Posts in Category: 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]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to highlight the location of subsarcolemmal (SSM) and interfibrillar mitochondria (IFM). Illustration credit: Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

Schematic of the interfibrillar mitochondrial defects in the aged heart. ETC indicates electron transport chain; IMM, mitochondrial inner membrane; NADH, nicotinamide adenine dinucleotide; PPL, phospholipid, proposed defect affecting subunit VIIa in complex IV; and Q, ubiquinone; Qo site, ubiquinol-binding site on cytochrome bl with proposed defect in Y132. Illustration credit, Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to show defects present in global and mitochondrial metabolism with age in concert with mechanisms of mitochondria-driven cellular injury. The aged heart exhibits impaired fatty acid oxidation (FAO) and preserved oxidation of glucose. Aging leads to defects in the electron transport chain that involve complexes III (CIII) and IV (CIV). Monoamine oxidase (MAO) and p66shc are significant sources of oxidants. There is a decrease in cardiolipin (CL). Antioxidant contents are relatively unchanged although a decrease in matrix antioxidant capacity leads to mitochondrial damage. Age-related damage enhances the production of reactive oxygen species (ROS) that lead to mitochondrial and cell damage. In addition, effector mechanisms of age-induced mitochondrial damage discussed include an increased susceptibility to mitochondrial permeability transition pore opening (MPTP; MPTP Opening in the Aged Heart: Relationship With ROS Production section), impaired mitochondrial dynamics favoring fusion over fission (Mitochondrial Fission and Fusion section), likely impaired mitophagy (Mitochondrial Biogenesis, Dynamics, and Removal section), and enhanced oxidant-derived signaling to activate cell death programs (Mitochondrial Metabolism–Based Signaling in Response to ROS Production section). Illustration credit: Ben Smith. ETC indicates electron transport chain. [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]

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Kai-Chien Yang, John W. Kyle, Jonathan C. Makielski, Samuel C. Dudley Jr

Oxidative phosphorylation and reactive oxygen species (ROS) production in mitochondria. The diagrams of the mitochondrial inner membrane show key components of the electron transport chain (ETC) above, and channels and transporters (below). Reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) produced from the tricarboxylic acid (TCA) cycle feed electrons to the ETC along the mitochondrial inner membrane. The electrons flow through the ETC with the following sequence: complex I and II→coenzyme Q [Q]→complex III→cytochrome C [Cyt C]→complex IV→O2, during which coupled redox reactions drive H+ across the inner membrane, forming the proton gradient and the negative mitochondrial membrane potential (ΔΨm=−150 to −180 mV). The free energy stored in the proton gradient and ΔΨm then drive H+ through the mitochondrial ATP synthase (complex V), converting ADP to ATP. An estimated 0.1% to 1% of the electrons leak prematurely to O2 at complexes I, II, or III, resulting in the formation of superoxide (O2•−). Multiple important mitochondrial channels located on the inner membrane including mitochondrial KATP channels (mito-KATP), the mitochondrial Na+/Ca2+ exchanger (mito-NCX), the inner membrane anion channel (IMAC), the permeability transition pore (PTP), and the mitochondrial calcium uniporter (MCU) also contribute to the regulation of mitochondrial function, myocardial ROS, and cellular cation homeostasis. [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]