The Ubiquitination of PINK1 Is Restricted to Its Mature 52-kDa Form

Abstract

SUMMARYAlong with Parkin, PINK1 plays a critical role in maintaining mitochondrial quality control. Although PINK1 is expressed constitutively, its level is kept low in healthy mitochondria by polyubiquitination and ensuing proteasomal degradation of its mature, 52 kDa, form. We show here that the target of PINK1 polyubiquitination is the mature form and is mediated by ubiquitination of a conserved lysine at position 137. Notably, the full-length protein also contains Lys-137 but is not ubiquitinated. On the basis of our data, we propose that cleavage of full-length PINK1 at Phe-104 disrupts the major hydrophobic membrane-spanning domain in the protein, inducing a conformation change in the resultant mature form that exposes Lys-137 to the cytosol for subsequent modification by the ubiquitination machinery. Thus, the balance between the full-length and mature PINK1 allows its levels to be regulated via ubiquitination of the mature form and ensures that PINK1 functions as a mitochondrial quality control factor.

Phosphoregulation on mitochondria: Integration of cell and organelle responses

“…Under basal conditions, PINK1 is transported into the mitochondrial matrix through the translocases of the outer membrane, TOM20 and TOM23, the translocation channel TOM40, and the translocase of inner membrane TIM23. Inside the mitochondrial matrix, PINK1 is cleaved by a mitochondrial processing peptidase (MPP) and a rhomboid protease, PARL . The cleaved PINK1 is then re‐transported into the cytosol and degraded by the ubiquitin (Ub) proteasome system (UPS) …”

“…Inside the mitochondrial matrix, PINK1 is cleaved by a mitochondrial processing peptidase (MPP) and a rhomboid protease, PARL . The cleaved PINK1 is then re‐transported into the cytosol and degraded by the ubiquitin (Ub) proteasome system (UPS) …”

“…Inside the mitochondrial matrix, PINK1 is cleaved by a mitochondrial processing peptidase (MPP) and a rhomboid protease, PARL. [170][171][172] The cleaved PINK1 is then re-transported into the cytosol and degraded by the ubiquitin (Ub) proteasome system (UPS). 171 When PINK1 transport through TOM is hindered, for instance by a depolarized mitochondria membrane potential (MMP), it and Ser402.…”

Unraveling PINK1 regulation: Ubiquitination of its mature form and insights for Parkinson's disease

“…Liu and colleagues studied this question and provided several important insights. They first confirmed PINK1 to be an outer mitochondrial membrane protein, which is often ubiquitinated in healthy mitochondria.…”

“…Using computational analysis, the authors proposed that preferential ubiquitination of mature PINK1 at K137 was because of conformational changes induced by proteolytic cleavage of the full‐length form that disrupted the membrane‐spanning domain, as well as because of ensuing membrane‐protein rearrangements. These conformational changes exposed the K137 site for ubiquitination in mature, but not full‐length PINK1 …”