scholarly journals Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 728 ◽  
Author(s):  
Giuseppe Paradies ◽  
Valeria Paradies ◽  
Francesca M. Ruggiero ◽  
Giuseppe Petrosillo
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Protein Import ◽  
Building Blocks ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Membrane Morphology ◽  
Transport Chain ◽  
Health And Disease

In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.

scholarly journals Cardiolipin, Non-Bilayer Structures and Mitochondrial Bioenergetics: Relevance to Cardiovascular Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1721
Author(s):  
Edward S. Gasanoff ◽  
Lev S. Yaguzhinsky ◽  
Győző Garab
Keyword(s):  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Mitochondrial Bioenergetics ◽  
Mitochondrial Membranes ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Functional Roles ◽  
Transport Chain ◽  
Energy Converting

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.

scholarly journals Physiological and pathological roles of mitochondrial SLC25 carriers

2013 ◽  
Vol 454 (3) ◽  
pp. 371-386 ◽  
Author(s):  
Manuel Gutiérrez-Aguilar ◽  
Christopher P. Baines
Keyword(s):  
Mitochondrial Membrane ◽  
Current Knowledge ◽  
Transmembrane Helix ◽  
Building Blocks ◽  
Proper Function ◽  
Inner Mitochondrial Membrane ◽  
Health And Disease ◽  
Metabolic Reactions ◽  
Solute Carrier

The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane-helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease.

scholarly journals Mitochondrial protein interaction landscape of SS-31

2019 ◽  
Author(s):  
Juan D. Chavez ◽  
Xiaoting Tang ◽  
Matthew D. Campbell ◽  
Gustavo Reyes ◽  
Philip A. Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Interaction ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Cross Linking ◽  
Pharmacological Effects ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Mechanistic Insight ◽  
Chemical Cross Linking

AbstractMitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

Study of the anti-angiogenic effects of cardiolipin by the aortic ring assay

2015 ◽  
Vol 93 (11) ◽  
pp. 1015-1019 ◽  
Author(s):  
Matthew L. Carnevale ◽  
Andreas Bergdahl
Keyword(s):  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Aortic Ring ◽  
Cell Types ◽  
Inner Mitochondrial Membrane ◽  
Transport Chain ◽  
Aortic Ring Assay ◽  
Cervical Dislocation ◽  
Sprout Growth

Cardiolipin (CL), a phospholipid found in the inner mitochondrial membrane in all cell types, is critical for the function of the electron transport chain. The role of CL is not fully understood, but it is assumed that the molecule maintains membrane potential and architecture and compensates for alterations in homeostasis that could affect the energy metabolism. The objective of this project was to determine the effects of increasing CL concentrations on angiogenic sprouting by using the aortic ring assay model. For this, 5-day-old C57Bl/6 pups were euthanized by cervical dislocation prior to removal of the aortas. The vessels were cleaned, cut in 0.5 mm wide rings, and placed in a collagen growth matrix supplemented with CL. The results revealed a highly significant reduction of sprout growth (both length and quantity) at low, physiological concentrations. In conclusion, the results of this study demonstrate that CL significantly reduces microvessel formation and that it could potentially provide an interesting novel therapeutic target for angiogenesis.

scholarly journals Effect of rapamycin on mitochondria and lysosomes in fibroblasts from patients with mtDNA mutations

2021 ◽  
Author(s):  
Nashwa J. Cheema ◽  
Jessie M. Cameron ◽  
David A. Hood
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Current Treatment ◽  
Basal Respiration ◽  
Healthy Individuals ◽  
Cellular Mechanisms ◽  
Mtdna Mutations ◽  
Cultured Skin ◽  
Patient Cell

Maintaining mitochondrial function and dynamics is crucial for cellular health. In muscle, defects in mitochondria result in severe myopathies where accumulation of damaged mitochondria causes deterioration and dysfunction. Importantly, understanding the role of mitochondria in disease is a necessity to determine future therapeutics. One of the most common myopathies is mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), which has no current treatment. Recently, MELAS patients treated with rapamycin exhibited improved clinical outcomes. However, the cellular mechanisms of rapamycin effects in MELAS patients are currently unknown. In this study, we used cultured skin fibroblasts as a window into the mitochondrial dysfunction evident in MELAS cells, as well as to study the mechanisms of rapamycin action, compared to control, healthy individuals. We observed that mitochondria from patients were fragmented, had a 3-fold decline in the average speed of motility, a 2-fold reduced mitochondrial membrane potential and a 1.5-2-fold decline in basal respiration. Despite the reduction in mitochondrial function, mitochondrial import protein Tim23 was elevated in patient cell lines. MELAS fibroblasts exhibited increased MnSOD levels and lysosomal function when compared to healthy controls. Treatment of MELAS fibroblasts with rapamycin for 24 hrs resulted in increased mitochondrial respiration compared to control cells, a higher lysosome content, and a greater localization of mitochondria to lysosomes. Our studies suggest that rapamycin has the potential to improve cellular health even in the presence of mtDNA defects, primarily via an increase in lysosomal content.

