Figure 1. The emerging role for parkin and PINK1 in mitochondrial dynamics and homeostasis.

A. Mounting evidence suggests that parkin operates downstream of PINK1 in a common pathway to regulate mitochondrial dynamics. In many cells, it appears to promote fission and/or inhibit fusion, though fission/fusion regulatory effects may differ by cell type or cellular environment. Such regulation may involve parkin-mediated regulation of mitochondrial fission/fusion machinery, either directly or indirectly, as through protein ubiquitination. Regulation may also involve some as yet unidentified parkin-mediated regulatory or protein-interaction pathway. B. How and through what pathway PINK1 and parkin interact is not known. The specific localization of both proteins is subject to controversy. Given current evidence, PINK1 may directly interact with and recruit parkin either, i. at the mitochondrial outer membrane, ii. in the cytosol, following cleavage and/or translocation of PINK1 out of the mitochondria, or iii. within the mitochondria. Alternatively, PINK1 may act through an intermediary (grey circles) to modify and/or recruit parkin to the mitochondria. PINK1 was also shown to directly phosphorylate cytosolic parkin, recruiting it to the mitochondria (blue pathways). However, where and how parkin exerts its effects on the mitochondria, whether inside the mitochondria, at the surface, or by interacting with surface proteins (pink ovoid), is unknown. C. Parkin was recently shown to localize to depolarized mitochondria, targeting them for mitophagy. The signals that target parkin to the damaged mitochondria, however, are not known. Whether this pathway is related to the fission/fusion regulatory functions of the PINK1/parkin pathway is also not known, though mitochondrial fission was previously shown to be an apparent prerequisite for mitophagy. See text for related references. ims = intermembrane space