TY - JOUR
T1 - MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress
AU - Nemani, Neeharika
AU - Carvalho, Edmund
AU - Tomar, Dhanendra
AU - Dong, Zhiwei
AU - Ketschek, Andrea
AU - Breves, Sarah L.
AU - Jaña, Fabián
AU - Worth, Alison M.
AU - Heffler, Julie
AU - Palaniappan, Palaniappan
AU - Tripathi, Aparna
AU - Subbiah, Ramasamy
AU - Riitano, Massimo F.
AU - Seelam, Ajay
AU - Manfred, Thomas
AU - Itoh, Kie
AU - Meng, Shuxia
AU - Sesaki, Hiromi
AU - Craigen, William J.
AU - Rajan, Sudarsan
AU - Shanmughapriya, Santhanam
AU - Caplan, Jeffrey
AU - Prosser, Benjamin L.
AU - Gill, Donald L.
AU - Stathopulos, Peter B.
AU - Gallo, Gianluca
AU - Chan, David C.
AU - Mishra, Prashant
AU - Madesh, Muniswamy
N1 - Funding Information:
We thank Craig B. Thompson, Richard Youle, Gia Voeltz, Tom Rapoport, and Gary Yellen for sharing Bax −/− Bak −/− MEFs, mito-Keima, mito-BFP, sec61-β, and Peredox plasmid constructs, respectively. We thank John Elrod for sharing the CypD KO MEFs. The authors also thank Shannon Modla for EM sample processing and image acquisition. This research was funded by the NIH ( R01GM109882 , R01HL086699 , R01HL119306 , and 1S10RR027327 to M.M. and R01 NS095471 to G.G.). N.N. and D.T. are supported by the AHA fellowships ( 17PRE33660720 , 17POST33660251 ). S.S. is supported by a NIH K99/R00 grant ( 1K99HL138268-01 ). Z.D. is supported by China Scholarship Council (No. 201403170252 ). F.J. is supported by FONDECYT postdoctoral fellowship # 3140458 . Access to the electron microscope was supported by NIH-NIGMS ( P20 GM103446 ) and NSF ( IIA-1301765 ).
Funding Information:
We thank Craig B. Thompson, Richard Youle, Gia Voeltz, Tom Rapoport, and Gary Yellen for sharing Bax?/?Bak?/? MEFs, mito-Keima, mito-BFP, sec61-?, and Peredox plasmid constructs, respectively. We thank John Elrod for sharing the CypD KO MEFs. The authors also thank Shannon Modla for EM sample processing and image acquisition. This research was funded by the NIH (R01GM109882, R01HL086699, R01HL119306, and 1S10RR027327 to M.M. and R01 NS095471 to G.G.). N.N. and D.T. are supported by the AHA fellowships (17PRE33660720, 17POST33660251). S.S. is supported by a NIH K99/R00 grant (1K99HL138268-01). Z.D. is supported by China Scholarship Council (No. 201403170252). F.J. is supported by FONDECYT postdoctoral fellowship #3140458. Access to the electron microscope was supported by NIH-NIGMS (P20 GM103446) and NSF (IIA-1301765).
Funding Information:
We thank Craig B. Thompson, Richard Youle, Gia Voeltz, Tom Rapoport, and Gary Yellen for sharing Bax−/−Bak−/− MEFs, mito-Keima, mito-BFP, sec61-β, and Peredox plasmid constructs, respectively. We thank John Elrod for sharing the CypD KO MEFs. The authors also thank Shannon Modla for EM sample processing and image acquisition. This research was funded by the NIH (R01GM109882, R01HL086699, R01HL119306, and 1S10RR027327 to M.M. and R01 NS095471 to G.G.). N.N. and D.T. are supported by the AHA fellowships (17PRE33660720, 17POST33660251). S.S. is supported by a NIH K99/R00 grant (1K99HL138268-01). Z.D. is supported by China Scholarship Council (No. 201403170252). F.J. is supported by FONDECYT postdoctoral fellowship #3140458. Access to the electron microscope was supported by NIH-NIGMS (P20 GM103446) and NSF (IIA-1301765).
Publisher Copyright:
© 2018 The Author(s)
PY - 2018/4/24
Y1 - 2018/4/24
N2 - Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST. Metazoan Ca2+ signal determines mitochondrial shape transition (MiST) and cellular quality control. Nemani et al. find that mitochondria undergo shape changes upon Ca2+ stress. MiST is distinct from matrix Ca2+-induced swelling and mitochondrial dynamics. The conserved Ca2+ sensor Miro1 enables MiST and promotes autophagy/mitophagy.
AB - Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST. Metazoan Ca2+ signal determines mitochondrial shape transition (MiST) and cellular quality control. Nemani et al. find that mitochondria undergo shape changes upon Ca2+ stress. MiST is distinct from matrix Ca2+-induced swelling and mitochondrial dynamics. The conserved Ca2+ sensor Miro1 enables MiST and promotes autophagy/mitophagy.
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U2 - 10.1016/j.celrep.2018.03.098
DO - 10.1016/j.celrep.2018.03.098
M3 - Article
C2 - 29694881
AN - SCOPUS:85045578026
VL - 23
SP - 1005
EP - 1019
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -