EMRE is essential for mitochondrial calcium uniporter activity in a mouse model

Julia C. Liu; Nicole C. Syder; Nima S. Ghorashi; Thomas B. Willingham; Randi J. Parks; Junhui Sun; Maria M. Fergusson; Jie Liu; Kira M. Holmström; Sara Menazza; Danielle A. Springer; Chengyu Liu; Brian Glancy; Toren Finkel; Elizabeth Murphy

doi:10.1172/jci.insight.134063

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model

Julia C. Liu, Nicole C. Syder, Nima S. Ghorashi, Thomas B. Willingham, Randi J. Parks, Junhui Sun, Maria M. Fergusson, Jie Liu, Kira M. Holmström, Sara Menazza, Danielle A. Springer, Chengyu Liu, Brian Glancy, Toren Finkel, Elizabeth Murphy

Physiology

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

50 Scopus citations

Abstract

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE’s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE^–/– mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

Original language	English (US)
Article number	e134063
Journal	JCI Insight
Volume	5
Issue number	4
DOIs	https://doi.org/10.1172/jci.insight.134063
State	Published - Feb 27 2020

Bibliographical note

Funding Information:
We are grateful to Michele Allen, Audrey Noguchi, and Morteza Peiravi in the NHLBI Murine Phenotyping Core for help with mouse phenotyping, and Zu-Xi Yu in the NHLBI Pathology Core for assistance with histology. We thank Albert Sek, Helene Rosenberg, and Lee Weinstein for generously providing mice, as well as Baylor, Sanger, Harwell, the EUCOMM consortium, and the MMRRC for the EMRE conditional knockout mice. We are grateful to the members of the Finkel and Murphy labs for thoughtful discussions and feedback. This work was supported by NIH intramural funds, a Leducq Transatlantic Network grant (to EM), and NIH grants 1R01HL142589 (to TF), 1FI2GM117605 (to JCL), and 1K22HL137901 (to JCL).

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© 2020, American Society for Clinical Investigation.

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Liu, J. C., Syder, N. C., Ghorashi, N. S., Willingham, T. B., Parks, R. J., Sun, J., Fergusson, M. M., Liu, J., Holmström, K. M., Menazza, S., Springer, D. A., Liu, C., Glancy, B., Finkel, T., & Murphy, E. (2020). EMRE is essential for mitochondrial calcium uniporter activity in a mouse model. JCI Insight, 5(4), Article e134063. https://doi.org/10.1172/jci.insight.134063

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title = "EMRE is essential for mitochondrial calcium uniporter activity in a mouse model",

abstract = "The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE{\textquoteright}s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE–/– mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.",

author = "Liu, {Julia C.} and Syder, {Nicole C.} and Ghorashi, {Nima S.} and Willingham, {Thomas B.} and Parks, {Randi J.} and Junhui Sun and Fergusson, {Maria M.} and Jie Liu and Holmstr{\"o}m, {Kira M.} and Sara Menazza and Springer, {Danielle A.} and Chengyu Liu and Brian Glancy and Toren Finkel and Elizabeth Murphy",

note = "Funding Information: We are grateful to Michele Allen, Audrey Noguchi, and Morteza Peiravi in the NHLBI Murine Phenotyping Core for help with mouse phenotyping, and Zu-Xi Yu in the NHLBI Pathology Core for assistance with histology. We thank Albert Sek, Helene Rosenberg, and Lee Weinstein for generously providing mice, as well as Baylor, Sanger, Harwell, the EUCOMM consortium, and the MMRRC for the EMRE conditional knockout mice. We are grateful to the members of the Finkel and Murphy labs for thoughtful discussions and feedback. This work was supported by NIH intramural funds, a Leducq Transatlantic Network grant (to EM), and NIH grants 1R01HL142589 (to TF), 1FI2GM117605 (to JCL), and 1K22HL137901 (to JCL). Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

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doi = "10.1172/jci.insight.134063",

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AU - Liu, Julia C.

AU - Syder, Nicole C.

AU - Ghorashi, Nima S.

AU - Willingham, Thomas B.

AU - Parks, Randi J.

AU - Sun, Junhui

AU - Fergusson, Maria M.

AU - Liu, Jie

AU - Holmström, Kira M.

AU - Menazza, Sara

AU - Springer, Danielle A.

AU - Liu, Chengyu

AU - Glancy, Brian

AU - Finkel, Toren

AU - Murphy, Elizabeth

N1 - Funding Information: We are grateful to Michele Allen, Audrey Noguchi, and Morteza Peiravi in the NHLBI Murine Phenotyping Core for help with mouse phenotyping, and Zu-Xi Yu in the NHLBI Pathology Core for assistance with histology. We thank Albert Sek, Helene Rosenberg, and Lee Weinstein for generously providing mice, as well as Baylor, Sanger, Harwell, the EUCOMM consortium, and the MMRRC for the EMRE conditional knockout mice. We are grateful to the members of the Finkel and Murphy labs for thoughtful discussions and feedback. This work was supported by NIH intramural funds, a Leducq Transatlantic Network grant (to EM), and NIH grants 1R01HL142589 (to TF), 1FI2GM117605 (to JCL), and 1K22HL137901 (to JCL). Publisher Copyright: © 2020, American Society for Clinical Investigation.

PY - 2020/2/27

Y1 - 2020/2/27

N2 - The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE’s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE–/– mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

AB - The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE’s impact on organismal physiology is less understood. Here we characterize a mouse model of EMRE deletion and show that EMRE is indeed required for mitochondrial calcium uniporter function in vivo. EMRE–/– mice are born less frequently; however, the mice that are born are viable, healthy, and do not manifest overt metabolic impairment, at rest or with exercise. Finally, to investigate the role of EMRE in disease processes, we examine the effects of EMRE deletion in a muscular dystrophy model associated with mitochondrial calcium overload.

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EMRE is essential for mitochondrial calcium uniporter activity in a mouse model

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