Posts Tagged: apoptosis

Autophagy and Mitophagy in Cardiovascular Disease

Autophagy and Mitophagy in Cardiovascular Disease

José Manuel Bravo-San Pedro, Guido Kroemer, Lorenzo Galluzzi

Detrimental effects of autophagy or mitophagy inhibition on cardiovascular health. Multiple genetic interventions that limit autophagic or mitophagic flux at the whole-body level or in specific compartments of the cardiovascular system have been associated with the spontaneous development of cardiovascular disorders. AP indicates autophagosome; APL, autophagolysosome; Atg5, autophagy related 5; Bnip3l, BCL2 interacting protein 3 like; Dnml1, dynamin 1 like; Fbxo32, F-box protein 32; L, lysosome; Lamp2, lysosomal-associated membrane protein 2; Mfn1, mitofusin 1; Park2, Parkinson disease (autosomal recessive, juvenile) 2, parkin; Pink1, PTEN-induced putative kinase 1; Sirt6, sirtuin 6; Tfrc, transferrin receptor; and Trp53, transformation-related protein 53. [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 Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

Gerald W. Dorn II, Richard N. Kitsis

Consequences of replicative vs asymmetrical mitochondrial fission. A, Replicative fission of one healthy old parent mitochondrion produces 2 small healthy daughter organelles that incorporate biogenically produced protein, DNA, and lipids (central rectangle) to grow into new mitochondria. B, Asymmetrical fission of a damaged or senescent mitochondrion produces 1 healthy daughter organelle that fuses with other healthy organelles to regenerate the collective, and 1 severely damaged/depolarized (red) daughter organelle that is rapidly eliminated by autophagosomal engulfment, thereby protecting the cell from mitotoxicity and providing new recycled components for biogenic repair. [Powerpoint File]

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

Gerald W. Dorn II, Richard N. Kitsis

Molecular mechanism of mitochondrial fission and fusion. The 3 molecular drivers of fission and fusion are schematically depicted as they would be associated with a normal mitochondrion. Replicative fission (left) is initiated by recruitment of cytosolic dynamin-related protein 1 (Drp1) to the organelle, Drp1 oligomerization, and constriction of the parent into 2 daughters. Asymmetrical fission uses the same mechanism. Fusion (right) requires initial mitofusin 1 (Mfn1)/Mfn2-mediated outer membrane tethering followed by fusion, and finally optic atrophy 1 (Opa1)–mediated inner membrane fusion. [Powerpoint File]

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

Gerald W. Dorn II, Richard N. Kitsis

Mitochondrial fusion and control of cardiomyocyte differentiation/heart development. Functional interactions between L-type calcium channels (LCC; blue), store-operated calcium channels (purple), mitochondria (green), calcineurin A (yellow), Notch (orange), and developmental gene expression as conceived in cardiomyocyte progenitor cells. Left, Normal stem cell with fused perinuclear mitochondria in which LCC calcium signaling is normal and capacitative calcium entry is low. Right, How mitochondrial fragmentation and subsarcollemmal redistribution disturbs LCC signaling through mitochondrial calcium uptake (sponge), invoking capacitative calcium entry that activates calcineurin and downstream Notch, repressing developmental gene expression. [Powerpoint File]

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

The Mitochondrial Dynamism-Mitophagy-Cell Death Interactome: Multiple Roles Performed by Members of a Mitochondrial Molecular Ensemble

Gerald W. Dorn II, Richard N. Kitsis

The (PTEN)-induced putative kinase 1 (PINK1)-Parkin mechanism of mitophagy. Left, Schematic diagram of PINK1-Parkin initiation of mitophagy signaling after asymmetrical mitochondrial fission. Right, Confocal fluorescent images showing mcherryParkin (red) translocation from cytosol to mitochondria (MitoTracker green) after mitochondrial depolarization with the uncoupling agent FCCP. Parkin-containing mitochondria appear yellow in the merged image. [Powerpoint File]

Acute Coronary Syndromes Compendium: Inflammation and its Resolution as Determinants of Acute Coronary Syndromes


Acute Coronary Syndromes Compendium: Inflammation and its Resolution as Determinants of Acute Coronary Syndromes

Peter Libby, Ira Tabas, Gabrielle Fredman, Edward A. Fisher

Inflammation in plaque rupture and thrombosis. This diagram shows a cross-section of the intima of part of an artery affected by atherosclerosis. Altered hydrodynamics, illustrated in the top left, cause loss of atheroprotective functions of endothelial cells—including vasodilator, anti-inflammatory, profibrinolytic, and anticoagulant properties. Antigens presented on antigen-presenting cells such as dendritic cells (DCs) can activate TH1 lymphocytes to produce interferon-γ (IFN-γ), which activates macrophages (MΦ, yellow). Other subtypes of lymphocytes (shown in blue) include TH2 lymphocytes, which can elaborate the anti-inflammatory cytokine interleukin 10 (IL-10) and regulatory T cells that secrete the anti-inflammatory cytokine transforming growth factor-β (TFG-β). On its surface, the macrophage contains Toll-like receptors (TLRs) 2 and 4, which can bind pathogen-associated molecular patterns and damage-associated molecular patterns (see text). The intracellular TLRs 3, 7, and 9 may also contribute to lipid accumulation and other proatherogenic functions of the macrophage. Macrophages can undergo stress of the endoplasmic reticulum (ER) under atherogenic conditions. Cholesterol crystals found in plaques can activate the NOD-, LRR- and pyrin domain-containing 3 inflammasome (see text) that can generate mature IL-1β from its inactive precursor. The activated macrophage secretes collagenases that can degrade the triple helical interstitial collagen that lends strength to the plaque’s fibrous cap. Activated macrophages also express tissue factor, a potent procoagulant, and elaborate proinflammatory cytokines that amplify and sustain the inflammatory process in the plaque. When the plaque ruptures because of a collagen-poor, weakened fibrous cap, blood in the lumen can contact tissue factor in the lipid core, triggering thrombus formation (red). When the thrombus forms, polymorphonuclear leukocytes (PMNs) can accumulate and elaborate myeloperoxidase (MPO), which in turn elaborates the potent pro-oxidant hypochlorous acid. Dying PMNs extrude DNA that can form neutrophil extracellular traps (NETs), which can entrap leukocytes and propagate thrombosis. Other inflammatory cells modulate atherosclerosis. B1 lymphocytes secrete natural antibody that can inhibit plaque inflammation. On the contrary, B2 lymphocytes, in part via B-cell activating factor (BAFF), can promote inflammation and plaque complication. Mast cells can augment atherogenesis by releasing histamine and the cytokines IFN-γ and IL-6. The consequences of a given plaque rupture depend not only on the solid state of the intimal plaque but also on the fluid phase of blood, as depicted in the top right. Systemic inflammation can give rise to cytokines, culminating in the overproduction of IL-6, the trigger of the hepatic acute phase response. The acute phase reactant fibrinogen (not shown) participates directly in thrombus formation. Another acute phase reactant, plasminogen activator inhibitor-1 (PAI-1), can impair fibrinolysis by inhibiting the endogenous fibrinolytic mediators, urokinase- and tissue-type plasminogen activators (uPA and tPA). (Illustration credit: Ben Smith.) [Powerpoint File]

Acute Coronary Syndromes Compendium: Inflammation and its Resolution as Determinants of Acute Coronary Syndromes


Acute Coronary Syndromes Compendium: Inflammation and its Resolution as Determinants of Acute Coronary Syndromes

