Mitochondrial SUMOylation as a critical regulator of proliferation and death (349.3)

Abstract

In our search for the mechanisms that regulate mitochondrial division, we uncovered a role for SUMOylation as a post‐translational modification that regulates the activity of the fission GTPase Drp1. Although we first documented the SUMOylation of Drp1 in the activation of mitochondrial fission, there are a large number of uncharacterized SUMOylated substrates on the mitochondria. To better understand the global impact of mitochondrial SUMOylation, we identified a mitochondrial anchored SUMO E3 ligase called MAPL (mitochondrial anchored protein ligase, also called MULAN/MUL1), and SenP5, a protease that acts upon mitochondrial substrates. We previously showed that SUMOylation on the mitochondria is stabilized during cell death, and is lost during mitosis. The mitotic loss is due, at least in part, to the recruitment of SenP5 to the mitochondrial during the G2/M transition. To examine the role of mitochondrial SUMOylation in vivo, we generated a MAPL knock‐out mouse strain, which provides further evidence for a global role of mitochondrial SUMOylation in the regulation of cell survival and proliferation. These mice present with increased proliferation within the gut, resulting in a lean phenotype due to nutrient maladsorption. After 12 months, nearly 90% of the MAPL KO animals develop hepatocellular carcinoma. Combined with an analysis of the human tumor samples, our data strongly implicate MAPL as a novel mitochondrial tumor suppressor. We will discuss these data, highlighting the importance of mitochondrial SUMOylation as a critical regulator of signaling from the mitochondria.