TY - JOUR
T1 - The mitochondrial Ca2+ uniporter channel synergizes with fluid shear stress to induce mitochondrial Ca2+ oscillations
AU - Patel, Akshar
AU - Simkulet, Matthew
AU - Maity, Soumya
AU - Venkatesan, Manigandan
AU - Matzavinos, Anastasios
AU - Madesh, Muniswamy
AU - Alevriadou, B. Rita
N1 - Funding Information:
This research was funded by the National Institutes of Health R01HL142673 to B.R.A. and M.M., and partially by the SUNY Empire Innovation and PRODiG Programs to B.R.A. The research was also partially funded by the Chilean National Agency for Research and Development (ANID) through a FONDECYT Regular grant award 1221220 to A.M., and National Institutes of Health R01GM109882, R01HL086699, R01GM135760, and 1S10RR027327 to M.M. We wish to thank Dr. Sudarsan Rajan, Temple University, for helpful discussions throughout this study, and Dr. Thomas M. Suchyna, University at Buffalo-SUNY, for the generous gift of GsMTx4 and instructions for its use.
Funding Information:
This research was funded by the National Institutes of Health R01HL142673 to B.R.A. and M.M., and partially by the SUNY Empire Innovation and PRODiG Programs to B.R.A. The research was also partially funded by the Chilean National Agency for Research and Development (ANID) through a FONDECYT Regular grant award 1221220 to A.M., and National Institutes of Health R01GM109882, R01HL086699, R01GM135760, and 1S10RR027327 to M.M. We wish to thank Dr. Sudarsan Rajan, Temple University, for helpful discussions throughout this study, and Dr. Thomas M. Suchyna, University at Buffalo-SUNY, for the generous gift of GsMTx4 and instructions for its use.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The mitochondrial calcium (Ca2+) uniporter (MCU) channel is responsible for mitochondrial Ca2+ influx. Its expression was found to be upregulated in endothelial cells (ECs) under cardiovascular disease conditions. Since the role of MCU in regulating cytosolic Ca2+ homeostasis in ECs exposed to shear stress (SS) is unknown, we studied mitochondrial Ca2+ dynamics (that is known to decode cytosolic Ca2+ signaling) in sheared ECs. To understand cause-and-effect, we ectopically expressed MCU in ECs. A higher percentage of MCU-transduced ECs exhibited mitochondrial Ca2+ transients/oscillations, and at higher frequency, under SS compared to sheared control ECs. Transients/oscillations correlated with mitochondrial reactive oxygen species (mROS) flashes and mitochondrial membrane potential (ΔΨm) flickers, and depended on activation of the mechanosensitive Piezo1 channel and the endothelial nitric oxide synthase (eNOS). A positive feedback loop composed of mitochondrial Ca2+ uptake/mROS flashes/ΔΨm flickers and endoplasmic reticulum Ca2+ release, in association with Piezo1 and eNOS, provided insights into the mechanism by which SS, under conditions of high MCU activity, may shape vascular EC energetics and function.
AB - The mitochondrial calcium (Ca2+) uniporter (MCU) channel is responsible for mitochondrial Ca2+ influx. Its expression was found to be upregulated in endothelial cells (ECs) under cardiovascular disease conditions. Since the role of MCU in regulating cytosolic Ca2+ homeostasis in ECs exposed to shear stress (SS) is unknown, we studied mitochondrial Ca2+ dynamics (that is known to decode cytosolic Ca2+ signaling) in sheared ECs. To understand cause-and-effect, we ectopically expressed MCU in ECs. A higher percentage of MCU-transduced ECs exhibited mitochondrial Ca2+ transients/oscillations, and at higher frequency, under SS compared to sheared control ECs. Transients/oscillations correlated with mitochondrial reactive oxygen species (mROS) flashes and mitochondrial membrane potential (ΔΨm) flickers, and depended on activation of the mechanosensitive Piezo1 channel and the endothelial nitric oxide synthase (eNOS). A positive feedback loop composed of mitochondrial Ca2+ uptake/mROS flashes/ΔΨm flickers and endoplasmic reticulum Ca2+ release, in association with Piezo1 and eNOS, provided insights into the mechanism by which SS, under conditions of high MCU activity, may shape vascular EC energetics and function.
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U2 - 10.1038/s41598-022-25583-7
DO - 10.1038/s41598-022-25583-7
M3 - Article
C2 - 36476944
AN - SCOPUS:85143328708
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 21161
ER -