Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai, Rajesh K.; Campanella, Michelangelo

doi:10.1111/bph.14697

Cited by 6 publications

(5 citation statements)

References 70 publications

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“…In addition to ACBD3, ACBD1 and ACBD2 are also mitochondrial proteins. ACBD1 was discussed previously as a part of the multiprotein complex transporting cholesterol into mitochondria [ 28 , 29 , 30 , 31 ], but unlike ACBD3, its role was not described in detail. In C6-2B glioma cells, an ACBD1-dependent formation of mitochondrial pregnenolone was described [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

Danhelovska

Zdrazilova

Stufkova

et al. 2021

IJMS

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The Acyl-CoA-binding domain-containing protein (ACBD3) plays multiple roles across the cell. Although generally associated with the Golgi apparatus, it operates also in mitochondria. In steroidogenic cells, ACBD3 is an important part of a multiprotein complex transporting cholesterol into mitochondria. Balance in mitochondrial cholesterol is essential for proper mitochondrial protein biosynthesis, among others. We generated ACBD3 knock-out (ACBD3-KO) HEK293 and HeLa cells and characterized the impact of protein absence on mitochondria, Golgi, and lipid profile. In ACBD3-KO cells, cholesterol level and mitochondrial structure and functions are not altered, demonstrating that an alternative pathway of cholesterol transport into mitochondria exists. However, ACBD3-KO cells exhibit enlarged Golgi area with absence of stacks and ribbon-like formation, confirming the importance of ACBD3 in Golgi stacking. The glycosylation of the LAMP2 glycoprotein was not affected by the altered Golgi structure. Moreover, decreased sphingomyelins together with normal ceramides and sphingomyelin synthase activity reveal the importance of ACBD3 in ceramide transport from ER to Golgi.

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Section: Discussionmentioning

confidence: 99%

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

Danhelovska

Zdrazilova

Stufkova

et al. 2021

IJMS

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“…CoQ-synthome and mitochondrial machinery organization could also be affected by a disruption of intracellular cholesterol trafficking towards mitochondria. In fact, an elevated mitochondrial cholesterol level has been detected in several mitochondrial pathological conditions, including Niemann-Pick Type C1-deficiency (NPC) [ 141 ], steatohepatitis [ 140 ], and Alzheimer’s disease [ 139 ]. A study using in vitro and in vivo models of mitochondrial cholesterol enrichment displayed an impairment in oxidative phosphorylation and respiratory supercomplex assembly.…”

Section: Coq Deficiency Syndromementioning

confidence: 99%

“…A study using in vitro and in vivo models of mitochondrial cholesterol enrichment displayed an impairment in oxidative phosphorylation and respiratory supercomplex assembly. This effect is due to the dysregulation of the enzyme in cholesterol synthesis 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMG-CoAR), which may down-regulate the mevalonate pathway and CoQ synthesis [ 139 ]. Furthermore, mitochondrial cholesterol trafficking is controlled by proteins such as STAR and MLN64, among others.…”

Section: Coq Deficiency Syndromementioning

confidence: 99%

Coenzyme Q at the Hinge of Health and Metabolic Diseases

et al. 2021

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Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.

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“…The insertion of cholesterol into the membrane lends rigidity and promotes the formation of protein-tethering platforms, such as lipid rafts [30,97]. In the mitochondria, cholesterol plays a number of major roles, some are as follows [104]: (a) a structural component of the OMM and IMM, providing the appropriate fluidity, curvature and biophysical properties; (b) a precursor of steroidogenesis, by which cholesterol is converted to biologically active steroid hormones, with the first biochemical reactions taking place in the mitochondrial matrix [105]; (c) the core of membrane platforms interacting with the ER, lysosomes and other vesicles or intracellular compartments; and (d) a tethering element for mitochondrial DNA.…”

Section: Cholesterol Transport To Mitochondriamentioning

confidence: 99%

Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine

Mollinedo

Gajate

2021

Pharmaceutics

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The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the FO sector of the F1FO–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy.

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Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Cited by 6 publications

References 70 publications

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

Knock-Out of ACBD3 Leads to Dispersed Golgi Structure, but Unaffected Mitochondrial Functions in HEK293 and HeLa Cells

Coenzyme Q at the Hinge of Health and Metabolic Diseases

Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine

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