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Review
. 2014 Mar;15(3):231-43.
doi: 10.1002/embr.201338225. Epub 2014 Feb 25.

Dynamic survey of mitochondria by ubiquitin

Mafalda Escobar-Henriques  1 , Thomas Langer
Affiliations
Review

Dynamic survey of mitochondria by ubiquitin

Mafalda Escobar-Henriques et al. EMBO Rep. 2014 Mar.

Abstract

Ubiquitin is a post-translational modifier with proteolytic and non-proteolytic roles in many biological processes. At mitochondria, it performs regulatory homeostatic functions and contributes to mitochondrial quality control. Ubiquitin is essential for mitochondrial fusion, regulates mitochondria-ER contacts, and participates in maternal mtDNA inheritance. Under stress, mitochondrial dysfunction induces ubiquitin-dependent responses that involve mitochondrial proteome remodeling and culminate in organelle removal by mitophagy. In addition, many ubiquitin-dependent mechanisms have been shown to regulate innate immune responses and xenophagy. Here, we review the emerging roles of ubiquitin at mitochondria.

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Figures

Figure 1
Figure 1
(A) Balanced fusion and fission events establish a large variety of mitochondrial network topologies in different cells and tissues and in response to various stimuli. (B) Mitochondria are physically tethered: to each other via mitofusins during fusion, to the mitochondrial transport machinery via Miro proteins, and to the ER via various protein complexes to allow the exchange of metabolites and signaling molecules and to mark sites for mitochondrial fission by Drp1. (C) Ubiquitylation of mitofusins has a dual function in yeast and mammals. Constitutive ubiquitylation, depending on the E3 ligase SCFMdm30 and the DUB Ubp12 in yeast and USP30 in mammals, promotes mitochondrial fusion. In contrast, ubiquitylation of mitofusins inhibits mitochondrial fusion upon growth arrest in yeast or in response to mitochondrial depolarization in mammals. The E3 ubiquitin ligase Parkin and other ligases ubiquitylate Mfn1 and Mfn2, marking them for proteasomal turnover. The DUB Ubp2 was identified in yeast to reverse Fzo1 ubiquitylation resulting in its stabilization. Ub, ubiquitin. Mfns, mitofusins. See Glossary for the other definitions and text for details.
Figure 2
Figure 2
(A) Regulation of mitochondrial proteostasis by the UPS in yeast. Nuclear-encoded mitochondrial precursor proteins, such as substrates of the MIA pathway, are ubiquitylated and degraded by the UPS in the cytosol, limiting their accumulation in mitochondria. (B) Ubiquitin-dependent mitophagy of dysfunctional mitochondria in mammals. The recruitment of the E3 ubiquitin ligase Parkin to the OM of depolarized organelles leads to the ubiquitylation and proteasomal degradation of OM proteins, such as Miro, Mfns, and VDAC, inhibiting various processes, including mitochondrial transport or fusion. It also triggers mitophagy through the recruitment of adaptor factors for the autophagy machinery, such as p62. Ub, ubiquitin. Mfns, mitofusins. See Glossary for the other definitions and text for details.
Figure 3
Figure 3
K63-linked ubiquitin chains, viral RNA, and the helicase RIG-1 participate in the assembly of a signal platform on mitochondria that contains MAVS. This allows several E3 ubiquitin ligases to activate LUBAC and TRAF transcription factors, which induce innate immunity genes. Moreover, ubiquitin is required for disassembly of the MAVS complex, terminating signal transduction. On the other hand, ubiquitin and Mfn2 impair MAVS assembly before signaling initiation. Ub, ubiquitin. See Glossary for the other definitions and text for details.
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