The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth.
*Collateral Circulation; *Coronary Circulation; *Energy Metabolism; *Neovascularization; angiogenesis; Animals; arteriogenesis; Coronary Vessels/metabolism; Humans; mitochondria; Mitochondria; Mitochondrial Proteins/metabolism; Muscle; Muscle/*metabolism; Myocytes; Oxidative Stress; Phenotype; Physiologic; Reactive Oxygen Species/*metabolism; redox-dependent signaling; Signal Transduction; Smooth; Smooth Muscle/*metabolism; Vascular/*metabolism
Coronary collateral growth is a process involving coordination between growth factors expressed in response to ischemia and mechanical forces. Underlying this response is proliferation of vascular smooth muscle and endothelial cells, resulting in an enlargement in the caliber of arterial-arterial anastomoses, i.e., a collateral vessel, sometimes as much as an order of magnitude. An integral element of this cell proliferation is the process known as phenotypic switching in which cells of a particular phenotype, e.g., contractile vascular smooth muscle, must change their phenotype to proliferate. Phenotypic switching requires that protein synthesis occurs and different kinase signaling pathways become activated, necessitating energy to make the switch. Moreover, kinases, using ATP to phosphorylate their targets, have an energy requirement themselves. Mitochondria play a key role in the energy production that enables phenotypic switching, but under conditions where mitochondrial energy production is constrained, e.g., mitochondrial oxidative stress, this switch is impaired. In addition, we discuss the potential importance of uncoupling proteins as modulators of mitochondrial reactive oxygen species production and bioenergetics, as well as the role of AMP kinase as an energy sensor upstream of mammalian target of rapamycin, the master regulator of protein synthesis.
Pung Yuh Fen; Sam Wai Johnn; Hardwick James P; Yin Liya; Ohanyan Vahagn; Logan Suzanna; Di Vincenzo Lola; Chilian William M
American journal of physiology. Heart and circulatory physiology
2013
2013-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00077.2013" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00077.2013</a>
Impairment of pH gradient and membrane potential mediates redox dysfunction in the mitochondria of the post-ischemic heart.
*Energy Metabolism; *Membrane potential; *Membrane Potential; *Mitochondria; *Myocardial ischemia and reperfusion; *Oxidative Stress; *pH gradient; *Redox dysfunction; Aconitate Hydratase/metabolism; Animal; Animals; Cell Line; Disease Models; Electron Transport Chain Complex Proteins/metabolism; Heart/*metabolism/pathology; Hydrogen Peroxide/metabolism; Hydrogen-Ion Concentration; Ionophores/pharmacology; Male; Mitochondria; Mitochondrial; Myocardial Infarction/*metabolism/pathology; Myocardium/*metabolism/pathology; Oxidation-Reduction; Potassium/metabolism; Rats; Sprague-Dawley; Superoxides/metabolism
The mitochondrial electrochemical gradient (Deltap), which comprises the pH gradient (DeltapH) and the membrane potential (DeltaPsi), is crucial in controlling energy transduction. During myocardial ischemia and reperfusion (IR), mitochondrial dysfunction mediates superoxide ((.)O2(-)) and H2O2 overproduction leading to oxidative injury. However, the role of DeltapH and DeltaPsi in post-ischemic injury is not fully established. Here we studied mitochondria from the risk region of rat hearts subjected to 30 min of coronary ligation and 24 h of reperfusion in vivo. In the presence of glutamate, malate and ADP, normal mitochondria (mitochondria of non-ischemic region, NR) exhibited a heightened state 3 oxygen consumption rate (OCR) and reduced (.)O2(-) and H2O2 production when compared to state 2 conditions. Oligomycin (increases DeltapH by inhibiting ATP synthase) increased (.)O2(-) and H2O2 production in normal mitochondria, but not significantly in the mitochondria of the risk region (IR mitochondria or post-ischemic mitochondria), indicating that normal mitochondrial (.)O2(-) and H2O2 generation is dependent on DeltapH and that IR impaired the DeltapH of normal mitochondria. Conversely, nigericin (dissipates DeltapH) dramatically reduced (.)O2(-) and H2O2 generation by normal mitochondria under state 4 conditions, and this nigericin quenching effect was less pronounced in IR mitochondria. Nigericin also increased mitochondrial OCR, and predisposed normal mitochondria to a more oxidized redox status assessed by increased oxidation of cyclic hydroxylamine, CM-H. IR mitochondria, although more oxidized than normal mitochondria, were not responsive to nigericin-induced CM-H oxidation, which is consistent with the result that IR induced DeltapH impairment in normal mitochondria. Valinomycin, a K(+) ionophore used to dissipate DeltaPsi, drastically diminished (.)O2(-) and H2O2 generation by normal mitochondria, but less pronounced effect on IR mitochondria under state 4 conditions, indicating that DeltaPsi also contributed to (.)O2(-) generation by normal mitochondria and that IR mediated DeltaPsi impairment. However, there was no significant difference in valinomycin-induced CM-H oxidation between normal and IR mitochondria. In conclusion, under normal conditions the proton backpressure imposed by DeltapH restricts electron flow, controls a limited amount of (.)O2(-) generation, and results in a more reduced myocardium; however, IR causes DeltapH impairment and prompts a more oxidized myocardium.
Kang Patrick T; Chen Chwen-Lih; Lin Paul; Chilian William M; Chen Yeong-Renn
Basic research in cardiology
2017
2017-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-017-0626-1" target="_blank" rel="noreferrer noopener">10.1007/s00395-017-0626-1</a>