GRAMD1C promotes autophagy initiation and mitochondrial bioenergetics through regulation of ER-mitochondria cholesterol transport

During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The origin and identity of the membranes that from the autophagosome remain to be fully characterized. Here, we investigated the role of cholesterol in starvation-induced autophagy and identify a role for the ER-localized cholesterol transport protein GRAMD1C in the regulation of autophagy and mitochondrial function. We demonstrate first that cholesterol depletion leads to a rapid induction of autophagy, possibly caused by an increased abundance of curved autophagy membranes. We further show that GRAMD1C is a negative regulator of starvation-induced autophagy. Similar to its yeast orthologue, GRAMD1C is recruited to mitochondria through its GRAM domain. Additionally, we find that GRAMD1C is involved in mitochondrial cholesterol transfer and the regulation of mitochondrial bioenergetics. Finally, we demonstrate that the GRAM family are genes involved in clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.