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Molecular machineries shaping the mitochondrial inner membrane

Nature Reviews Molecular Cell Biology volume 26, pages 706–724 (2025) Cite this article

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Abstract

Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein–lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.

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Fig. 1: Key factors of mitochondrial inner membrane architecture.
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Fig. 2: Subunit composition, modular organization and interaction partners of MICOS.
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Fig. 3: Structure and assembly of the dynamin-like GTPase OPA1.
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Fig. 4: Model for OPA1-dependent mitochondrial inner membrane fusion.
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Acknowledgements

O.D. and Mvd.L. acknowledge funding of the German Research Foundation (DFG) via DFG Research Group 2848 (projects P02 and P06). We are grateful to all members of this Research Group for intensive discussions on mitochondrial nanoscale architecture and heterogeneity of the mitochondrial inner membrane. Structural figures were prepared by the PyMol Molecular Graphics System, whereas structural thumbnails in Figs. 1a, 4b and 4c were generated with BioRender.

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Authors and Affiliations

  1. Structural Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

    Oliver Daumke

  2. Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany

    Oliver Daumke

  3. Medical Biochemistry & Molecular Biology, Center for Molecular Signalling (PZMS), Saarland University Medical School, Homburg/Saar, Germany

    Martin van der Laan

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  1. Oliver Daumke
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Glossary

AlphaFold 3

An artificial intelligence-based structure prediction algorithm.

BH3-only protein

A family of apoptosis-promoting proteins that are part of the larger B cell lymphoma 2 (Bcl2) family and regulate the activity of other Bcl2 members by hetero-assembly.

Disulfide relay pathway

Also known as the Mia40/CHCHD4 pathway. A protein machinery in the mitochondrial intermembrane space that couples the trapping of incoming mitochondrial preproteins to the introduction of disulfide bridges into client proteins to drive their concerted import and folding.

Glycation

Covalent attachment of a sugar to a protein.

Transition state analogue

A molecule mimicking the transition state of a chemical reaction.

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Daumke, O., van der Laan, M. Molecular machineries shaping the mitochondrial inner membrane. Nat Rev Mol Cell Biol 26, 706–724 (2025). https://doi.org/10.1038/s41580-025-00854-z

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