Gramd1c, also known as Aster-C, encodes an endoplasmic reticulum (ER) resident protein involved in non-vesicular cholesterol transport [1,4]. It plays a crucial role in maintaining cellular cholesterol distribution, with its functions related to autophagy, mitochondrial bioenergetics, and various disease-associated pathways [1-5].

In terms of autophagy, short-term cholesterol depletion rapidly induces autophagy, and GRAMD1C functions as a negative regulator of starvation-induced autophagy. Both its cholesterol-transporting VASt domain and membrane-binding GRAM domain are required for this suppression [2]. In addition, cells lacking GRAMD1C show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting its role in facilitating cholesterol transfer at ER-mitochondria contact sites [2].

In mice globally lacking Aster-C (Gramd1c-/ -), there are no significant alterations in fecal, liver, or plasma cholesterol under different dietary cholesterol conditions, indicating a minor role in whole-body cholesterol balance [4]. In Parkinson's disease, GRAMD1C is upregulated, and knocking down its expression reduces 6-OHDA-induced apoptosis in PC12 cells, suggesting its involvement in the apoptotic pathway of the disease [3].

In conclusion, GRAMD1C is an important regulator in cellular cholesterol-related processes, autophagy, and mitochondrial bioenergetics. The study of GRAMD1C knockout mouse models has provided insights into its functions, revealing its potential significance in diseases such as Parkinson's disease and in understanding whole-body cholesterol balance [2,3,4].