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Building and decoding ubiquitin chains for mitophagy

Nature Reviews Molecular Cell Biology volume 19, pages 93–108 (2018)Cite this article

Subjects

Key Points

  • The serine/threonine-protein kinase PINK1, mitochondrial and the E3 ubiquitin-protein ligase parkin form a signal transduction pathway that marks damaged mitochondria with ubiquitin chains to promote mitophagy. Understanding this pathway is important, as it crucial for several physiological processes and, when defective, it is associated with diseases such as Parkinson disease.

  • Parkin activation is a multistep process involving phosphorylation of its N-terminal ubiquitin-like domain and binding to Ser65-phosphorylated ubiquitin on the mitochondrial outer membrane (MOM).

  • The phosphorylation of parkin and ubiquitin is catalysed by the kinase PINK1 when PINK1 is stabilized on the outer membrane of damaged mitochondria.

  • The combination of parkin activation to promote ubiquitin chain assembly on the MOM and its retention on mitochondria via ubiquitin chain phosphorylation by PINK1 creates a feedforward mechanism for mitochondrial quality control.

  • Ubiquitin chains on mitochondria are recognized by multiple ubiquitin binding autophagy receptors, which coordinate the assembly of an autophagosomal membrane around ubiquitylated mitochondria.

  • Recent studies suggest a new model in which parkin functions to decrease the presentation of mitochondrially derived antigenic peptides on the surface of cells, thereby blocking a form of autoimmunity that can be detrimental to neurons.

Abstract

Mitochondria produce energy in the form of ATP via oxidative phosphorylation. As defects in oxidative phosphorylation can generate harmful reactive oxygen species, it is important that damaged mitochondria are efficiently removed via a selective form of autophagy known as mitophagy. Owing to a combination of cell biological, structural and proteomic approaches, we are beginning to understand the mechanisms by which ubiquitin-dependent signals mark damaged mitochondria for mitophagy. This Review discusses the biochemical steps and regulatory mechanisms that promote the conjugation of ubiquitin to damaged mitochondria via the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin-protein ligase parkin and how ubiquitin chains promote autophagosomal capture. Recently discovered roles for parkin and PINK1 in the suppression of mitochondrial antigen presentation provide alternative models for how this pathway promotes the survival of neurons. A deeper understanding of these processes has major implications for neurodegenerative diseases, including Parkinson disease, where defects in mitophagy and other forms of selective autophagy are prominent.

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Figure 1: Overview of parkin-dependent mitophagy.
Figure 2: Structural anatomy of parkin and pSer65-Ub.
Figure 3: Feedforward mechanism of parkin activation in response to mitochondrial depolarization.
Figure 4: Principles of mitophagy receptor recruitment and activation.

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Acknowledgements

J.W.H. is supported by grants from the US National Institutes of Health (AG011085, R37NS083524 and GM095567), Harvard Brain Initiative ALS seed grant programme, the Michael J. Fox Foundation and the generous support of Ned Goodnow. A.O. is supported by a fellowship from the Edward R. and Anne G. Lefler Center for the study of neurodegenerative disorders at Harvard Medical School. J.-M.H. is supported by a Sara Elizabeth O'Brien Trust Postdoctoral Fellowship.

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  1. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    J. Wade Harper, Alban Ordureau & Jin-Mi Heo

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  1. J. Wade Harper
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J.W.H., A.O. and J.-M.H. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to J. Wade Harper.

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Glossary

Ubiquitin

A 76-amino-acid protein that can be covalently conjugated to lysine residues in other proteins to specify several protein fates. Poly-ubiquitin chains can be generated using seven internal lysine residues in ubiquitin or its first methionine. Lys11-linked or Lys48-linked chains usually target proteins for degradation, whereas other chains, such as Lys63-linked or Met1-linked chains, have signalling roles.

Parkinson disease

A long-term disease of the central nervous system that primarily affects motor functions as a result of loss of dopaminergic neurons.

E3 ubiquitin-protein ligase

A protein or protein complex that can facilitate the transfer of ubiquitin from an E2 conjugating enzyme to a substrate.

General autophagy machinery

Composed of protein and lipid kinases that coordinate the formation of autophagic membranes and the ATG8 conjugation machinery, which is involved in maturation of autophagosomal membranes and fusion with lysosomes.

Amyotrophic lateral sclerosis

(ALS). A progressive and fatal motor neuron disorder that affects the function of voluntary muscles, leading to an inability to move, swallow, speak and breathe.

Translocase of the outer membrane

(TOM). The TOM complex is a multi-protein channel that functions to facilitate import of nuclear-encoded but mitochondrial-localized proteins into all intra-mitochondrial compartments. The only proteins that do not pass through the TOM complex during import are single-pass mitochondrial outer membrane proteins.

N-end rule ubiquitin ligase

A subfamily of RING E3 ubiquitin ligases, including UBR1, UBR2 and UBR3, that use their N-terminal UBR domain to bind to substrates containing hydrophobic or arginine residues at their N-terminus.

Isopeptide bond

An amide bond formed between the amino group of a lysine side chain on a protein (substrate) and the C-terminus of another protein (ubiquitin).

Nanobody

A type of single-chain antibody frequently used to stabilize weak interactions for structural biology.

diGLY capture proteomics

In this approach, di-Gly-Gly ubiquitin 'remnants' that remain on substrate lysine residues after trypsinization are captured using a specific antibody and identified using mass spectrometry.

ε-Amino group

Refers to the NH3+ group in a lysine side chain, which is often used as a recipient for ubiquitin transfer in proteins.

Piecemeal mitophagy

A process through which subdomains of mitochondria harbouring misfolded matrix proteins are separated from the areas of mitochondria that are healthy before engulfment by autophagy.

Xenophagy

The process by which intracellular bacteria are targeted for autophagy.

Starvation-induced bulk autophagy

The process by which nutrient deprivation leads to engulfment of cytosolic contents in autophagosomes followed by delivery to lysosomes.

Dendritic cells

Antigen-presenting immune cells that activate T cells.

T cells

Lymphocytes that function in cell-mediated immunity and contain the T cell receptor on their cell surface.

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Harper, J., Ordureau, A. & Heo, JM. Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol 19, 93–108 (2018). https://doi.org/10.1038/nrm.2017.129

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