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Trends in Endocrinology and Metabolism:... Apr 2021Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS)... (Review)
Review
Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target.
Topics: Cardiolipins; Central Nervous System; Humans; Mitochondria; Neurodegenerative Diseases; Neurons
PubMed: 33640250
DOI: 10.1016/j.tem.2021.01.006 -
Hepatology (Baltimore, Md.) Jun 2022Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of...
BACKGROUND AND AIMS
Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC).
APPROACH AND RESULTS
Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio-resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling-mediated translational control of hypoxia inducible factor-1α (HIF-1α) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients.
CONCLUSIONS
We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.
Topics: Carcinoma, Hepatocellular; Cardiolipins; Cell Line, Tumor; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Radiation Tolerance; Sterol Regulatory Element Binding Protein 1
PubMed: 34580888
DOI: 10.1002/hep.32177 -
Nature Aug 2023Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical...
Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
Topics: Humans; Biocatalysis; Cardiolipins; GTP Phosphohydrolases; Membrane Fusion; Mitochondria; Mitochondrial Membranes; Mutation; Protein Domains; Protein Multimerization; Mitochondrial Dynamics
PubMed: 37612504
DOI: 10.1038/s41586-023-06441-6 -
Trends in Cell Biology Jan 2018Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids.... (Review)
Review
Membrane organelles comprise both proteins and lipids. Remodeling of these membrane structures is controlled by interactions between specific proteins and lipids. Mitochondrial structure and function depend on regulated fusion and the division of both the outer and inner membranes. Here we discuss recent advances in the regulation of mitochondrial dynamics by two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL). These two lipids interact with the core components of mitochondrial fusion and division (Opa1, mitofusin, and Drp1) to activate and inhibit these dynamin-related GTPases. Moreover, lipid-modifying enzymes such as phospholipases and lipid phosphatases may organize local lipid composition to spatially and temporarily coordinate a balance between fusion and division to establish mitochondrial morphology.
Topics: Cardiolipins; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Membranes; Mitochondrial Proteins; Phosphatidic Acids
PubMed: 28911913
DOI: 10.1016/j.tcb.2017.08.011 -
Oxidative Medicine and Cellular... 2019Chronic kidney disease (CKD) is highly incident and prevalent in the world. The death of patients with CKD is primarily due to cardiovascular disease. Renal... (Review)
Review
Chronic kidney disease (CKD) is highly incident and prevalent in the world. The death of patients with CKD is primarily due to cardiovascular disease. Renal transplantation (RT) emerges as the best management alternative for patients with CKD. However, the incidence of acute renal graft dysfunction is 11.8% of the related living donor and 17.4% of the cadaveric donor. Anticardiolipin antibodies (ACAs) or antiphospholipid antibodies (APAs) are important risk factors for acute renal graft dysfunction. The determination of ACA or APA to candidates for RT could serve as prognostic markers of early graft failure and would indicate which patients could benefit from anticoagulant therapy. Cardiolipin is a fundamental molecule that plays an important role in the adequate conformation of the mitochondrial cristae and the correct assembly of the mitochondrial respiratory supercomplexes and other proteins essential for proper mitochondrial function. Cardiolipin undergoes a nonrandom oxidation process by having pronounced specificity unrelated to the polyunsaturation pattern of its acyl groups. Accumulation of hydroxyl derivatives and cardiolipin hydroperoxides has been observed in the affected tissues, and recent studies showed that oxidation of cardiolipin is carried out by a cardiolipin-specific peroxidase activity of cardiolipin-bound cytochrome c. Cardiolipin could be responsible for the proapoptotic production of death signals. Cardiolipin modulates the production of energy and participates in inflammation, mitophagy, and cellular apoptosis. The determination of cardiolipin or its antibodies is an attractive therapeutic, diagnostic target in RT and kidney diseases.
Topics: Antibodies; Cardiolipins; Graft Rejection; Humans; Kidney Transplantation; Mitochondria; Mitophagy; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors
PubMed: 31885786
DOI: 10.1155/2019/3836186 -
Cells Jul 2021The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and... (Review)
Review
The present review is an attempt to conceptualize a contemporary understanding about the roles that cardiolipin, a mitochondrial specific conical phospholipid, and non-bilayer structures, predominantly found in the inner mitochondrial membrane (IMM), play in mitochondrial bioenergetics. This review outlines the link between changes in mitochondrial cardiolipin concentration and changes in mitochondrial bioenergetics, including changes in the IMM curvature and surface area, cristae density and architecture, efficiency of electron transport chain (ETC), interaction of ETC proteins, oligomerization of respiratory complexes, and mitochondrial ATP production. A relationship between cardiolipin decline in IMM and mitochondrial dysfunction leading to various diseases, including cardiovascular diseases, is thoroughly presented. Particular attention is paid to the targeting of cardiolipin by Szeto-Schiller tetrapeptides, which leads to rejuvenation of important mitochondrial activities in dysfunctional and aging mitochondria. The role of cardiolipin in triggering non-bilayer structures and the functional roles of non-bilayer structures in energy-converting membranes are reviewed. The latest studies on non-bilayer structures induced by cobra venom peptides are examined in model and mitochondrial membranes, including studies on how non-bilayer structures modulate mitochondrial activities. A mechanism by which non-bilayer compartments are formed in the apex of cristae and by which non-bilayer compartments facilitate ATP synthase dimerization and ATP production is also presented.