Mitochondrial Ca2+ Buffering Regulates Synaptic Transmission Between Retinal Amacrine Cells

2002 ◽  
Vol 87 (3) ◽  
pp. 1426-1439 ◽  
Author(s):  
Kathryn Medler ◽  
Evanna L. Gleason
Keyword(s):  
Synaptic Transmission ◽  
Mitochondrial Membrane ◽  
Amacrine Cell ◽  
Critical Role ◽  
Amacrine Cells ◽  
Normal Function ◽  
Inner Mitochondrial Membrane ◽  
Physiological Properties ◽  
Low Levels

The diverse functions of retinal amacrine cells are reliant on the physiological properties of their synapses. Here we examine the role of mitochondria as Ca2+ buffering organelles in synaptic transmission between GABAergic amacrine cells. We used the protonophore p-trifluoromethoxy-phenylhydrazone (FCCP) to dissipate the membrane potential across the inner mitochondrial membrane that normally sustains the activity of the mitochondrial Ca2+ uniporter. Measurements of cytosolic Ca2+ levels reveal that prolonged depolarization-induced Ca2+ elevations measured at the cell body are altered by inhibition of mitochondrial Ca2+ uptake. Furthermore, an analysis of the ratio of Ca2+ efflux on the plasma membrane Na-Ca exchanger to influx through Ca2+ channels during voltage steps indicates that mitochondria can also buffer Ca2+ loads induced by relatively brief stimuli. Importantly, we also demonstrate that mitochondrial Ca2+ uptake operates at rest to help maintain low cytosolic Ca2+ levels. This aspect of mitochondrial Ca2+ buffering suggests that in amacrine cells, the normal function of Ca2+-dependent mechanisms would be contingent upon ongoing mitochondrial Ca2+ uptake. To test the role of mitochondrial Ca2+ buffering at amacrine cell synapses, we record from amacrine cells receiving GABAergic synaptic input. The Ca2+ elevations produced by inhibition of mitochondrial Ca2+uptake are localized and sufficient in magnitude to stimulate exocytosis, indicating that mitochondria help to maintain low levels of exocytosis at rest. However, we found that inhibition of mitochondrial Ca2+ uptake during evoked synaptic transmission results in a reduction in the charge transferred at the synapse. Recordings from isolated amacrine cells reveal that this is most likely due to the increase in the inactivation of presynaptic Ca2+ channels observed in the absence of mitochondrial Ca2+ buffering. These results demonstrate that mitochondrial Ca2+ buffering plays a critical role in the function of amacrine cell synapses.

scholarly journals Autophagy in unicellular eukaryotes

2010 ◽  
Vol 365 (1541) ◽  
pp. 819-830 ◽  
Author(s):  
Jan A. K. W. Kiel
Keyword(s):  
Molecular Mechanisms ◽  
Yeast Species ◽  
Developmental Change ◽  
Building Blocks ◽  
Extracellular Medium ◽  
New Host ◽  
Growth And Survival ◽  
Atp Production ◽  
Unicellular Eukaryotes

Cells need a constant supply of precursors to enable the production of macromolecules to sustain growth and survival. Unlike metazoans, unicellular eukaryotes depend exclusively on the extracellular medium for this supply. When environmental nutrients become depleted, existing cytoplasmic components will be catabolized by (macro)autophagy in order to re-use building blocks and to support ATP production. In many cases, autophagy takes care of cellular housekeeping to sustain cellular viability. Autophagy encompasses a multitude of related and often highly specific processes that are implicated in both biogenetic and catabolic processes. Recent data indicate that in some unicellular eukaryotes that undergo profound differentiation during their life cycle (e.g. kinetoplastid parasites and amoebes), autophagy is essential for the developmental change that allows the cell to adapt to a new host or form spores. This review summarizes the knowledge on the molecular mechanisms of autophagy as well as the cytoplasm-to-vacuole-targeting pathway, pexophagy, mitophagy, ER-phagy, ribophagy and piecemeal microautophagy of the nucleus, all highly selective forms of autophagy that have first been uncovered in yeast species. Additionally, a detailed analysis will be presented on the state of knowledge on autophagy in non-yeast unicellular eukaryotes with emphasis on the role of this process in differentiation.

