Three-Dimensional Analysis of Mitochondrial Crista Ultrastructure in a Patient with Leigh Syndrome by In Situ Cryoelectron Tomography
Abstract
Mitochondrial diseases produce profound neurological dysfunction via mutations affecting mitochondrial energy production, including the relatively common Leigh syndrome (LS). We recently described an LS case caused by a pathogenic mutation in USMG5, encoding a small supernumerary subunit of mitochondrial ATP synthase. This protein is integral for ATP synthase dimerization, and patient fibroblasts revealed an almost total loss of ATP synthase dimers. Here, we utilize in situ cryoelectron tomography (cryo-ET) in a clinical case-control study of mitochondrial disease to directly study mitochondria within cultured fibroblasts from a patient with LS and a healthy human control subject. Through tomographic analysis of patient and control mitochondria, we find that loss of ATP synthase dimerization due to the pathogenic mutation causes profound disturbances of mitochondrial crista ultrastructure. Overall, this work supports the crucial role of ATP synthase in regulating crista architecture in the context of human disease.
Additional Information
© 2018 The Author(s). Under a Creative Commons license - Attribution 4.0 International (CC BY 4.0) Received 24 April 2018, Revised 6 July 2018, Accepted 16 July 2018, Available online 20 July 2018. Published: August 31, 2018. This work was supported by the Marriott Mitochondrial Disorders Clinical Research Network (M.H. and E.A.S.), the US National Institutes of Health (P01-HD080642 to E.A.S. and M.H. and F30-NS093798 to S.S.), the John F. and Nancy A. Emmerling Fund of The Pittsburgh Foundation (Z.F.), the U.S. Department of Defense (PR141292 to Z.F. and W911F-15-1-0169 to E.A.S.), the Howard Hughes Medical Institute (J.F.), and the US National Institute of Health (R01 GM29169 to J.F.). Image analysis was conducted at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310); we would also like to thank Drs. Grant Jensen, Christoph Wigge, William Rice, Alex Noble, Edward Eng, Bridget Carragher, and Clint Potter for their assistance and advice regarding image analysis. Author Contributions: S.E.S., R.G., S.D.C., E.B., Z.J.F., M.J.-F., P.Z., M.H., E.A.S., J.F., and Z.F. conceived of and designed the study. M.H., E.B., M.J.-F., E.A.S., J.F., and Z.F. provided reagents. S.E.S., R.G., Z.J.F., and Z.F. conducted the experimental procedures. S.E.S., R.G., S.D.C., E.B., Z.J.F., P.Z., K.T., M.H., E.A.S., J.F., and Z.F. provided data analysis and interpretation. S.E.S. and Z.F. wrote the manuscript, which was edited by the co-authors. The authors declare no competing interests.Attached Files
Published - main.pdf
Supplemental Material - 1-s2.0-S2589004218301020-mmc1.pdf
Supplemental Material - 1-s2.0-S2589004218301020-mmc2.mp4
Supplemental Material - 1-s2.0-S2589004218301020-mmc3.mp4
Supplemental Material - 1-s2.0-S2589004218301020-mmc4.mp4
Supplemental Material - 1-s2.0-S2589004218301020-mmc5.mp4
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Additional details
- PMCID
- PMC6137323
- Eprint ID
- 102443
- DOI
- 10.1016/j.isci.2018.07.014
- Resolver ID
- CaltechAUTHORS:20200409-115738252
- Marriott Mitochondrial Disorders Clinical Research Network
- P01-HD080642
- NIH
- F30-NS093798
- NIH Postdoctoral Fellowship
- Pittsburgh Foundation
- PR141292
- Department of Defense
- W911F-15-1-0169
- Army Research Office (ARO)
- Howard Hughes Medical Institute (HHMI)
- R01 GM29169
- NIH
- 349247
- Simons Foundation
- NYSTAR
- GM103310
- NIH
- Created
-
2020-04-10Created from EPrint's datestamp field
- Updated
-
2022-03-09Created from EPrint's last_modified field