Oxford Journals

Mitochondria

Mitochondrial morphology and cardiovascular disease

Ong S , Hausenloy D J Cardiovasc Res 2010;88:16-29 - Click here to view the abstract

Mitochondrial fission

The process of mitochondrial fission is under the control of the mitochondrial fission proteins Drp1 and Fis1. Drp1 is located mainly in the cytosol and comprises a GTPase, a central region, and a GTPase effector domain (GED) or assembly domain. Fis1 is localized in the outer mitochondrial membrane with most of the protein facing into the cytosol, acting as a docking station for Drp1. On activation, Drp1 translocates to the mitochondria (a process which is regulated by phosphorylation and sumoylation), oligomerizes, and constricts the mitochondrial scission site, a process which requires GTPase, thereby resulting in mitochondrial fission.

Mitochondrial morphology and cardiovascular disease

Ong S , Hausenloy D J Cardiovasc Res 2010;88:16-29 - Click here to view the abstract

Mitochondrial fusion

The process of mitochondrial fusion is under the control of the mitochondrial fusion proteins Mfn1 and 2 and OPA-1. Mitochondrial membrane fusion has been shown to be a distinct two-step process which occurs separately for the inner and outer membrane, but in chronology. Both the outer and inner membranes of the mitochondria must fuse properly in order for the matrix contents to mix properly. (A) The mitochondrial fusion proteins Mfn1 and Mfn2 are located on the outer mitochondrial membrane with a cytosolic GTPase domain and two hydrophobic heptad repeat (HR) regions separated by a transmembrane repeat. The C-terminal HR region (HR2) mediates oligomerization between Mfn molecules on adjacent mitochondria, allowing the membranes to fuse. GTP hydrolysis facilitates the fusion process. (B) The mitochondrial fusion protein OPA1 comprises an N-terminal mitochondrial import sequence (MIS), hydrophobic heptad repeat (HR) segments, coiled-coil domain (C C), a GTPase domain, a central domain, and a GTPase effector domain (GED) at the C-terminus. OPA1 mediates the fusion of the inner mitochondrial membranes.

Key mechanisms and targets that modulate Ca2+ transport in the postischaemic heart

Talukder MA et al. Cardiovasc Res (2009) 84(3): 345-352 first published online July 29, 2009 doi:10.1093/cvr/cvp264 - Click here to view the abstract

During myocardial ischaemia and reperfusion (I/R) there is accumulation of cytosolic Ca²⁺ due to defects in multiple Ca²⁺ handling proteins such as SERCA2a, NCX, LTCC, and RyR2. Importantly, the resultant cytosolic Ca²⁺ overload with myocardial reperfusion causes an increased influx of Ca²⁺ into mitochondria and results in the opening of the mitochondrial permeability transition pore (mPTP). In addition to Ca²⁺ overload, I/R is associated with increased generation of myocardial reactive oxygen species (ROS). While small amounts of Ca²⁺ and oxygen are necessary for optimal cardiac function, cytosolic free Ca²⁺ overload and increased oxidative stress are thought to be major contributors to myocardial I/R-induced injury and myocyte death. The potential targets to modulate Ca²⁺ overload and reduce myocardial ischaemia-reperfusion injury are: (1) Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), (2) Na⁺/Ca²⁺ exchanger (NCX), (3) SR Ca²⁺ release channel RyR, (4), L-type Ca²⁺ channel (LTCC), (5) Na⁺-H⁺ exchanger (NHE), and (6) Ca²⁺ and calmodulin-dependent protein kinase II (CaMKII).

SAFE PATHWAY: An alternate cardioprotective signalling route

Lacerda L et al. Cardiovasc Res (2009) 84(2): 201-208 first published online August 7, 2009 doi:10.1093/cvr/cvp274 - Click here to view the abstract

Activation of the survivor activating factor enhancement (SAFE) pathway, as represented by the binding of a low concentration of endogenous or exogenous tumour necrosis factor alpha (TNFα) to its TNF receptor 2 (TNFR2) at the onset of reperfusion with the subsequent activation of the transcription factor signal transducer and activator of transcription-3 (STAT-3), initiates a cardioprotective signalling cascade in both ischaemic pre- and postconditioning that is activated independently of the well-known reperfusion injury salvage kinases (RISK) pathway. The delineation of the SAFE pathway further emphasizes the importance of RISK-independent pathways in cardioprotection, which may have potential therapeutic application in the mitigation of ischaemic-reperfusion injury.

Abbreviations: RISK: Reperfusion Injury Salvage Kinases; SAFE: Survivor Activating Factor Enhancement; S1P: sphingosine-1-phosphate; TNFα: tumour necrosis factor alpha; GPCR: green protein coupled receptors; S1P R1/R3: sphingosine-1-phosphate receptors 1 or 3; TNFR2: tumour necrosis factor alpha receptor 2; MEK: mitogen-activated protein kinase; PI3K: phosphoinositide 3- kinase; Erk1/2: extracellular regulated kinases 1/2; Akt: protein kinase B; GSK-3β: glycogen synthase kinase-3 beta; JAK: janus kinase; STAT-3: signal transducer and activator of transcription-3; mPTP: mitochondrial permeability transition pore; P: phosphorylation

Cardioprotective growth factors

Cardiovasc Res (2009) 83(2): 179-194 first published online February 13, 2009 doi:10.1093/cvr/cvp062 - Click here to view the abstract

This schematic provides a simplified overview of the intracellular transduction pathways underlying cardioprotection elicited by the growth factors: transforming growth factor-β1 (TGF-β1), cardiotrophin-1 (CT-1), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), insulin, insulin-like growth factor (IGF), and urocortin. Ligand binding to their respective cell-surface receptors on the cardiomyocyte activates intracellular signalling kinase cascades including Raf-Ras-Mek1/2-Erk1/2 and PI3K-Akt of the reperfusion injury salvage kinase (RISK) pathway, the JAK-STAT pathway, and various anti-apoptotic mechanisms (including the phosphorylation and inhibition of Bax and BAD as well as the inhibition of cytochrome C release).

