Three-dimensional analysis of mitochondrial crista ultrastructure in a patient with Leigh syndrome by in situ cryoelectron tomography

Siegmund, S. E. et al. (2018) Three-dimensional analysis of mitochondrial crista ultrastructure in a patient with Leigh syndrome by in situ cryoelectron tomography. iScience, 6, pp. 83-91. (doi: 10.1016/j.isci.2018.07.014) (PMID:30240627) (PMCID:PMC6137323)

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.

• Item Type: Articles
• Additional Information: 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).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Carter, Dr Stephen
• Authors: Siegmund, S. E., Grassucci, R., Carter, S. D., Barca, E., Farino, Z. J., Juanola-Falgarona, M., Zhang, P., Tanji, K., Hirano, M., Schon, E. A., Frank, J., and Freyberg, Z.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: iScience
• Publisher: Elsevier (Cell Press)
• ISSN: 2589-0042
• ISSN (Online): 2589-0042
• Published Online: 20 June 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in iScience 6: 83-91
• Publisher Policy: Reproduced under a Creative Commons License