FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation

Santhanam Shanmughapriya; Dhanendra Tomar; Zhiwei Dong; Katherine J. Slovik; Neeharika Nemani; Kalimuthusamy Natarajaseenivasan; Edmund Carvalho; Christy Lu; Kaitlyn Corrigan; Venkata Naga Srikanth Garikipati; Jessica Ibetti; Sudarsan Rajan; Carlos Barrero; Kurt Chuprun; Raj Kishore; Salim Merali; Ying Tian; Wenli Yang; Muniswamy Madesh

doi:10.1038/s41467-018-05856-4

FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation

Santhanam Shanmughapriya, Dhanendra Tomar, Zhiwei Dong, Katherine J. Slovik, Neeharika Nemani, Kalimuthusamy Natarajaseenivasan, Edmund Carvalho, Christy Lu, Kaitlyn Corrigan, Venkata Naga Srikanth Garikipati, Jessica Ibetti, Sudarsan Rajan, Carlos Barrero, Kurt Chuprun, Raj Kishore, Salim Merali, Ying Tian, Wenli Yang, Muniswamy Madesh

Medicine

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9 Scopus citations

Abstract

Although many factors contribute to cellular differentiation, the role of mitochondria Ca²⁺ dynamics during development remains unexplored. Because mammalian embryonic epiblasts reside in a hypoxic environment, we intended to understand whether _mCa²⁺ and its transport machineries are regulated during hypoxia. Tissues from multiple organs of developing mouse embryo evidenced a suppression of MICU1 expression with nominal changes on other MCU complex components. As surrogate models, we here utilized human embryonic stem cells (hESCs)/induced pluripotent stem cells (hiPSCs) and primary neonatal myocytes to delineate the mechanisms that control _mCa²⁺ and bioenergetics during development. Analysis of MICU1 expression in hESCs/hiPSCs showed low abundance of MICU1 due to its direct repression by Foxd1. Experimentally, restoration of MICU1 established the periodic _cCa²⁺ oscillations and promoted cellular differentiation and maturation. These findings establish a role of _mCa²⁺ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1.

Original language	English (US)
Article number	3449
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05856-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-05856-4

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Shanmughapriya, S., Tomar, D., Dong, Z., Slovik, K. J., Nemani, N., Natarajaseenivasan, K., Carvalho, E., Lu, C., Corrigan, K., Garikipati, V. N. S., Ibetti, J., Rajan, S., Barrero, C., Chuprun, K., Kishore, R., Merali, S., Tian, Y., Yang, W., & Madesh, M. (2018). FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. Nature communications, 9(1), [3449]. https://doi.org/10.1038/s41467-018-05856-4

FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. / Shanmughapriya, Santhanam; Tomar, Dhanendra; Dong, Zhiwei; Slovik, Katherine J.; Nemani, Neeharika; Natarajaseenivasan, Kalimuthusamy; Carvalho, Edmund; Lu, Christy; Corrigan, Kaitlyn; Garikipati, Venkata Naga Srikanth; Ibetti, Jessica; Rajan, Sudarsan; Barrero, Carlos; Chuprun, Kurt; Kishore, Raj; Merali, Salim; Tian, Ying; Yang, Wenli; Madesh, Muniswamy.

In: Nature communications, Vol. 9, No. 1, 3449, 01.12.2018.

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

Shanmughapriya, S, Tomar, D, Dong, Z, Slovik, KJ, Nemani, N, Natarajaseenivasan, K, Carvalho, E, Lu, C, Corrigan, K, Garikipati, VNS, Ibetti, J, Rajan, S, Barrero, C, Chuprun, K, Kishore, R, Merali, S, Tian, Y, Yang, W & Madesh, M 2018, 'FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation', Nature communications, vol. 9, no. 1, 3449. https://doi.org/10.1038/s41467-018-05856-4

Shanmughapriya, Santhanam ; Tomar, Dhanendra ; Dong, Zhiwei ; Slovik, Katherine J. ; Nemani, Neeharika ; Natarajaseenivasan, Kalimuthusamy ; Carvalho, Edmund ; Lu, Christy ; Corrigan, Kaitlyn ; Garikipati, Venkata Naga Srikanth ; Ibetti, Jessica ; Rajan, Sudarsan ; Barrero, Carlos ; Chuprun, Kurt ; Kishore, Raj ; Merali, Salim ; Tian, Ying ; Yang, Wenli ; Madesh, Muniswamy. / FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. In: Nature communications. 2018 ; Vol. 9, No. 1.

