Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL

TLDR

PINK1 is a mitochondrial kinase linked to familial Parkinson’s disease that functions with Parkin to mediate mitophagy, yet its sub‑mitochondrial localization remains unclear because it is rapidly degraded. The study investigates how the inner‑membrane protease PARL regulates PINK1 cleavage and stability in relation to mitochondrial membrane potential. Using biochemical assays, the authors showed that PARL cleaves PINK1 in a membrane‑potential–dependent manner, producing distinct mitochondrial forms. Loss of PARL prevents PINK1 degradation, yielding a stable 60‑kDa mitochondrial form, while loss of membrane potential causes accumulation of full‑length 63‑kDa PINK1 on the outer membrane to recruit Parkin, demonstrating that inner‑ versus outer‑membrane localization controls PINK1 stability and mitophagy signaling.

Abstract

PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson’s disease. It has been found to work in the same pathway as the E3 ligase Parkin in the maintenance of flight muscles and dopaminergic neurons in Drosophila melanogaster and to recruit cytosolic Parkin to mitochondria to mediate mitophagy in mammalian cells. Although PINK1 has a predicted mitochondrial import sequence, its cellular and submitochondrial localization remains unclear in part because it is rapidly degraded. In this study, we report that the mitochondrial inner membrane rhomboid protease presenilin-associated rhomboid-like protein (PARL) mediates cleavage of PINK1 dependent on mitochondrial membrane potential. In the absence of PARL, the constitutive degradation of PINK1 is inhibited, stabilizing a 60-kD form inside mitochondria. When mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form on the outer mitochondrial membrane, where it can recruit Parkin to impaired mitochondria. Thus, differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function.