TY - JOUR
T1 - FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation
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.
AB - 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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U2 - 10.1038/s41467-018-05856-4
DO - 10.1038/s41467-018-05856-4
M3 - Article
C2 - 30158529
AN - SCOPUS:85052663860
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3449
ER -