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Antioxidants & Redox Signaling Oct 2023Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane.... (Review)
Review
Mitochondrial (mt) reticulum network in the cell possesses amazing ultramorphology of parallel lamellar cristae, formed by the invaginated inner mitochondrial membrane. Its non-invaginated part, the inner boundary membrane (IBM) forms a cylindrical sandwich with the outer mitochondrial membrane (OMM). Crista membranes (CMs) meet IBM at crista junctions (CJs) of mt cristae organizing system (MICOS) complexes connected to OMM sorting and assembly machinery (SAM). Cristae dimensions, shape, and CJs have characteristic patterns for different metabolic regimes, physiological and pathological situations. Cristae-shaping proteins were characterized, namely rows of ATP-synthase dimers forming the crista lamella edges, MICOS subunits, optic atrophy 1 (OPA1) isoforms and mitochondrial genome maintenance 1 (MGM1) filaments, prohibitins, and others. Detailed cristae ultramorphology changes were imaged by focused-ion beam/scanning electron microscopy. Dynamics of crista lamellae and mobile CJs were demonstrated by nanoscopy in living cells. With tBID-induced apoptosis a single entirely fused cristae reticulum was observed in a mitochondrial spheroid. The mobility and composition of MICOS, OPA1, and ATP-synthase dimeric rows regulated by post-translational modifications might be exclusively responsible for cristae morphology changes, but ion fluxes across CM and resulting osmotic forces might be also involved. Inevitably, cristae ultramorphology should reflect also mitochondrial redox homeostasis, but details are unknown. Disordered cristae typically reflect higher superoxide formation. To link redox homeostasis to cristae ultramorphology and define markers, recent progress will help in uncovering mechanisms involved in proton-coupled electron transfer the respiratory chain and in regulation of cristae architecture, leading to structural determination of superoxide formation sites and cristae ultramorphology changes in diseases. 39, 635-683.
Topics: Mitochondrial Membranes; Superoxides; Homeostasis; Oxidation-Reduction; Adenosine Triphosphate; Mitochondrial Proteins
PubMed: 36793196
DOI: 10.1089/ars.2022.0173 -
International Journal of Molecular... Mar 2022Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a... (Review)
Review
Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a multivariate physiology is structurally and functionally reflected upon their membrane configuration and lipid composition. Mitochondrial double membrane lipids, with cardiolipin as the protagonist, show an impressive level of complexity that is mandatory for maintenance of mitochondrial health and protection from apoptosis. Given that lipidomics is an emerging field in cancer research and that mitochondria are the organelles with the most important role in malignant maintenance knowledge of the mitochondrial membrane, lipid physiology in health is mandatory. In this review, we will thus describe the delicate nature of the healthy mitochondrial double membrane and its role in apoptosis. Emphasis will be given on mitochondrial membrane lipids and the changes that they undergo during apoptosis induction and progression.
Topics: Apoptosis; Cardiolipins; Membrane Lipids; Mitochondria; Mitochondrial Membranes
PubMed: 35409107
DOI: 10.3390/ijms23073738 -
Proceedings of the National Academy of... Mar 2019Mitochondrial ATP synthases form dimers, which assemble into long ribbons at the rims of the inner membrane cristae. We reconstituted detergent-purified mitochondrial...
Mitochondrial ATP synthases form dimers, which assemble into long ribbons at the rims of the inner membrane cristae. We reconstituted detergent-purified mitochondrial ATP synthase dimers from the green algae sp. and the yeast into liposomes and examined them by electron cryotomography. Tomographic volumes revealed that ATP synthase dimers from both species self-assemble into rows and bend the lipid bilayer locally. The dimer rows and the induced degree of membrane curvature closely resemble those in the inner membrane cristae. Monomers of mitochondrial ATP synthase reconstituted into liposomes do not bend membrane visibly and do not form rows. No specific lipids or proteins other than ATP synthase dimers are required for row formation and membrane remodelling. Long rows of ATP synthase dimers are a conserved feature of mitochondrial inner membranes. They are required for cristae formation and a main factor in mitochondrial morphogenesis.
Topics: Chlorophyceae; Chlorophyta; Lipid Bilayers; Liposomes; Mitochondria; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases; Molecular Dynamics Simulation; Protein Conformation; Yarrowia
PubMed: 30760595
DOI: 10.1073/pnas.1816556116 -
Chemistry & Biology Jan 2014For stressed cells to induce the mitochondrial pathway of apoptosis, a cohort of pro-apoptotic BCL-2 proteins must collaborate with the outer mitochondrial membrane to... (Review)
Review
For stressed cells to induce the mitochondrial pathway of apoptosis, a cohort of pro-apoptotic BCL-2 proteins must collaborate with the outer mitochondrial membrane to permeabilize it. BAK and BAX are the two pro-apoptotic BCL-2 family members that are required for mitochondrial outer membrane permeabilization. While biochemical and structural insights of BAK/BAX function have expanded in recent years, very little is known about the role of the outer mitochondrial membrane in regulating BAK/BAX activity. In this review, we will highlight the impact of mitochondrial composition (both protein and lipid) and mitochondrial interactions with cellular organelles on BAK/BAX function and cellular commitment to apoptosis. A better understanding of how BAK/BAX and mitochondrial biology are mechanistically linked will likely reveal novel insights into homeostatic and pathological mechanisms associated with apoptosis.
Topics: Animals; Apoptosis; Humans; Mitochondrial Membranes; Organelles; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein
PubMed: 24269152
DOI: 10.1016/j.chembiol.2013.10.009 -
Biochimica Et Biophysica Acta.... Nov 2020In the present work, we investigated the interaction of flavonoids (quercetin, naringenin and catechin) with cellular and artificial membranes. The flavonoids...
In the present work, we investigated the interaction of flavonoids (quercetin, naringenin and catechin) with cellular and artificial membranes. The flavonoids considerably inhibited membrane lipid peroxidation in rat erythrocytes treated with tert-butyl hydroperoxide (700 μM), and the IC values for prevention of this process were equal to 9.7 ± 0.8 μM, 8.8 ± 0.7 μM, and 37.8 ± 4.4 μM in the case of quercetin, catechin and naringenin, respectively, and slightly decreased glutathione oxidation. In isolated rat liver mitochondria, quercetin, catechin and naringenin (10-50 μM) dose-dependently increased the sensitivity to Ca ions - induced mitochondrial permeability transition. Using the probes TMA-DPH and DPH we showed that quercetin rather than catechin and naringenin strongly decreased the microfluidity of the 1,2-dimyristoyl-sn-glycero-3-phosphocholine liposomal membrane bilayer at different depths. On the contrary, using the probe Laurdan we observed that naringenin transfer the bilayer to a more ordered state, whereas quercetin dose-dependently decreased the order of lipid molecule packing and increased hydration in the region of polar head groups. The incorporation of the flavonoids, quercetin and naringenin and not catechin, into the liposomes induced an increase in the zeta potential of the membrane and enlarged the area of the bilayer as well as lowered the temperature and the enthalpy of the membrane phase transition. The effects of the flavonoids were connected with modification of membrane fluidity, packing, stability, electrokinetic properties, size and permeability, prevention of oxidative stress, which depended on the nature of the flavonoid molecule and the nature of the membrane.
Topics: Animals; Erythrocytes; Flavonoids; Liposomes; Mitochondria, Liver; Mitochondrial Membranes; Oxidation-Reduction; Permeability; Rats; tert-Butylhydroperoxide
PubMed: 32814117
DOI: 10.1016/j.bbamem.2020.183442 -
International Journal of Molecular... Feb 2020Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II....
Doxorubicin (DXR) is a drug widely used in chemotherapy. Its mode of action is based on its intercalation properties, involving the inhibition of topoisomerase II. However, few studies have reported the mitochondrial effects of DXR while investigating cardiac toxicity induced by the treatment, mostly in pediatric cases. Here, we demonstrate that DXR alters the mitochondrial membrane composition associated with bioenergetic impairment and cell death in human cancer cells. The remodeling of the mitochondrial membrane was explained by phosphatidylserine decarboxylase (PSD) inhibition by DXR. PSD catalyzes phosphatidylethanolamine (PE) synthesis from phosphatidylserine (PS), and DXR altered the PS/PE ratio in the mitochondrial membrane. Moreover, we observed that DXR localized to the mitochondrial compartment and drug uptake was rapid. Evaluation of other topoisomerase II inhibitors did not show any impact on the mitochondrial membrane composition, indicating that the DXR effect was specific. Therefore, our findings revealed a side molecular target for DXR and PSD, potentially involved in DXR anti-cancer properties and the associated toxicity.
Topics: Carboxy-Lyases; Cardiotoxicity; Cell Death; Doxorubicin; HeLa Cells; Humans; Mitochondrial Membranes; Neoplasms; Phosphatidylethanolamines; Phosphatidylserines
PubMed: 32075281
DOI: 10.3390/ijms21041317 -
Molecular and Cellular Endocrinology Apr 2012Growing evidence supports that mitochondrial calcium uptake is important for cell metabolism, signaling and survival. However, both the molecular nature of the... (Review)
Review
Growing evidence supports that mitochondrial calcium uptake is important for cell metabolism, signaling and survival. However, both the molecular nature of the mitochondrial Ca(2+) transport sites and the calcium signals they respond to remained elusive. Recent RNA interference studies have identified new candidate proteins for Ca(2+) transport across the inner mitochondrial membrane, including LETM1, MCU, MICU1 and NCLX. The sensitivity of these factors to several drugs has been tested and in parallel, some new inhibitors of mitochondrial Ca(2+) uptake have been described. This paper provides an update on the pharmacological aspects of the molecular mechanisms of the inner mitochondrial membrane Ca(2+) transport.
Topics: Animals; Calcium; Calcium-Binding Proteins; Humans; Ion Transport; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes
PubMed: 22123069
DOI: 10.1016/j.mce.2011.11.011 -
Current Biology : CB Jun 2022Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients...
Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients into the energy-rich compound ATP. Mitochondrial ATP biosynthesis is a marvel of thermodynamic efficiency. Via the tricarboxylic acid cycle (TCA) and fatty acid β-oxidation, mitochondria extract electrons from dietary carbon compounds and pass them to nucleotides that ultimately deliver them to the respiratory chain complexes located in invaginations in the inner mitochondrial membrane (IMM) known as cristae. The respiratory chain complexes donate electrons in stepwise redox reactions to molecular oxygen and, with the exception of complex II, use the liberated energy to pump protons across the proton-impermeable IMM, generating a proton electrochemical gradient. This gradient is then utilized by the ATP synthase, which, in a rotary mechanism, catalyzes the formation of the high-energy γ-phosphate chemical bond between ADP and inorganic phosphate. The conversion of the chemical energy of carbon compounds into a physical, vectorial form of energy (the electrochemical gradient) maximizes the yield of the ATP biosynthetic process and is perhaps one of the foundations of life as we know it.
Topics: Adenosine Triphosphate; Carbon; Mitochondria; Mitochondrial Membranes; Protons
PubMed: 35728541
DOI: 10.1016/j.cub.2022.05.006 -
Trends in Cell Biology Dec 2020Mitochondria are dynamic organelles that have essential metabolic and regulatory functions. Earlier studies using electron microscopy (EM) revealed an immense diversity... (Review)
Review
Mitochondria are dynamic organelles that have essential metabolic and regulatory functions. Earlier studies using electron microscopy (EM) revealed an immense diversity in the architecture of cristae - infoldings of the mitochondrial inner membrane (IM) - in different cells, tissues, bioenergetic and metabolic conditions, and during apoptosis. However, cristae were considered to be largely static entities. Recently, advanced super-resolution techniques have revealed that cristae are independent bioenergetic units that are highly dynamic and remodel on a timescale of seconds. These advances, coupled with mechanistic and structural studies on key molecular players, such as the MICOS (mitochondrial contact site and cristae organizing system) complex and the dynamin-like GTPase OPA1, have changed our view on mitochondria in a fundamental way. We summarize these recent findings and discuss their functional implications.
Topics: Cardiolipins; Energy Metabolism; Humans; Mitochondrial Membranes; Mitochondrial Proteins; Models, Biological
PubMed: 32978040
DOI: 10.1016/j.tcb.2020.08.008 -
Biochimica Et Biophysica Acta.... Apr 2017The elaborate membrane architecture of mitochondria is a prerequisite for efficient respiration and ATP generation. The cristae membranes, invaginations of the inner... (Review)
Review
The elaborate membrane architecture of mitochondria is a prerequisite for efficient respiration and ATP generation. The cristae membranes, invaginations of the inner mitochondrial membrane, represent a specialized compartment that harbors the complexes of the respiratory chain and the FF-ATP synthase. Crista junctions form narrow openings that connect the cristae membranes to the inner boundary membrane. The mitochondrial contact site and cristae organizing system (MICOS) is located at crista junctions where it stabilizes membrane curvature and forms contact sites between the mitochondrial inner and outer membranes. MICOS is a large machinery, consisting of two dynamic subcomplexes that are anchored in the inner membrane and expose domains to the intermembrane space. The functions of MICOS in mitochondrial membrane architecture and biogenesis are influenced by numerous interaction partners and the phospholipid environment.
Topics: Animals; DNA, Mitochondrial; Gene Expression Regulation; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Phospholipids; Protein Binding; Proton-Translocating ATPases; Saccharomyces cerevisiae; Signal Transduction; Species Specificity
PubMed: 27614134
DOI: 10.1016/j.bbamcr.2016.05.020