Many of the acute cardioprotective mechanisms manifested at the time of reperfusion converge on the mitochondria and include the inhibition of the mitochondrial permeability transition pore (mPTP), which can be achieved through several different mechanisms including the phosphorylation and inhibition of GSK3β; the opening of the ATP-sensitive mitochondrial potassium (Mito K_ATPM) channel by the eNOS-NO-PKG-PKC-ε cascade which produces mitochondrial ROS, which inhibits mitochondrial permeability transition pore opening; and the intracellular calcium modulation due to augmented SERCA uptake of calcium into the sarcoplasmic reticulum. More long-term cardioprotection may be achieved through the genetic transcription of various cardioprotective mediators such as iNOS, NF_κB, MMP-1, phospholipase-1, and so on (not shown on diagram, see text for details).

mPTP regulation by ANT (adenine nucleotide translocator), CyP-D (cyclophilin D), and P_i

Zorov DB et al. Cardiovasc Res (2009) 83(2): 213-225 first published online May 15, 2009 doi:10.1093/cvr/cvp151 - Click here to view the abstract

Regulation and pharmacology of the mitochondrial permeability transition pore

The core structure of the mPTP remains unresolved. Known mPTP regulatory elements are depicted on the left side of the figure, whereas the right side indicates symbolically the threshold for mPTP-induction by oxidant stress. The middle row (horizontally) depicts the basal state of ANT and CyP-D as they relate to the basal threshold for mPTP induction by oxidant stress. The top row reflects factors that facilitate mPTP induction: atractyloside, Ca²⁺, and indirect effects of P_i. The bottom row includes factors that are known to inhibit mPTP induction: genetic deletion of ANT (ANT is dispensable for mPTP formation per se; inhibition of CyP-D by CsA remains protective), ADP, or bongkrekic acid (requirement/role of CyP-D under these conditions is unknown), CsA and genetic deletion of CyP-D in the presence of P_i (atractyloside, CsA and Ca²⁺ are no longer effective when compared with WT). Note the opposing mechanisms of P_i in mPTP induction: (i) P_i as a direct mPTP desensitizer (bottom row) is opposed by CyP-D binding (top row), whereas (ii) P_i may also act as an indirect mPTP sensitizer (through regulation of Mg²⁺ and/or polyphosphate levels; top row). Note that Ca²⁺ is not a major factor in mPTP induction in intact cardiomyocytes and neurons.

Abbreviations:
mPTP mitochondrial permeability transition pore
ANT adenine nucleotide translocator
BKA bongkrekic acid
CyP-D cyclophilin D
P_i inorganic phosphate
CsA cyclosporin A
ADP adenosine diphosphate
Ppif gene encoding CyP-D in mouse
WT wild-type

Protein kinase activation in cardioprotection

Boengler K et al. Cardiovasc Res (2009) 83(2): 247-261 first published online January 28, 2009 doi:10.1093/cvr/cvp033 - Click here to view the abstract

There are three major signalling cascades of protein kinase activation in cardioprotection: (A) the GPCR/NPR-AKT-eNOS-PKG pathway, (B) the reperfusion-injury salvage kinase (RISK) pathway, and (C) the survival activating factor enhancement (SAFE) pathway, which centrally involves gp130-JAK-STAT signalling. In each system, there are molecules that are decreased in expression and/or activity with advancing age (marked in yellow) and possibly contribute to the loss of cardioprotection with aging. Such loss of cardioprotection with aging is one major problem in the translation of experimental data from (usually young and healthy) animals to the clinical situation in elderly humans.

Abbreviations: AMPK, AMP-activated kinase; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CB-R, cannabinoid receptor; Cx43, connexin 43; eNOS, endothelial NO synthase; ERK, extracellular regulated kinase; FGF-2, fibroblast growth factor 2; gp130, glycoprotein 130; GPCR, G-protein-coupled receptor; GSK3β, glycogen synthase kinase 3 β; H11K, H11 kinase; IGF, insulin-like growth factor 1; IL-6, interleukin 6; iNOS, inducible NO synthase; JAK, janus kinase; KATP, ATP-dependent potassium channel, MnSOD, manganese superoxide dismutase; MPTP, mitochondrial permeability transition pore; NO, nitric oxide; NPR, natriuretic peptide receptor; p38, p38 mitogen activated protein kinase; P70S6K, p70 ribsosomal S6 protein kinase; pGC, particulate guanylyl cyclase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; SIRT1, sirtuin 1; STAT3, signal transducer and activator of transcription 3; TNF-R, tumour necrosis factor receptor; UCN, urocortins.