A ubiquitin-dependent mitophagy complex maintains mitochondrial function and insulin secretion in beta cells.

Mitochondrial autophagy or mitophagy is a key component of mitochondrial quality control, which is necessary to maintain cellular bioenergetics. Pancreatic islet β-cells, which release insulin in response to circulating blood glucose levels, are particularly susceptible to mitochondrial dysfunction due to their high metabolic activity and energy requirements for insulin processing, maturation, and secretion. Therefore, dysregulated mitophagy has drawn interest in the etiology of β-cell failure in diabetes. We demonstrate that the pivotal β-cell mitophagy regulator, CLEC16A, is an E3 ligase that forms a ubiquitin-dependent tripartite complex with RNF41/NRDP1 and USP8. Maintenance of the CLEC16A-RNF41-USP8 mitophagy complex is necessary for maximal cellular respiration and insulin secretion. Further, we observe that diabetogenic metabolic stressors, including elevated glucose and fatty acids, destabilize the CLEC16A-RNF41-USP8 complex and lead to β-cell apoptosis. Thus, the β-cell mitophagy pathway requires ubiquitin signals to stabilize the CLEC16A-RNF41-USP8 complex and maintain mitochondrial quality control.