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Publications

Journal Article Ppublish 22 citations

PubMed: 38225406 DOI: 10.1038/s44318-024-00027-2

In situ architecture of Opa1-dependent mitochondrial cristae remodeling.

EMBO J 43(3):391-413

Authors: Michelle Y Fry, Paula P Navarro, Pusparanee Hakim, Virly Y Ananda, Xingping Qin, Juan C Landoni, Sneha Rath, Zintis Inde, Camila Makhlouta Lugo, Bridget E Luce, Yifan Ge, Julie L McDonald, Ilzat Ali, Leillani L Ha, Benjamin P Kleinstiver, David C Chan, Kristopher A Sarosiek, Luke H Chao

Affiliations

  • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Molecular and Integrative Physiological Sciences (MIPS) Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Lab of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • Institute of Physics, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
  • Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, China.
  • Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
  • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
  • Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.

Abstract

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.

MeSH

Molecular Biology, Mitochondria, Membranes

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