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research article

In situ architecture of Opa1-dependent mitochondrial cristae remodeling

Fry, Michelle Y.
•
Navarro, Paula P.
•
Hakim, Pusparanee
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February 1, 2024
Embo Journal

Cristae membrane state plays a central role in regulating mitochondrial function and cellular metabolism. The protein Optic atrophy 1 (Opa1) is an important crista remodeler that exists as two forms in the mitochondrion, a membrane-anchored long form (l-Opa1) and a processed short form (s-Opa1). The mechanisms for how Opa1 influences cristae shape have remained unclear due to lack of native three-dimensional views of cristae. We perform in situ cryo-electron tomography of cryo-focused ion beam milled mouse embryonic fibroblasts with defined Opa1 states to understand how each form of Opa1 influences cristae architecture. In our tomograms, we observe a variety of cristae shapes with distinct trends dependent on s-Opa1:l-Opa1 balance. Increased l-Opa1 levels promote cristae stacking and elongated mitochondria, while increased s-Opa1 levels correlated with irregular cristae packing and round mitochondria shape. Functional assays indicate a role for l-Opa1 in wild-type apoptotic and calcium handling responses, and show a compromised respiratory function under Opa1 imbalance. In summary, we provide three-dimensional visualization of cristae architecture to reveal relationships between mitochondrial ultrastructure and cellular function dependent on Opa1-mediated membrane remodeling.|Mitochondrial inner-membrane morphology plays essential roles in regulating organelle physiology, but how molecular factors regulate cristae form and function is unclear. In this article, in situ cryo-electron tomography coupled to functional experiments show how different variants of Opa1 influence mitochondrial membrane architecture and activities.Mitochondria with predominantly membrane-anchored long Opa1 isoform (l-Opa1) show crista stacking, longer cristae, reduced globular cristae and an absence of tubular cristae. Mitochondria with mostly processed short Opa1 isoform (s-Opa1) showed irregular cristae packing with wider cristae junctions and narrower cristae. l-Opa1 expressing cells show wild-type-like cristae junction properties, apoptotic response and calcium handling. Imbalance in Opa1 processing leads to compromised respiratory function and an increase in amorphous cristae.|In situ cryo-electron tomography of mitochondria reveals the role of balanced Opa1 proteolytic processing in the determination of cristae structure.

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Type
research article
DOI
10.1038/s44318-024-00027-2
Web of Science ID

WOS:001220415700007

Author(s)
Fry, Michelle Y.
•
Navarro, Paula P.
•
Hakim, Pusparanee
•
Ananda, Virly Y.
•
Qin, Xingping
•
Landoni, Juan Cruz  
•
Rath, Sneha
•
Inde, Zintis
•
Lugo, Camila Makhlouta
•
Luce, Bridget E.
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Date Issued

2024-02-01

Publisher

Springernature

Published in
Embo Journal
Volume

43

Issue

3

Start page

391

End page

413

Subjects

Life Sciences & Biomedicine

•

Cristae Remodeling

•

Mitochondrial Biology

•

Cryo-Electron Tomography

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Cryo-Focused Ion Beam Milling

Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LEB  
FunderGrant Number

Schweizerischer Nationalfonds zur Frderung der Wissenschaftlichen Forschung (SNF)

DK043351

Boston Area Diabetes and Endocrinology Research Center (BADERC) Award

DK057521

Jane Coffin Childs Fund for Medical Research

P2BSP3_188112

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Available on Infoscience
June 5, 2024
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/208330
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