E2 ubiquitin conjugase Bendless is essential for PINK1-Park activity to regulate Mitofusin under mitochondrial stress

Abstract Cells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen in Drosophila , we identify that mutations in lrpprc2 , a homolog of the human LRPPRC gene that is linked to the French-Canadian Leigh syndrome, results in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that in the case of lrpprc2 mutants, PINK1-Park regulates mitochondrial dynamics by inducing degradation of the mitochondrial fusion protein Mitofusin/Marf. We also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss of bendless results in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen in lrpprc2 . Additionally, we show that loss of Bendless in lrpprc2 mutant eye results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.