The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics

Matthew Yoke Wui Ng, Chara Charsou, Ana Lapao, Sakshi Singh, Laura Trachsel-Moncho, Sebastian W. Schultz, Sigve Nakken, Michael J. Munson and Anne Simonsen ()
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Matthew Yoke Wui Ng: University of Oslo
Chara Charsou: University of Oslo
Ana Lapao: University of Oslo
Sakshi Singh: University of Oslo
Laura Trachsel-Moncho: University of Oslo
Sebastian W. Schultz: University of Oslo
Sigve Nakken: University of Oslo
Michael J. Munson: University of Oslo
Anne Simonsen: University of Oslo

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

Date: 2022
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DOI: 10.1038/s41467-022-33933-2

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