, M, Taylor, A, Sesaki, H, Lyssiotis, CA, Wu, J, Kersten, S, Beard, DA & Qi, L 2020, 'Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes', Science, vol. 368, no. 6486, aay2494. https://doi.org/10.1126/science.aay2494

@article{9906439aead4445793ba6f815f4202dc,

title = "Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes",

abstract = "The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic “megamitochondria” with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.",

author = "Zhangsen Zhou and Mauricio Torres and Haibo Sha and Halbrook, {Christopher J.} and {van den Bergh}, Fran{\c c}oise and Reinert, {Rachel B.} and Tatsuya Yamada and Siwen Wang and Yingying Luo and Hunter, {Allen H.} and Chunqing Wang and Sanderson, {Thomas H.} and Meilian Liu and Aaron Taylor and Hiromi Sesaki and Lyssiotis, {Costas A.} and Jun Wu and Sander Kersten and Beard, {Daniel A.} and Ling Qi",

note = "Funding Information: We thank D. Fang, L. M. Hendershot, D. Lombard, J. Lin, S. Soleimanpour, T.-P. Su, and R. Wojcikiewicz for providing reagents; F. Mao for data analysis; P. Arvan, L. Rui, Y. Shi, S. Sun, and O. MacDougald for constructive comments on the manuscript; and other members in the Arvan and Qi laboratories for technical assistance and insightful discussions. Funding: This work is supported by 1R01GM123266 and R01GM130695 (H.Se.); HL144657 (D.A.B.); 1R01DK107583 (J.W.); R01DK110439 and P20GM121176 (M.L.); R01NS086819 and R01NS091242 (T.H.S.); UL1TR000433, F32CA228328, and P30DK034933 (C.J.H.); and 1R01GM113188, 1R01DK105393, 1R01DK120047, and 1R35GM130292 (L.Q.). Metabolomics studies performed at the University of Michigan were supported by NIH grant DK097153. Z.Z. is supported by ADA Postdoctoral Fellowship (1-19-PDF-093). M.T. was supported in part by the Pew Latin American Postdoctoral Fellowship. R.B.R. is supported by the Training Program in Endocrinology and Metabolism (5T32DK007245). C.A.L. was supported by a 2017 AACR NextGen Grant for Transformative Cancer Research (17-20-01-LYSS) and an ACS Research Scholar Grant (RSG-18-186-01). Author contributions: Z.Z. and M.T. designed and performed most of the experiments; H.Sh., S.K., C.J.H., F.V.d.B., C.A.L., T.Y., S.W., Y.L., C.W., M.L., H.Se., and A.H.H. performed the experiments; A.T., J.W., T.H.S., and D.A.B. provided reagents and insightful discussion; R.B.R. edited the manuscript and provided insightful discussion; L.Q. directed the Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",

year = "2020",

month = apr,

day = "3",

doi = "10.1126/science.aay2494",

language = "English (US)",

volume = "368",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6486",

}

TY - JOUR

T1 - Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes

AU - Zhou, Zhangsen

AU - Torres, Mauricio

AU - Sha, Haibo

AU - Halbrook, Christopher J.

AU - van den Bergh, Françoise

AU - Reinert, Rachel B.

AU - Yamada, Tatsuya

AU - Wang, Siwen

AU - Luo, Yingying

AU - Hunter, Allen H.

AU - Wang, Chunqing

AU - Sanderson, Thomas H.

AU - Liu, Meilian

AU - Taylor, Aaron

AU - Sesaki, Hiromi

AU - Lyssiotis, Costas A.

AU - Wu, Jun

AU - Kersten, Sander

AU - Beard, Daniel A.

AU - Qi, Ling

N1 - Funding Information: We thank D. Fang, L. M. Hendershot, D. Lombard, J. Lin, S. Soleimanpour, T.-P. Su, and R. Wojcikiewicz for providing reagents; F. Mao for data analysis; P. Arvan, L. Rui, Y. Shi, S. Sun, and O. MacDougald for constructive comments on the manuscript; and other members in the Arvan and Qi laboratories for technical assistance and insightful discussions. Funding: This work is supported by 1R01GM123266 and R01GM130695 (H.Se.); HL144657 (D.A.B.); 1R01DK107583 (J.W.); R01DK110439 and P20GM121176 (M.L.); R01NS086819 and R01NS091242 (T.H.S.); UL1TR000433, F32CA228328, and P30DK034933 (C.J.H.); and 1R01GM113188, 1R01DK105393, 1R01DK120047, and 1R35GM130292 (L.Q.). Metabolomics studies performed at the University of Michigan were supported by NIH grant DK097153. Z.Z. is supported by ADA Postdoctoral Fellowship (1-19-PDF-093). M.T. was supported in part by the Pew Latin American Postdoctoral Fellowship. R.B.R. is supported by the Training Program in Endocrinology and Metabolism (5T32DK007245). C.A.L. was supported by a 2017 AACR NextGen Grant for Transformative Cancer Research (17-20-01-LYSS) and an ACS Research Scholar Grant (RSG-18-186-01). Author contributions: Z.Z. and M.T. designed and performed most of the experiments; H.Sh., S.K., C.J.H., F.V.d.B., C.A.L., T.Y., S.W., Y.L., C.W., M.L., H.Se., and A.H.H. performed the experiments; A.T., J.W., T.H.S., and D.A.B. provided reagents and insightful discussion; R.B.R. edited the manuscript and provided insightful discussion; L.Q. directed the Publisher Copyright: © 2020 American Association for the Advancement of Science. All rights reserved.

PY - 2020/4/3

Y1 - 2020/4/3

N2 - The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic “megamitochondria” with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

AB - The endoplasmic reticulum (ER) engages mitochondria at specialized ER domains known as mitochondria-associated membranes (MAMs). Here, we used three-dimensional high-resolution imaging to investigate the formation of pleomorphic “megamitochondria” with altered MAMs in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics, at least in part, by regulating the turnover of the MAM protein, sigma receptor 1 (SigmaR1). Thus, our study provides molecular insights into ER-mitochondrial cross-talk and expands our understanding of the physiological importance of Sel1L-Hrd1 ERAD.

UR - http://www.scopus.com/inward/record.url?scp=85082977920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082977920&partnerID=8YFLogxK

U2 - 10.1126/science.aay2494

DO - 10.1126/science.aay2494

M3 - Article

C2 - 32193362

AN - SCOPUS:85082977920

SN - 0036-8075

VL - 368

JO - Science

JF - Science

IS - 6486

M1 - aay2494

ER -

Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this