Review Article | Published:

Mitochondrial proteins: from biogenesis to functional networks

Nature Reviews Molecular Cell Biologyvolume 20pages267284 (2019) | Download Citation

Abstract

Mitochondria are essential for the viability of eukaryotic cells as they perform crucial functions in bioenergetics, metabolism and signalling and have been associated with numerous diseases. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. In this Review, we discuss the emerging role of the mitochondrial protein import machinery as a key organizer of these mitochondrial protein networks. The preprotein translocases that reside on the mitochondrial membranes not only function during organelle biogenesis to deliver newly synthesized proteins to their final mitochondrial destination but also cooperate with numerous other mitochondrial protein complexes that perform a wide range of functions. Moreover, these protein networks form membrane contact sites, for example, with the endoplasmic reticulum, that are key for integration of mitochondria with cellular function, and defects in protein import can lead to diseases.

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Acknowledgements

This work was supported by European Research Council (ERC) Consolidator Grant No. 648235, the Excellence Initiative and Strategy of the German federal and state governments (EXC 294 BIOSS; GSC-4 Spemann Graduate School; EXC 2189 CIBSS), the Deutsche Forschungsgemeinschaft (PF 202/8-1 and 202/9-1; WA 1598/5-1) and the Sonderforschungsbereiche 746 and 1140.

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Affiliations

  1. Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    • Nikolaus Pfanner
    •  & Nils Wiedemann
  2. CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany

    • Nikolaus Pfanner
    • , Bettina Warscheid
    •  & Nils Wiedemann
  3. Institute of Biology II, Biochemistry – Functional Proteomics, Faculty of Biology, University of Freiburg, Freiburg, Germany

    • Bettina Warscheid

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Contributions

The authors contributed equally to all aspects of the article.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Nikolaus Pfanner or Nils Wiedemann.

Glossary

Oxidative phosphorylation

Oxidation of metabolites liberates energy that is used to synthesize ATP; in mitochondria, this is performed by the respiratory chain, which generates a proton gradient across the inner membrane to drive ATP production by the F1F0-ATP synthase.

Insertase

Membrane-bound machinery that facilitates the insertion of precursor proteins into the lipid phase of a membrane, such as the oxidase assembly (OXA) insertase of the mitochondrial inner membrane.

Mitochondrial contact site and cristae organizing system

(MICOS). A large protein complex of the inner membrane with a dual role: maintenance of the cristae architecture of the inner membrane and the formation of contact sites between the inner and the outer membranes.

TOM complex

The translocase of the outer membrane (TOM) is a protein complex that forms the major mitochondrial entry site for precursor proteins synthesized in the cytosol.

Heat shock protein 70

(Hsp70). A large family of ATP-dependent molecular chaperones of ~70 kDa that bind loosely folded proteins and prevent their misfolding or aggregation. The major mitochondrial heat shock protein 70 (mtHsp70) has a dual role in driving ATP-dependent protein import into the matrix and assisting in folding of proteins.

N-end rule pathway

A pathway in which the amino-terminal amino acid residue links proteins to regulated proteolysis. A destabilizing residue promotes rapid degradation, whereas a stabilizing residue leads to a longer half-life of a protein.

SAM complex

The sorting and assembly machinery (SAM) inserts β-barrel proteins into the mitochondrial outer membrane; it is also known as topogenesis of outer membrane β-barrel proteins (TOB).

Mitochondrial unfolded protein response

(UPRmt). A stress response induced by mitochondrial dysfunction that upregulates the transcription of nuclear genes encoding mitochondrial chaperones, proteases and further components that support mitochondrial recovery and survival.

Respirasomes

Large supercomplexes in the mitochondrial inner membrane consisting of complexes I, III and IV of the respiratory chain.

Inner boundary membrane

The mitochondrial inner membrane consists of two domains: the folded cristae, which form invaginations, and the inner boundary membrane, which is located adjacent to the mitochondrial outer membrane.

Crista junctions

Narrow apertures at the beginning of cristae of the mitochondrial inner membrane that link cristae to the inner boundary membrane.

Synthetic growth defects

Mutations or deletions in different genes that result in a stronger growth defect if combined in the same cell.

Nucleoid

A mitochondrial DNA–protein assembly located in the matrix containing the packaging factor mitochondrial transcription factor A (TFAM).

ER–mitochondria encounter structure

(ERMES). A multisubunit protein complex that connects the endoplasmic reticulum (ER) and the mitochondrial outer membrane. ERMES is likely involved in lipid transfer between the organelles and is required for maintaining the morphology of mitochondria.

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DOI

https://doi.org/10.1038/s41580-018-0092-0