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Mitochondrial homeostasis is tightly controlled by ubiquitination. The mitochondrial integral membrane ubiquitin ligase MARCH5 is a crucial regulator of mitochondrial membrane fission, fusion, and disposal through mitophagy. In addition, the lipid composition of mitochondrial membranes can determine mitochondrial dynamics and organelle turnover. However, how lipids influence the ubiquitination processes that control mitochondrial homeostasis remains unknown. Here, we show that lipids common to the mitochondrial membranes interact with MARCH5 and affect its activity and stability depending on the lipid composition in vitro. As the only one of the tested lipids, cardiolipin binding to purified MARCH5 induces a significant decrease in thermal stability, whereas stabilisation increases the strongest in the presence of phosphatidic acid. Furthermore, we observe that the addition of lipids to purified MARCH5 alters the ubiquitination pattern. Specifically, cardiolipin enhances auto-ubiquitination of MARCH5. Our work shows that lipids can directly affect the activity of ubiquitin ligases and suggests that the lipid composition in mitochondrial membranes could control ubiquitination-dependent mechanisms that regulate the dynamics and turnover of mitochondria.

Phospholipids alter activity and stability of mitochondrial membrane-bound ubiquitin ligase MARCH5