Proteins Involved in Mitochondrial Cholesterol Transport

Abstract Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.

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Evolutionary Origin of the Mitochondrial Cholesterol Transport Machinery Reveals a Universal Mechanism of Steroid Hormone Biosynthesis in Animals

PLoS ONE ◽

10.1371/journal.pone.0076701 ◽

2013 ◽

Vol 8 (10) ◽

pp. e76701 ◽

Cited By ~ 33

Author(s):

Jinjiang Fan ◽

Vassilios Papadopoulos

Keyword(s):

Steroid Hormone ◽

Evolutionary Origin ◽

Cholesterol Transport ◽

Steroid Hormone Biosynthesis ◽

Hormone Biosynthesis ◽

Mitochondrial Cholesterol ◽

Universal Mechanism

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

10.1101/2021.08.04.455032 ◽

2021 ◽

Author(s):

Matthew Yoke Wui Ng ◽

Chara Charsou ◽

Ana Sofia Da Silva Lapao ◽

Sakshi Singh ◽

Laura Trachsel-Moncho ◽

...

Keyword(s):

Renal Carcinoma ◽

Membrane Vesicles ◽

Negative Regulator ◽

Cholesterol Transport ◽

Cholesterol Depletion ◽

Mitochondrial Bioenergetics ◽

Rapid Induction ◽

Cell Renal Carcinoma ◽

Mitochondrial Cholesterol

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.

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BPA interferes with StAR-mediated mitochondrial cholesterol transport to induce germline dysfunctions

Reproductive Toxicology ◽

10.1016/j.reprotox.2019.08.001 ◽

2019 ◽

Vol 90 ◽

pp. 24-32 ◽

Cited By ~ 3

Author(s):

Yichang Chen ◽

Blake Panter ◽

Aleena Hussain ◽

Katherine Gibbs ◽

Daniel Ferreira ◽

...

Keyword(s):

Cholesterol Transport ◽

Mitochondrial Cholesterol

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Estrogen-Mediated Mitochondrial Cholesterol Transport and Metabolism to Pregnenolone in the Rabbit Luteinized Ovary1

Biology of Reproduction ◽

10.1095/biolreprod57.2.360 ◽

1997 ◽

Vol 57 (2) ◽

pp. 360-366 ◽

Cited By ~ 5

Author(s):

Steven J. Cok ◽

Rick V. Hay ◽

John A. Holt

Keyword(s):

Cholesterol Transport ◽

Mitochondrial Cholesterol

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Mitochondrial cholesterol transport: A possible target in the management of hyperlipidemia

Lipids ◽

10.1007/s11745-005-1491-0 ◽

2005 ◽

Vol 40 (12) ◽

pp. 1237-1244 ◽

Cited By ~ 4

Author(s):

E. A. Hall ◽

S. Ren ◽

P. B. Hylemon ◽

K. Redford ◽

A. del Castillo ◽

...

Keyword(s):

Cholesterol Transport ◽

Mitochondrial Cholesterol

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Translocator protein: pharmacology and steroidogenesis

Biochemical Society Transactions ◽

10.1042/bst20150061 ◽

2015 ◽

Vol 43 (4) ◽

pp. 572-578 ◽

Cited By ~ 26

Author(s):

Andrew Midzak ◽

Barry Zirkin ◽

Vassilios Papadopoulos

Keyword(s):

Drug Binding ◽

Translocator Protein ◽

Biological Research ◽

Cholesterol Transport ◽

Steroid Biosynthesis ◽

Steroid Production ◽

Steroid Synthesis ◽

Binding Partners ◽

Evolutionarily Conserved ◽

Mitochondrial Cholesterol

The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis.

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