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title = "FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation",

abstract = "Although many factors contribute to cellular differentiation, the role of mitochondria Ca2+ dynamics during development remains unexplored. Because mammalian embryonic epiblasts reside in a hypoxic environment, we intended to understand whether mCa2+ and its transport machineries are regulated during hypoxia. Tissues from multiple organs of developing mouse embryo evidenced a suppression of MICU1 expression with nominal changes on other MCU complex components. As surrogate models, we here utilized human embryonic stem cells (hESCs)/induced pluripotent stem cells (hiPSCs) and primary neonatal myocytes to delineate the mechanisms that control mCa2+ and bioenergetics during development. Analysis of MICU1 expression in hESCs/hiPSCs showed low abundance of MICU1 due to its direct repression by Foxd1. Experimentally, restoration of MICU1 established the periodic cCa2+ oscillations and promoted cellular differentiation and maturation. These findings establish a role of mCa2+ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1.",

author = "Santhanam Shanmughapriya and Dhanendra Tomar and Zhiwei Dong and Slovik, {Katherine J.} and Neeharika Nemani and Kalimuthusamy Natarajaseenivasan and Edmund Carvalho and Christy Lu and Kaitlyn Corrigan and Garikipati, {Venkata Naga Srikanth} and Jessica Ibetti and Sudarsan Rajan and Carlos Barrero and Kurt Chuprun and Raj Kishore and Salim Merali and Ying Tian and Wenli Yang and Muniswamy Madesh",

note = "Funding Information: We thank Dr. Walter J. Koch for the reagents provided for the isolation of NRVMs. Daniel Martinez for tissue array sample processing, construction of the array, immunohistochemical analysis, and image acquisition. We also thank Juan Arbelaez of the iPSC Core Facility at the University of Pennsylvania for generating GM942 iPSC lines. Access to CHOP pathology core was supported by the 2017 MITO RAG CHOP core grant. S.S. and M.M., thank Dr. Marni Falk for the core grant. This research was funded by the National Institutes of Health (R01GM109882, R01HL086699, R01HL119306, R01HL142673 and 1S10RR027327 to M.M and by the Institute for Regenerative Medicine of the University of Pennsylvania to W.Y.; S.S. is supported by the NIH K99/R00 grant (1 K99 HL138268-01). E.C. and N.N., are supported by the AHA fellowships (18POST33990217, and 17PRE33660720). Z.D. is supported by China Scholarship Council (No.201403170252). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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doi = "10.1038/s41467-018-05856-4",

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AU - Shanmughapriya, Santhanam

AU - Tomar, Dhanendra

AU - Dong, Zhiwei

AU - Slovik, Katherine J.

AU - Nemani, Neeharika

AU - Natarajaseenivasan, Kalimuthusamy

AU - Carvalho, Edmund

AU - Lu, Christy

AU - Corrigan, Kaitlyn

AU - Garikipati, Venkata Naga Srikanth

AU - Ibetti, Jessica

AU - Rajan, Sudarsan

AU - Barrero, Carlos

AU - Chuprun, Kurt

AU - Kishore, Raj

AU - Merali, Salim

AU - Tian, Ying

AU - Yang, Wenli

AU - Madesh, Muniswamy

N1 - Funding Information: We thank Dr. Walter J. Koch for the reagents provided for the isolation of NRVMs. Daniel Martinez for tissue array sample processing, construction of the array, immunohistochemical analysis, and image acquisition. We also thank Juan Arbelaez of the iPSC Core Facility at the University of Pennsylvania for generating GM942 iPSC lines. Access to CHOP pathology core was supported by the 2017 MITO RAG CHOP core grant. S.S. and M.M., thank Dr. Marni Falk for the core grant. This research was funded by the National Institutes of Health (R01GM109882, R01HL086699, R01HL119306, R01HL142673 and 1S10RR027327 to M.M and by the Institute for Regenerative Medicine of the University of Pennsylvania to W.Y.; S.S. is supported by the NIH K99/R00 grant (1 K99 HL138268-01). E.C. and N.N., are supported by the AHA fellowships (18POST33990217, and 17PRE33660720). Z.D. is supported by China Scholarship Council (No.201403170252). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Although many factors contribute to cellular differentiation, the role of mitochondria Ca2+ dynamics during development remains unexplored. Because mammalian embryonic epiblasts reside in a hypoxic environment, we intended to understand whether mCa2+ and its transport machineries are regulated during hypoxia. Tissues from multiple organs of developing mouse embryo evidenced a suppression of MICU1 expression with nominal changes on other MCU complex components. As surrogate models, we here utilized human embryonic stem cells (hESCs)/induced pluripotent stem cells (hiPSCs) and primary neonatal myocytes to delineate the mechanisms that control mCa2+ and bioenergetics during development. Analysis of MICU1 expression in hESCs/hiPSCs showed low abundance of MICU1 due to its direct repression by Foxd1. Experimentally, restoration of MICU1 established the periodic cCa2+ oscillations and promoted cellular differentiation and maturation. These findings establish a role of mCa2+ dynamics in regulation of cellular differentiation and reveal a molecular mechanism underlying this contribution through differential regulation of MICU1.

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FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation

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