Topics: Animals; Cardiolipins; Cardiovascular Diseases; Energy Metabolism; Humans; Lipid Bilayers; Mitochondria; Mitochondrial Membranes
PubMed: 34359891
DOI: 10.3390/cells10071721 -
Current Opinion in Microbiology Aug 2023The formation of lateral microdomains is emerging as a central organizing principle in bacterial membranes. These microdomains are targets of antibiotic development and... (Review)
Review
The formation of lateral microdomains is emerging as a central organizing principle in bacterial membranes. These microdomains are targets of antibiotic development and have the potential to enhance natural product synthesis, but the rules governing their assembly are unclear. Previous studies have suggested that microdomain formation is promoted by lipid phase separation, particularly by cardiolipin (CL) and isoprenoid lipids, and there is strong evidence that CL biosynthesis is required for recruitment of membrane proteins to cell poles and division sites. New work demonstrates that additional bacterial lipids may mediate membrane protein localization and function, opening the field for mechanistic evaluation of lipid-driven membrane organization in vivo.
Topics: Membrane Proteins; Membranes; Bacteria; Cardiolipins; Biophysics; Cell Membrane
PubMed: 37058914
DOI: 10.1016/j.mib.2023.102315 -
Biochimica Et Biophysica Acta.... Jan 2017Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor... (Review)
Review
Among mitochondrial lipids, cardiolipin occupies a unique place. It is the only phospholipid that is specific to mitochondria and although it is merely a minor component, accounting for 10-20% of the total phospholipid content, cardiolipin plays an important role in the molecular organization, and thus the function of the cristae. This review covers the formation of cardiolipin, a phospholipid dimer containing two phosphatidyl residues, and its assembly into mitochondrial membranes. While a large body of literature exists on this topic, the review focuses on papers that appeared in the past three years. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Topics: Animals; Cardiolipins; Humans; Mitochondria; Mitochondrial Membranes; Phospholipids; Protein Biosynthesis
PubMed: 27556952
DOI: 10.1016/j.bbalip.2016.08.010 -
Trends in Biochemical Sciences Jan 2012Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP... (Review)
Review
Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is important for a diverse range of mitochondrial activities beyond the process of ATP production. Thus not surprisingly, derangements in cardiolipin metabolism are now appreciated to contribute to an assortment of pathological conditions. A comprehensive inventory of enzymes involved in cardiolipin biosynthesis and remodeling was just recently obtained. Post-biosynthesis, the acyl chain composition of cardiolipin is modified by up to three distinct remodeling enzymes that produce either a homogeneous tissue-specific mature form of cardiolipin or alternatively 'bad' cardiolipin that has been linked to mitochondrial dysfunction. In this review, we initially focus on the newly identified players in cardiolipin metabolism and then shift our attention to how changes in cardiolipin metabolism contribute to human disease.
Topics: Cardiolipins; Disease; Enzymes; Health Status; Humans
PubMed: 22014644
DOI: 10.1016/j.tibs.2011.09.003 -
The Journal of Histochemistry and... May 2015Cardiolipin (CL) is a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane (IMM) in eukaryotic cells. Two chiral carbons and... (Review)
Review
Cardiolipin (CL) is a unique dimeric phospholipid that exists almost exclusively in the inner mitochondrial membrane (IMM) in eukaryotic cells. Two chiral carbons and four fatty acyl chains in CL result in a flexible body allowing interactions with respiratory chain complexes and mitochondrial substrate carriers. Due to its high content of unsaturated fatty acids, CL is particularly prone to reactive oxygen species (ROS)-induced oxidative attacks. Under mild mitochondrial damage, CL is redistributed to the outer mitochondrial membrane (OMM) and serves as a recognition signal for dysfunctional mitochondria, which are rapidly sequestered by autophagosomes. However, peroxidation of CL is far greater in response to severe stress than under normal or mild-damage conditions. The accumulation of oxidized CL on the OMM results in recruitment of Bax and formation of the mitochondrial permeability transition pore (MPTP), which releases Cytochrome c (Cyt c) from mitochondria. Over the past decade, the significance of CL in the function of mitochondrial bioenergy has been explored. Moreover, approaches to analyzing CL have become more effective and accurate. In this review, we discuss the unique structural features of CL as well as the current understanding of CL-based molecular mechanisms of mitophagy and apoptosis.
Topics: Animals; Apoptosis; Autophagy; Cardiolipins; Humans; Mitochondria; Mitophagy; Oxidation-Reduction; Protein Transport
PubMed: 25673287
DOI: 10.1369/0022155415574818