Cell Reports (Apr 2018)
MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress
- Neeharika Nemani,
- Edmund Carvalho,
- Dhanendra Tomar,
- Zhiwei Dong,
- Andrea Ketschek,
- Sarah L. Breves,
- Fabián Jaña,
- Alison M. Worth,
- Julie Heffler,
- Palaniappan Palaniappan,
- Aparna Tripathi,
- Ramasamy Subbiah,
- Massimo F. Riitano,
- Ajay Seelam,
- Thomas Manfred,
- Kie Itoh,
- Shuxia Meng,
- Hiromi Sesaki,
- William J. Craigen,
- Sudarsan Rajan,
- Santhanam Shanmughapriya,
- Jeffrey Caplan,
- Benjamin L. Prosser,
- Donald L. Gill,
- Peter B. Stathopulos,
- Gianluca Gallo,
- David C. Chan,
- Prashant Mishra,
- Muniswamy Madesh
Affiliations
- Neeharika Nemani
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Edmund Carvalho
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Dhanendra Tomar
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Zhiwei Dong
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Andrea Ketschek
- Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Sarah L. Breves
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Fabián Jaña
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Alison M. Worth
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Julie Heffler
- Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Palaniappan Palaniappan
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Aparna Tripathi
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Ramasamy Subbiah
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Massimo F. Riitano
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Ajay Seelam
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Thomas Manfred
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Kie Itoh
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Shuxia Meng
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
- Hiromi Sesaki
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- William J. Craigen
- Department of Molecular and Human Genetics, The Mitochondrial Diagnostic Laboratory, Baylor College of Medicine, Houston, TX 77030, USA
- Sudarsan Rajan
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Santhanam Shanmughapriya
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Jeffrey Caplan
- Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA
- Benjamin L. Prosser
- Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Donald L. Gill
- Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA
- Peter B. Stathopulos
- Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada
- Gianluca Gallo
- Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- David C. Chan
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
- Prashant Mishra
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Muniswamy Madesh
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Corresponding author
- Journal volume & issue
-
Vol. 23,
no. 4
pp. 1005 – 1019
Abstract
Summary: 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. Keywords: mitochondrial shape, MiST, calcium, Miro, EF hand, PTP, MCU, mitophagy, autophagy, mitochondrial dynamics
