Cellular cholesterol transport links kidney cancer and autophagy

A study entitled 'The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics' by Matthew Yoke Wui Ng and colleagues from the Simonsen Lab at the Institute of Basic Medical Sciences and the Center for Cancer Cell Reprogramming, was recently published in Nature Communications. This study addresses the role of cholesterol in regulation of autophagy and explores how autophagy might be linked to a type of kidney cancer called Clear Cell Renal Carcinoma (ccRCC).

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Matthew Yoke Wui Ng and Chara Charsou, lead authors on this publication

 

Autophagy is an evolutionary conserved process by which cells break down components of itself to maintain homeostasis. This process is especially prominent in cells under stress and nutrient deprived conditions. Autophagy involves the formation of membrane bound vesicles called autophagosomes, which engulf cargo to be decomposed and transport it to the lysosomes where breakdown occurs. Dysfunctional autophagy, and its dysregulation, has been linked to severe human disorders such as cancer and neurodegeneration, thus highlighting the importance of understanding how the process is regulated.

In their study, Ng and coworkers identified the cholesterol transport protein GRAMD1C as a negative regulator of autophagy and mitochondrial bioenergetics. Interestingly, high expression of GRAMD1C and other proteins of the GRAMD1 family were found to correlate with better overall survival of ccRCC patients. Furthermore, GRAMD1C expression was decreased in advanced stage tumours. ccRCC is characterized by accumulation of cholesterol in mitochondria, the powerhouse of cells, and altered mitochondrial function that affects cellular energy. However , the functional significance of cholesterol accumulation in ccRCC cells remains unknown.

This study showed that when GRAMD1C is removed from cells, cholesterol accumulates in mitochondria and is not transported to the endomembrane network (endoplasmic reticulum, ER) from where autophagosomes are formed. Lack of cholesterol at the ER was found to promote the formation of autophagosomes and thus autophagy. This was confirmed by short term treatment of cells with a commonly used drug (MBCD) to deplete cholesterol, which resulted in a rapid induction of autophagy. Further experiments showed that cholesterol depletion promoted the membrane bending needed for recruitment of the early autophagy machinery components to autophagosome initiation sites in the ER.

Thus, the correlation between low GRAMD1C expression levels and reduced overall survival of ccRCC patients might be explained by increased autophagy levels. The role of autophagy in cancer development is however highly complex, as autophagy can both protect healthy cells against malignant transformation and promote tumor cell survival under certain conditions, such as hypoxic stress and chemotherapy. The correlation between GRAMD1C expression levels, autophagy and ccRCC patient overall survival is likely more complex than changes to autophagy but underlines the importance of cholesterol transport proteins in autophagy and mitochondrial bioenergetics.The Simonsen Lab aims to further explore how regulation of membrane cholesterol during autophagosome biogenesis is linked to cancer development.

Further readings -

The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics

GRAMD1C-mediated cholesterol transport regulates autophagosome biogenesis and mitochondrial bioenergetics

 

 

 

Published Nov. 8, 2022 5:15 PM - Last modified Nov. 9, 2022 7:41 AM