Figure 7.

Schematic model of the Clec16a-Nrdp1-USP8 mitophagy complex. A: Under physiologic conditions, Clec16a promotes nondegradative ubiquitination (Ub) of the E3 ligase Nrdp1 to facilitate complex formation between Clec16a, USP8, and Nrdp1. This complex functions to promote normal mitophagy initiation and balance mitochondrial quality control, which in turn leads to normal β-cell function and regulated insulin release. B: However, under conditions of impaired Clec16a function, such as pharmacologic inhibition by the chemotherapeutic lenalidomide or glucolipotoxicity, Clec16a-mediated Nrdp1 ubiquitination is inhibited and the Clec16a-USP8-Nrdp1 complex is destabilized. This leads to dysfunctional mitophagy, loss of mitophagic quality control, and dysregulated mitochondrial respiration, ultimately leading to compromised β-cell insulin release.