Mitochondrial quality control by the Pink1/Parkin system

Abstract

Mitochondrial dysfunction represents a prominent pathological feature in many neurodegenerative diseases, particularly in Parkinson's disease (PD). Mutations in the genes encoding the proteins Pink1 and Parkin have been identified as genetic risk factors in familiar cases of PD. Research during the last decade has identified both proteins as crucial components of an organellar quality control system that contributes to the maintenance of mitochondrial function in healthy cells. The Pink1/Parkin system acts as a sensor for mitochondrial quality and is activated, in particular, after the loss of the electric potential across the inner mitochondrial membrane. Pink1 molecules accumulate at the surface of damaged mitochondria to recruit and activate Parkin, which, in turn, elicits a signaling pathway eventually leading to the autophagic removal of the damaged organelles. This review summarizes recent advances in our knowledge of the functional role of the Pink1/Parkin system in preventing the accumulation of damaged mitochondria by mitophagy.

Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import

“…This generates an N-terminal degron motif, leading to rapid degradation of PINK1 in the cytosol by the ubiquitin proteasome system. Damaged mitochondria that cannot maintain ΔΨ fail to import PINK1 to the IMM, leading to accumulation of uncleaved PINK1 in the outer mitochondrial membrane (OMM), where it recruits and activates Parkin and triggers mitophagy 16 . Although the mitochondrial targeting signal of PINK1 reaches the mitochondrial matrix, it is not known whether the TIM23 complex is essential for PINK1 trans-location.…”

Notch1 provides myocardial protection by improving mitochondrial quality control

“…As a substrate for phosphorylation of Pink1, Mfn2 loses its ability to fusion with mitochondria and converts to Parkin receptor after being phosphorylated. After binding to Parkin, p‐Mfn2 is degraded by ubiquitination to prevent abnormal fusion to form unhealthy mitochondria, which facilitates the removal of the damaged mitochondria by mitophagy (Lee et al, ; Rub et al, ). Parkin‐mediated mitophagy attenuates if the Mfn2 expression is reduced in the myocardium (Cardenas et al, ).…”

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

“…With a decrease in ΔΨ m , Pink1 remains on the mitochondrial surface, where it phosphorylates a wide range of proteins, most notably Parkin and Ubiquitin. Phosphorylated Parkin in turn ubiquitinates proteins of the outer mitochondrial membrane, eventually resulting in LC3b mediated lysosomal phagophore formation and degradation (Kitagishi et al, 2017; Lazarou et al, 2015; Rub et al, 2017). …”