Mitochondrial cholesterol import

Elustondo, Pia A.; Martin, L. A.; Karten, Barbara

doi:10.1016/j.bbalip.2016.08.012

Cited by 117 publications

(112 citation statements)

References 237 publications

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“…Sterols, oxysterol, and bile acids are synthesized in mitochondria. These molecules originate from cholesterol that is imported into mitochondria from several sources: ER, LD, and endosomes (reviewed by Elustondo et al ). Here, we focus on cholesterol transport from the ER, which is performed by STARD1 .…”

Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 99%

Metabolic implications of organelle–mitochondria communication

2019

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Cellular organelles are not static but show dynamism—a property that is likely relevant for their function. In addition, they interact with other organelles in a highly dynamic manner. In this review, we analyze the proteins involved in the interaction between mitochondria and other cellular organelles, especially the endoplasmic reticulum, lipid droplets, and lysosomes. Recent results indicate that, on one hand, metabolic alterations perturb the interaction between mitochondria and other organelles, and, on the other hand, that deficiency in proteins involved in the tethering between mitochondria and the ER or in specific functions of the interaction leads to metabolic alterations in a variety of tissues. The interaction between organelles is an emerging field that will permit to identify key proteins, to delineate novel modulation pathways, and to elucidate their implications in human disease.

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Section: Contacts Between Mitochondria and Other Organellesmentioning

confidence: 99%

Metabolic implications of organelle–mitochondria communication

2019

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“…While the mitochondrial membrane has a lower CLR content (10%), there is a clear bias for CLR in the outer mitochondrial membrane. Trafficking CLR to the inner mitochondrial membrane is in fact the rate-limiting step in the steroidogenesis biosynthesis pathway (15). CLR has often been studied in conjunction with membrane dynamics.…”

Section: Introductionmentioning

confidence: 99%

Structural Determinants of Cholesterol Recognition in Helical Integral Membrane Proteins

Marlow

Meiler

Kuenze

et al. 2020

Preprint

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Cholesterol (CLR) is an integral component of mammalian membranes. It has been shown to modulate membrane dynamics and alter integral membrane protein (IMP) function. However, understanding the molecular mechanisms of these processes is complicated by limited and conflicting structural data: Specifically, in co-crystal structures of CLR-IMP complexes it is difficult to distinguish specific and biologically relevant CLR-IMP interactions from a nonspecific association captured by the crystallization process. The only widely recognized search algorithm for CLR-IMP interaction sites is sequence-based, i.e. searching for the so-called 'CRAC' or 'CARC' motifs. While these motifs are present in numerous IMPs, there is inconclusive evidence to support their necessity or sufficiency for CLR binding. Here we leverage the increasing number of experimental CLR-IMP structures to systematically analyze putative interaction sites based on their spatial arrangement and evolutionary conservation. From this analysis we create three-dimensional representations of general CLR interaction sites that form clusters across multiple IMP classes and classify them as being either specific or nonspecific. Information gleaned from our characterization will eventually enable a structurebased approach for prediction and design of CLR-IMP interaction sites. SIGNIFICANCE CLR plays an important role in composition and function of membranes and often surrounds and interacts with IMPs. It is a daunting challenge to disentangle CLRs dual roles as a direct modulator of IMP function through binding or indirect actor as a modulator of membrane plasticity. Only recently studies have delved into characterizing specific CLR-IMP interactions. We build on this previous work by using a combination of structural and evolutionary characteristics to distinguish specific from nonspecific CLR interaction sites. Understanding how CLR interacts with IMPs will underpin future development towards detecting and engineering CLR-IMP interaction sites.

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“…130,133 STARD3 has been proposed to receive endosomal cholesterol from NPC2 bypassing NPC1 and deliver the molecule directly to the mitochondria in a nonvesicular pathway without passing through the PM or ER. 130,133 This STARD3-mediated cholesterol trafficking represents one of many mitochondrial import pathways 128,134 and is largely dispensable for lipid metabolism under physiological conditions. 135 However, in NPC1 disease where cholesterol levels in LEs/LYs are high, cholesterol transport by STARD3 elevates mitochondrial cholesterol levels, 130,136,137 which in turn exacerbates NPC1 phenotype due to increased oxidative stress and neurotoxicity.…”

Section: Cholesterol Transport From Les/lys To Mitochondriamentioning

confidence: 99%

Routes and mechanisms of post‐endosomal cholesterol trafficking: A story that never ends

Luo

Jiang

Yang

et al. 2017

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Mammalian cells acquire most exogenous cholesterol through receptor-mediated endocytosis of low-density lipoproteins (LDLs). After internalization, LDL cholesteryl esters are hydrolyzed to release free cholesterol, which then translocates to late endosomes (LEs)/lysosomes (LYs) and incorporates into the membranes by co-ordinated actions of Niemann-Pick type C (NPC) 1 and NPC2 proteins. However, how cholesterol exits LEs/LYs and moves to other organelles remain largely unclear. Growing evidence has suggested that nonvesicular transport is critically involved in the post-endosomal cholesterol trafficking. Numerous sterol-transfer proteins (STPs) have been identified to mediate directional cholesterol transfer at membrane contact sites (MCSs) formed between 2 closely apposed organelles. In addition, a recent study reveals that lysosome-peroxisome membrane contact (LPMC) established by a non-STP synaptotagmin VII and a specific phospholipid phosphatidylinositol 4,5-bisphosphate also serves as a novel and important path for LDL-cholesterol trafficking. These findings highlight an essential role of MCSs in intracellular cholesterol transport, and further work is needed to unveil how various routes are regulated and integrated to maintain proper cholesterol distribution and homeostasis in eukaryotic cells.

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Mitochondrial cholesterol import

Cited by 117 publications

References 237 publications

Metabolic implications of organelle–mitochondria communication

Metabolic implications of organelle–mitochondria communication

Structural Determinants of Cholesterol Recognition in Helical Integral Membrane Proteins

Routes and mechanisms of post‐endosomal cholesterol trafficking: A story that never ends

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