MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress
Open accessAbstract
Mitochondria shape cytosolic calcium ([Ca 2+ ] c ) transients and utilize the mitochondrial Ca 2+ ([Ca 2+ ] m ) in exchange for bioenergetics output. Conversely, dysregulated [Ca 2+ ] c causes [Ca 2+ ] m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca 2+ uptake exhibited elevated [Ca 2+ ] c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca 2+ -induced shape change that is distinct from mitochondrial fission and swelling. [Ca 2+ ] c elevation, but not MCU-mediated Ca 2+ 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, Ca 2+ -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 Ca 2+ sensor that decodes metazoan Ca 2+ signals as MiST.
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Cytosolic calcium modulates mitochondrial morphology, promoting transitions between tubular and spherical shapes.
“Notably, cytosolic calcium has been implicated in modulating mitochondrial morphology, promoting transitions between tubular and spherical shapes53,90.”
From CYFIP1 governs the development of cortical axons by modulating calcium availability (2025) · cites this paper as [53]
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CYFIP1 governs the development of cortical axons by modulating calcium availability
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“Speci fi cally,elevatedcytosoliccalciumlevelscan trigger increased mitochondrial fi ssion or a mitochondrial shape transition, leading to a rounder mitochondrial shape 52,53 .”
- Authors
- Nemani, N., Carvalho, E., Tomar, D., Dong, Z., Ketschek, A., Breves, S. L., Jaña, F., Worth, A. M., Heffler, J., Palaniappan, P., Tripathi, A., Subbiah, R., Riitano, M. F., Seelam, A., Manfred, T., Itoh, K., Meng, S., Sesaki, H., Craigen, W. J., Rajan, S., Shanmughapriya, S., Caplan, J., Prosser, B. L., Gill, D. L., Stathopulos, P. B., Gallo, G., Chan, D. C., Mishra, P., & Madesh, M.
- Affiliations
- Temple University (US)
- Shriners Hospitals for Children - Philadelphia (US)
- University of Pennsylvania (US)
- Johns Hopkins University (US)
- California Institute of Technology (US)
- Baylor College of Medicine (US)
- Delaware Biotechnology Institute (US)
- Pennsylvania State University (US)
- Western University (CA)
- Children's Medical Center (US)
- Corresponding author
- Madesh, Muniswamy
- ORCID
- Nemani, Neeharika
- Carvalho, Edmund
- Tomar, Dhanendra
- Dong, Zhiwei
- Ketschek, Andrea
- Jaña, Fabián
- Worth, Alison M.
- Heffler, Julie
- Riitano, Massimo F.
- Itoh, Kie
- Sesaki, Hiromi
- Rajan, Sudarsan
- Shanmughapriya, Santhanam
- Caplan, Jeffrey
- Prosser, Benjamin L.
- Gill, Donald L.
- Stathopulos, Peter B.
- Gallo, Gianluca
- Chan, David C.
- Mishra, Prashant
- Madesh, Muniswamy
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 23
- Issue
- 4
- Pages
- 1005-1019
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5973819
- OpenAlex
- W2803005522
- Cited by
- 111
- References
- 11
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 10 · 2023: 11 · 2022: 14 · 2021: 14 · 2020: 21 · 2019: 15 · 2018: 3
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- TUScholarShare (Temple University) (submittedVersion, cc-by)
- Funders
- National Science Foundation (IIA-1301765)
- American Historical Association (1K99HL138268-01, 17PRE33660720, 17POST33660251)
- China Scholarship Council (201403170252)
- National Institutes of Health (R01HL119306, R01HL086699, R01GM109882, 1S10RR027327, R01 NS095471)
- Fondo Nacional de Desarrollo CientÃfico, Tecnológico y de Innovación Tecnológica (3140458)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- Miro1, mitochondrial calcium, intracellular calcium, GPCR activation, calcium stress, EF-hand domain, KIF5B, tubulin, mitophagy, autophagy, mitochondrial calcium uptake, mitochondrial permeability transition pore, cell death, calcium signaling
- MeSH terms
- Animals, Calcium, HeLa Cells, Humans, Mice, Mutant Strains, Mitochondria, Stress, Physiological, rho GTP-Binding Proteins, Receptors, G-Protein-Coupled, Mice, Mitochondrial Dynamics
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