scholarly journals Alignment of sarcoplasmic reticulum-mitochondrial junctions with mitochondrial contact points

2011 ◽  
Vol 301 (5) ◽  
pp. H1907-H1915 ◽  
Author(s):  
Cecília García-Pérez ◽  
Timothy G. Schneider ◽  
György Hajnóczky ◽  
György Csordás
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Mitochondrial Membrane ◽  
Inner Mitochondrial Membrane ◽  
Mitofusin 2 ◽  
Atp Production ◽  
Contact Points ◽  
Transmission Electron

Propagation of ryanodine receptor (RyR2)-derived Ca2+ signals to the mitochondrial matrix supports oxidative ATP production or facilitates mitochondrial apoptosis in cardiac muscle. Ca2+ transfer likely occurs locally at focal associations of the sarcoplasmic reticulum (SR) and mitochondria, which are secured by tethers. The outer mitochondrial membrane and inner mitochondrial membrane (OMM and IMM, respectively) also form tight focal contacts (contact points) that are enriched in voltage-dependent anion channels, the gates of OMM for Ca2+. Contact points could offer the shortest Ca2+ transfer route to the matrix; however, their alignment with the SR-OMM associations remains unclear. Here, in rat heart we have studied the distribution of mitochondria-associated SR in submitochondrial membrane fractions and evaluated the colocalization of SR-OMM associations with contact points using transmission electron microscopy. In a sucrose gradient designed for OMM purification, biochemical assays revealed lighter fractions enriched in OMM only and heavier fractions containing OMM, IMM, and SR markers. Pure OMM fractions were enriched in mitofusin 2, an ∼80 kDa mitochondrial fusion protein and SR-mitochondrial tether candidate, whereas in fractions of OMM + IMM + SR, a lighter (∼50 kDa) band detected by antibodies raised against the NH2 terminus of mitofusin 2 was dominating. Transmission electron microscopy revealed mandatory presence of contact points at the junctional SR-mitochondrial interface versus a random presence along matching SR-free OMM segments. For each SR-mitochondrial junction at least one tether was attached to contact points. These data establish the contact points as anchorage sites for the SR-mitochondrial physical coupling. Close coupling of the SR, OMM, and IMM is likely to provide a favorable spatial arrangement for local ryanodine receptor-mitochondrial Ca2+ signaling.

Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants

1996 ◽  
Vol 29 (2) ◽  
pp. 169-202 ◽  
Author(s):  
Vladimir P. Skulachev
Keyword(s):  
Resting State ◽  
Mitochondrial Membrane ◽  
High Rate ◽  
Oxygen Species ◽  
Inner Mitochondrial Membrane ◽  
Enzymatic Formation ◽  
Male Sex ◽  
Low Levels ◽  
Cellular Components

AbstractTo proceed at a high rate, phosphorylating respiration requires ADP to be available. In the resting state, when the energy consumption is low, the ADP concentration decreases so that phosphorylating respiration ceases. This may result in an increase in the intracellular concentrations of O2as well as of one-electron O2reductants such asThese two events should dramatically enhance non-enzymatic formation of reactive oxygen species, i.e. of, and OHׁ, and, hence, the probability of oxidative damage to cellular components. In this paper, a concept is put forward proposing that non-phosphorylating (uncoupled or non-coupled) respiration takes part in maintenance of low levels of both O2and the O2reductants when phosphorylating respiration fails to do this job due to lack of ADP.In particular, it is proposed that some increase in the H+leak of mitochondrial membrane in State 4 lowers, stimulates O2consumption and decreases the level ofwhich otherwise accumulates and serves as one-electron O2reductant. In this connection, the role of natural uncouplers (thyroid hormones), recouplers (male sex hormones and progesterone), non-specific pore in the inner mitochondrial membrane, and apoptosis, as well as of non-coupled electron transfer chains in plants and bacteria will be considered.

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