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

doi:10.1016/j.celrep.2018.03.098

MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca²⁺ Stress

Cell Rep. 2018 Apr 24;23(4):1005-1019. doi: 10.1016/j.celrep.2018.03.098.

Authors

Neeharika Nemani¹, Edmund Carvalho¹, Dhanendra Tomar¹, Zhiwei Dong¹, Andrea Ketschek², Sarah L Breves¹, Fabián Jaña¹, Alison M Worth¹, Julie Heffler³, Palaniappan Palaniappan¹, Aparna Tripathi¹, Ramasamy Subbiah¹, Massimo F Riitano¹, Ajay Seelam¹, Thomas Manfred¹, Kie Itoh⁴, Shuxia Meng⁵, Hiromi Sesaki⁴, William J Craigen⁶, Sudarsan Rajan¹, Santhanam Shanmughapriya¹, Jeffrey Caplan⁷, Benjamin L Prosser³, Donald L Gill⁸, Peter B Stathopulos⁹, Gianluca Gallo², David C Chan⁵, Prashant Mishra¹⁰, Muniswamy Madesh¹¹

Affiliations

¹ 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.
² Department of Anatomy and Cell Biology, Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
³ Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁶ Department of Molecular and Human Genetics, The Mitochondrial Diagnostic Laboratory, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware, Newark, DE 19711, USA.
⁸ Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA 17033, USA.
⁹ Department of Physiology and Pharmacology, Western University, London, ON N6A 5C1, Canada.
¹⁰ Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹¹ 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. Electronic address: madeshm@temple.edu.

Abstract

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.

Keywords: EF hand; MCU; MiST; Miro; PTP; autophagy; calcium; mitochondrial dynamics; mitochondrial shape; mitophagy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Calcium / metabolism*
HeLa Cells
Humans
Mice
Mice, Mutant Strains
Mitochondria / genetics
Mitochondria / metabolism*
Mitochondrial Dynamics*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Stress, Physiological*
rho GTP-Binding Proteins / genetics
rho GTP-Binding Proteins / metabolism*

Substances

Miro-1 protein, mouse
Receptors, G-Protein-Coupled
rho GTP-Binding Proteins
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding