Posts Tagged: mitochondria

Calcium and Excitation-Contraction Coupling in the Heart

Calcium and Excitation-Contraction Coupling in the Heart

David A. Eisner, Jessica L. Caldwell, Kornél Kistamás, Andrew W. Trafford

Structures involved in Ca cycling. A, Schematic diagram. This shows surface membrane, transverse tubule, sarcoplasmic reticulum (SR), and mitochondria, as well as the various channels and transporters mentioned in the text. B, High-resolution transverse section of a ventricular myocyte showing t-tubule network. Reprinted from Jayasinghe et al39 with permission of the publisher. Copyright ©2009, Biophysical Society. C, Cartoon of dyad emphasizing the major proteins involved in Ca cycling. B-AR indicates beta adrenoceptor; MCU, mitochondrial Ca uniporter; NCX, sodium–calcium exchange; NCLX, mitochondrial Na–Ca exchange; PMCA, plasma membrane Ca-ATPase; RyR, ryanodine receptor; and SERCA, sarco/endoplasmic reticulum Ca-ATPase. [Powerpoint File]

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Henry Gewirtz, Vasken Dilsizian

Diagrammatic representation of myocardial cell and potential targets of radiotracer imaging and mapping of the surface renin–angiotensin system. ACE indicates angiotensin-converting enzyme; AGT, angiotensinogen; Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; and AT2R, angiotensin II type 2 receptor. Reproduced with permission from Schindler and Dilsizian.61 Copyright © 2012, Elsevier. [Powerpoint File]

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Henry Gewirtz, Vasken Dilsizian

Myocyte metabolic pathways outlined for glucose and fatty acid metabolism with focus on the mitochondrion. The electron transport chain (ETC), complexes I–V, is a series of proton pumps. The last of which, complex V, supplies protons to a proton-sensitive ATPase and thereby generates ATP. CPT1,2 indicates carnitine palmitoyltransferase 1,2; FA, fatty acid; PDH, pyruvate dehydrogenase; and TCA, tricarboxylic acid (Krebs cycle). Reproduced with permission from Huss and Kelly.30 Copyright © 2005, American Society for Clinical Investigation. [Powerpoint File]

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Myocardial Viability: Survival Mechanisms and Molecular Imaging Targets in Acute and Chronic Ischemia

Henry Gewirtz, Vasken Dilsizian

Key myocyte organelles and ion channels and their function under conditions of ischemia and reperfusion. Ischemia (left panel) causes influx of Ca2+ and decline in pH, both of which, if not severe, facilitate maintenance of closed mitochondrial permeability transition pore (mPTP). On reperfusion (right panel), key events include restoration of physiological pH, burst of reactive oxygen species (ROS) from mitochondria, release of Ca2+ from the sarcoplasmic reticulum (SR), and opening of mPTP which results in collapse of its Δψ. Reproduced with permission from Hausenloy and Yellon.27 Copyright © 2013, American Society for Clinical Investigation. [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Schematic representation of the heme oxygenase pathway. Heme, either derived from intracellular sources, such as hemoproteins and mitochondria, or from damaged tissues and red blood cell hemolysis (extracellular sources) is used by heme oxygenase enzymes (HO-1 and HO-2) to generate carbon monoxide (CO), biliverdin, and iron. Biliverdin is converted to bilirubin by biliverdin reductase (BVR), whereas iron is stored in the ferritin protein. Although heme oxygenase enzymes were initially localized in the endoplasmic reticulum, recent reports suggest that HO-1 can be found under certain conditions in other cellular compartments such as the nucleus.19 [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Interaction of carbon monoxide (CO) with mitochondria. CO at high concentrations is known to inhibit mitochondrial respiration by competing with oxygen for the binding to cytochrome c oxidase (complex IV). In contrast, controlled delivery of CO gas and CO-releasing moleculess at nontoxic concentrations can protect cardiac tissue by promoting mitochondrial biogenesis, uncoupling activity, and metabolic switch (see text for details). The molecular mechanism(s) underlying these effects remains to be defined. However, the interaction of CO with mitochondrial targets different from cytochrome c oxidase is likely as the electron transport chain contains other heme-complexes that may display distinct sensitivities to CO. ROS indicates reactive oxygen species. [Powerpoint File]

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E. Otterbein*, Roberta Foresti*, Roberto Motterlini*

Heme release and cardiac repair. Ischemia-reperfusion injury leads to the sudden release of cellular contents including heme, mitochondrial DNA, and ATP. These cellular danger-associated molecular patterns (DAMPs) have each been shown to induce heme oxygenase-1 (HO-1). HO-1 expression and the subsequent generation CO, biliverdin (BV), and bilirubin (BR) target a variety of cell types that impact cellular repair and tissue regeneration. [Powerpoint File]

Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy

Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy

Victoria R. Pell, Edward T. Chouchani, Michael P. Murphy, Paul S. Brookes, Thomas Krieg

Respiratory Complex I and II Yin-Yang during ischemia and reperfusion. Under normoxic conditions, both complex I (red) and complex II (blue) work in the forward direction (dashed gray line indicates direction of electron flow), taking electrons from NADH and succinate, respectively, and reducing ubiquinone (Q) to ubiquinol (QH2). Electrons are eventually passed down the respiratory chain to O2, and complex I pumps protons to generate a transmembrane ΔpH. During ischemia, QH2 generated by complex I working forward, is oxidized by complex II working in reverse. In this Yin-Yang formation, fumarate acts as an electron acceptor, resulting in accumulation of succinate. This process allows complex I to continue pumping protons during ischemia. At reperfusion, the rapid consumption of accumulated succinate generates too much QH2 for the reoxygenated terminal respiratory chain to handle (dotted line). Coupled with residual acidic pH from ischemia, this drives reverse electron transfer in complex I, resulting in the generation of significant amounts of reactive oxygen species (ROS). [Powerpoint File]

Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

Opher S. Kornfeld, Sunhee Hwang, Marie-Hélène Disatnik, Che-Hong Chen, Nir Qvit, Daria Mochly-Rosen

Targeting reactive oxygen species (ROS) using scavengers. A, General ROS scavengers (purple symbol) target and reduce both pathological (red) and physiological (green) ROS. These ROS scavengers do not have localization specificity and must be administered at stoichiometric (at least 1:1) amounts. In addition, ROS scavengers may get oxidized (red symbol) and instead exert an opposite effect than intended. B, Mitochondria-targeted antioxidants (eg, SS31, MitoQ, SkQ, and mCat; see text for details) aim at ROS-producing sites. Whereas some, such as SS31 (orange symbol), do not have to be administered at stoichiometric doses; they may still reduce both pathological and pathological ROS. The electron transport machinery (complexes I–IV) and cytochrome c are depicted in the inner mitochondrial membrane/matrix interface. CL indicates cardiolipin. [Powerfile File]

Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

Opher S. Kornfeld, Sunhee Hwang, Marie-Hélène Disatnik, Che-Hong Chen, Nir Qvit, Daria Mochly-Rosen

Targeting downstream reactive oxygen species (ROS) signaling pathways that are beneficial for the cell. A, Summary of physiological ROS-mediated protein kinase C (PKC) ε activation and translocation to the mitochondria and its mitochondrial substrates. B, Pharmacological inhibition of mitochondrial permeability transition pore (mPTP) opening as a therapeutic strategy. C, Activation of the mitoKATP channel as a therapeutic strategy. D, Activation of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) as a therapeutic strategy and the molecular events affected by it (see text for details). 4HNE indicates 4-hydroxy-2-nonenal; 5-HD, 5-hydroxydecanoate; and Alda-1, aldehyde dehydrogenase activator. [Powerpoint File]

Regulated Necrotic Cell Death: The Passive Aggressive Side of Bax and Bak

Regulated Necrotic Cell Death: The Passive Aggressive Side of Bax and Bak

Jason Karch, Jeffery D. Molkentin

Mitochondrial permeability transition pore (MPTP)-dependent necrotic pathway. When a cell receives a stress that leads to increased levels of intracellular calcium, the mitochondrial calcium uniporter (MCU) takes up the calcium into the matrix of the mitochondria where it can trigger MPTP opening through cyclophilin D (CypD). The MPTP is thought to be composed of the F1F0 ATP synthase regulated by ANT and the mitochondrial phosphate carrier (PiC). On prolonged opening of the MPTP, there is an osmotic alteration and mitochondrial swelling and dysfunction occur with loss of ATP production and reactive oxygen species (ROS) generation. MPTP-dependent mitochondrial dysfunction requires the presence of Bax or Bak on the outer mitochondrial membrane. Therefore, proteins that affect the content of Bax/Bak on the outer mitochondrial membrane, such as the prosurvival the Bcl-2 family members, can secondarily affect MPTP-dependent mitochondrial dysfunction. ANT indicates adenine nucleotide translocator; BH, Bcl-2 homology; IMM, inner mitochondrial membrane; IMS, intramitochondrial membrane space; and OMM, outer mitochondrial membrane. [Powerpoint File]

Regulated Necrotic Cell Death: The Passive Aggressive Side of Bax and Bak

Regulated Necrotic Cell Death: The Passive Aggressive Side of Bax and Bak

Jason Karch, Jeffery D. Molkentin

Necroptotic pathway. The combinatorial treatment with an apoptotic death receptor ligand and a caspase inhibitor leads to necroptosis with receptor-interacting protein kinase 1 (RIP1) activation. Without the caspase inhibitor present, caspase 8 would normally cleave and inactivate RIP1. When RIP1 is left unchecked in the presence of a caspase inhibitor, it complexes with RIP3 and together they lead to the phosphorylation and activation of mixed lineage kinase like (MLKL). MLKL is a required protein for necroptosis. [Powerpoint File]

The Ins and Outs of Mitochondrial Calcium

The Ins and Outs of Mitochondrial Calcium

Toren Finkel, Sara Menazza, Kira M. Holmström, Randi J. Parks, Julia Liu, Junhui Sun, Jie Liu, Xin Pan, Elizabeth Murphy

Mitochondrial ion transport mechanisms involved in regulating calcium entry (red arrows) and efflux (green arrows). Calcium enters the mitochondria primarily through the mitochondria calcium uniporter (MCU). Although MCU seems to be the main calcium influx pathway, other influx mechanisms such as ryanodine receptor 1 (not shown) or leucine zipper-EF-hand–containing transmembrane protein 1 (LETM1) have also been proposed.13–15 Questions remain, however, as others have suggested that LETM1 is, in fact, a mitochondrial K+/H+ exchanger.16,17 Calcium efflux is driven by Na+–Ca2+–Li+ exchanger using the influx of sodium down its electrochemical gradient. The intracellular sodium is set below the cytosolic sodium by the sodium–proton exchanger (NHE), which uses the energy of the inwardly directed proton gradient to maintain mitochondrial sodium below the concentration of sodium in the cytosol. [Powerpoint File]

The Ins and Outs of Mitochondrial Calcium

The Ins and Outs of Mitochondrial Calcium

Toren Finkel, Sara Menazza, Kira M. Holmström, Randi J. Parks, Julia Liu, Junhui Sun, Jie Liu, Xin Pan, Elizabeth Murphy

Molecular components of the uniporter complex. Data strongly suggest that mitochondrial calcium uniporter (MCU) is the pore. Most but not all experimental evidence suggest that MICU1 and MICU2 are located within the inner mitochondrial space. Essential MCU regulator (EMRE) seems to link MCU with MICU1 and to be necessary for MCU to open and allow calcium entry (red circles) into the mitochondrial matrix. Not pictured here is MCUb, the dominant negative form of MCU that exists in various ratios with MCU. See text for further details. [Powerpoint File]

How Mitochondrial Dynamism Orchestrates Mitophagy

How Mitochondrial Dynamism Orchestrates Mitophagy

Orian S. Shirihai, Moshi Song, Gerald W. Dorn II

Mechanisms of mitochondrial quality improvement, from macro to micro. Top, PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy of an intact organelle, as with the depolarized daughter of an asymmetrical fission event (see Figure 3). Left, Bit-by-bit autophagy of localized mitochondrial damage, which is excised and engulfed by an autophagosome via Parkin activity. Bottom, PINK1/Parkin-mediated formation of mitochondria-derived vesicle, incorporating damaged components into a vesicle that transports them to lysosomes. Right, PINK1–Parkin-independent proteasomal removal of outer mitochondrial membrane proteins, and protease-dependent degradation of internal mitochondrial proteins, the most selective of the quality improvement processes. [Powerpoint File]