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Review
. 2022 Oct 11;23(20):12105.
doi: 10.3390/ijms232012105.

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

Eliona Tsefou  1   2 , Robin Ketteler  1
Affiliations
Review

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

Eliona Tsefou et al. Int J Mol Sci. .

Abstract

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration.

Keywords: DUB inhibitors; Parkin; Parkinson disease; deubiquitinating enzymes; mitophagy.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Ubiquitylation pathway. Free ubiquitin (Ub) binds to substates via the sequential steps of three enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugated enzyme) and E3 (ubiquitin-ligating enzyme). After the binding of Ub to different substrates, such as proteins or organelles (e.g., mitochondria), they undergo degradation via the proteasomal or autophagy pathway, depending on the type of the Ub modification. Ub can be removed by deubiquitinating enzymes (DUBs) in the cells, which cleave the peptide bond between Ub and its substrates.
Figure 2
Figure 2
PINK1/Parkin-mediated mitophagy. In healthy mitochondria, the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) is imported into the mitochondria via the Translocase of the Outer Membrane (TOM) and Translocase of the Inner Membrane (TIM) complexes. When the mitochondrial membrane potential is intact, PINK1 will be cleaved by two proteases (mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like (PARL)) and translocate to the cytosol for proteasomal degradation. On the other hand, in damaged mitochondria the membrane potential is disrupted, which leads to the stabilisation and dimerisation of PINK1 in the OMM, which results in the autophosphorylation and activation of PINK1. The activated PINK1 phosphorylates pre-existing Ub substrates in the OMM, which results in the recruitment and phosphorylation of Parkin to the OMM. Phosphorylated Parkin further ubiquitinates proteins in the OMM, which leads to the coating of the OMM with Ub and the consequent recruitment of the autophagosome to the damaged mitochondria. Several DUBs have been identified as key regulators of the pathway. These enzymes can interact with Parkin either directly (USP8, USP13, USP33 and Ataxin 3) or indirectly (USP30, USP15 and USP36) to regulate its activity.
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