Peter Libby, Ira Tabas, Gabrielle Fredman, Edward A. Fisher

Life, death, and transit of macrophages in generating the plaque’s necrotic core. Blood monocytes interact with adhesion molecules expressed by endothelial cells exposed to inflammatory mediators. They first roll and attach more firmly and ultimately diapedese into the intima in response to chemoattractant molecules that bind to surface receptors on the leukocyte—exemplified here by chemokine receptor 2 (CCR2). The monocytes recruited to the intimal lesion can proliferate, giving rise to daughter cells, or can differentiate into macrophages with a proinflammatory slant (denoted M1) or those that are alternatively activated (denoted M2). Macrophages can traffic, including leaving the plaque by emigration, as shown here on the macrovascular surface. Retention factors such as netrin-1 or semaphorin-3 can promote accumulation of mononuclear phagocytes in the plaque. Macrophages can die by oncosis (sometimes called necrosis) or by programmed cell death (apoptosis). Advanced plaques show a defect in clearance of apoptotic cells leading to their accumulation, a process called mummification because of a defect in efferocytosis (see text). Dying cells can also release apoptotic bodies and microparticles bearing the potent procoagulant tissue factor that triggers thrombus formation in disrupted plaques. The detritus of dead and dying cells that accumulate because of defective efferocytosis give rise to the lipid-rich necrotic core of the plaque. (Illustration credit: Ben Smith.) [Powerpoint File]

Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control

Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control

Dieter A. Kubli, Åsa B. Gustafsson

Induction of autophagy. B-cell lymphoma (BCL)-2 prevents the induction of autophagy by binding BECLIN1 and activating molecule in BECLIN1-regulated autophagy (AMBRA1). Displacement by BH3-only proteins leads to activation of the BECLIN1–vacuolar protein sorting (VPS) 34–VPS15 complex and phagophore nucleation. Elongation of the membrane requires 2 ubiquitin-like conjugation systems: autophagy protein (ATG)12-ATG5-ATG16L and conjugation of microtubule-associated protein 1 light chain 3 (LC3)-I with phosphatidylethanolamine (PE) to form LC3-II. After maturation of the autophagosome, it fuses with the lysosome to degrade the cargo. (illustration credit: Ben Smith.) [Powerpoint File]

Mitochondria and Endothelial Function

Mitochondria and Endothelial Function

Matthew A. Kluge, Jessica L. Fetterman, Joseph A. Vita

Conceptual illustration of the mitochondrial life cycle and the contribution of mitochondrial dynamics and mitophagy to quality control. Biogenesis is regulated by peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), which activates nuclear respiratory factor (NRF)-1 and NRF-2 and transcription factor A mitochondrial (TFAM) and transcription factor B mitochondrial (TFBM). Mitochondria undergo cycles of fusion to form elongated mitochondrial networks and fission into smaller individual organelles. Fusion is mediated by mitofusin (MFN) 1, MFN2, and optic atrophy protein 1 (OPA1). Fission is mediated by dynamin-related protein-1 (DRP1) and fission 1 (FIS1). During their normal lifespan and in the setting of increased oxidative stress, damage to mitochondrial components accumulates. Fission provides a mechanism to isolate damaged components for elimination. Mitophagy involves mitochondrial depolarization, retention phosphatase and tensin homolog–induced putative kinase protein 1 (PINK1) in the mitochondrial membrane, and recruitment of Parkin, which targets the mitochondria to autophagosome. P62 also plays a role in targeting cargo to the autophagosome and is subsequently degraded during active autophagy. Assembly of the phagosome involves beclin-1 and conjugation of microtubule-associated protein 1 light chain 3 (LC3) onto phosphatidylethanolamine to form of LC3-II. (Illustration Credit: Ben Smith) [Powerpoint File]

Regulation of Cell Survival and Death by Pyridine Nucleotides

Regulation of Cell Survival and Death by Pyridine Nucleotides

Shin-ichi Oka, Chiao-Po Hsu, Junichi Sadoshima

Sirt1-mediated protein deacetylation. Sirt1 hydrolyzes NAD+ to generate ADP-ribose units and nicotinamide. The acetyl group of the Sirt1 target proteins is removed and attached to the ADP-ribose to generate 2-O-acetyl-ADP-ribose. [Powerpoint File]