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At least 19 recordsLinked to original sources
PubMed1990

Respiratory control and ADP:O coupling ratios of isolated chick heart mitochondria.

Heart mitochondria isolated from 14- to 21-day-old chicks are highly coupled and often have respiratory control ratio (RCR) values exceeding 100. This paper presents data from a study of some of the properties of these mitochondria. The studies show that: (a) The ADP:O ratios and the state 4 rates of respiration are highly dependent upon the concentration of mitochondria at which these parameters are measured. (b) The mitochondrial isolate is contaminated with at least two divalent cation-stimulated ATPase, of which one is the F1F0-ATPase of broken mitochondria. (c) The oligomycin-sensitive component of state 4 respiration is completely inhibited by ethylene glycol bis(beta-amino-ethylether) N,N'-tetraacetic acid (EGTA). This inhibition is biphasic and attributable to the differential affinity of EGTA for Ca(II) and Mg(II). (d) Ca(II) and Mg(II) stimulate state 4 respiration, thereby depressing RCR values. These cations also decrease ADP:O ratios from greater than or equal to 3.25 to 3.0 for some NAD-linked substrates. (e) Uncoupled (i.e., oligomycin-insensitive) state 4 respiration can be abolished by treating the mitochondria with Nagarse and by preincubating mitochondria with exogenous substrate. (f) The ADP:O ratios obtained when these heart mitochondria oxidize pyruvate/malate, alpha-ketoglutarate, and beta-hydroxybutyrate are fractional and significantly greater than 3.0.

3-Hydroxybutyric Acid↗
PubMed1984

K+/H+ antiport in heart mitochondria.

Heart mitochondria depleted of endogenous divalent cations by treatment with A23187 and EDTA swell in (a) K+ acetate or (b) K+ nitrate when an uncoupler is present. These mitochondria also exchange matrix 42K+ with external K+, Na+, or Li+ in a reaction that does not require respiration and is insensitive to uncouplers. Untreated control mitochondria do not swell in either medium nor do they show the passive cation exchange. Both the swelling and the exchange reactions are inhibited by Mg2+ and by quinine and other lipophilic amines. Swelling and exchange are both strongly activated at alkaline pH, and the exchange reaction is also increased markedly by hypotonic conditions. All of these properties correspond to those reported for a respiration-dependent extrusion of K+ from Mg2+-depleted mitochondria, a reaction attributed to a latent Mg2+- and H+-sensitive K+/H+ antiport. The swelling reactions are strongly inhibited by dicyclohexylcarbodiimide reacted under hypotonic conditions, but the exchange reaction is not sensitive to this reagent. Heart mitochondria depleted of Mg2+ show marked increases in their permeability to H+, to anions, and possibly to cations, and the permeability to each of these components is further increased at alkaline pH. This generalized increase in membrane permeability makes it likely that K+/H+ antiport is not the only pathway available for K+ movement in these mitochondria. It is concluded that the swelling, 42K+ exchange, and K+ extrusion data are all consistent with the presence of the putative K+/H+ antiport but that definitive evidence for the participation of such a component in these reactions is still lacking.

Animals↗
PubMed1980

Induction of Na+/K+ exchange in swollen heart mitochondria.

Heart mitochondria swollen passively in nitrate salts contract in a respiration-dependent reaction which can be attributed to an endogenous cation/H+ exchange component (or components). The rate of contraction increases with increased extent of passive swelling in both Na+ and K+ salts. Since nearly constant internal cation concentrations are maintained during osmotic swelling, this result suggests that both Na+/H+ and K+/H+ exchange is enhanced by increased matrix volume. Endogenous Mg2+ is also lost with increased matrix volume, and this observation, in conjunction with other evidence available in the literature, suggests that monovalent cation/H+ exchanges may be regulated by divalent cations. Passive exchange of Na+/K+, 42K+/K+, and 24Na+/Na+ can be readily demonstrated in mitochondria swollen in nitrate. All these exchanges are low or not detectable in unswollen control mitochondria, and it appears that they are manifestations of the activated cation/H+ component (or components) functioning in the absence of delta pH.

Animals↗
PubMed1995

Evidence for the involvement of a membrane-associated cyclosporin-A-binding protein in the Ca(2+)-activated inner membrane pore of heart mitochondria.

Heart and liver mitochondria contain a pore in the inner membrane that is activated by Ca2+ and oxidative stress and that has been implicated in cell injury. Pore opening is blocked by cyclosporin A (CSA). Following previous indications that the interaction of CSA with the pore is inhibited by Ca2+ and promoted by ADP, we have investigated how covalent labelling of heart mitochondria by a photoactive CSA derivative is influenced by these agents. In situ photolabelling of an 11-22-kDa (approximately) membrane fraction was selectively increased in the presence of ADP and decreased in the presence of Ca2+. This fraction also accounted for all the high affinity [3H]CSA-binding capacity and contained peptidylprolyl cis-trans isomerase activity (PPIase). The membrane PPIase was extracted using Chaps as detergent, and was purified to a 22-kDa protein (SDS/PAGE). The enzyme was inhibited by CSA (Ki 5 nM). The major component of the 11-22-kDa fraction, photolabelled in an ADP/Ca(2+)-sensitive manner, also migrated at 22 kDa on SDS/PAGE; a minor 11-kDa component was also detected. On the basis of these criteria, it is suggested that the membrane PPIase may be the target for CSA when it blocks the pore. The presence of a similar PPIase in the membrane fraction of liver mitochondria was also demonstrated. The implications of these findings are discussed.

Adenosine Diphosphate↗
PubMed2004

Production and export of metabolites from liver and heart mitochondria and anaplerosis.

A method to study the export of citric acid cycle intermediates from rat liver mitochondria supplied with various individual substrates or combinations of substrates was designed to focus on the role of mitochondria in anaplerosis and cataplerosis. Under most conditions malate, citrate, and aspartate were exported in far higher amounts than isocitrate and alpha-ketoglutarate. In the presence of pyruvate alone or pyruvate in combination with most other substrates, citrate export equaled or was only slightly less than malate export. This contrasts with pancreatic islet mitochondria where citrate export is unaffected by many substrates. Malate and succinate potentiated pyruvate-induced citrate export and succinate caused massive malate export from liver mitochondria. Heart mitochondria, which possess very little or no pyruvate carboxylase, unlike liver and pancreatic islet mitochondria, did not produce malate from pyruvate. Heart mitochondria produced malate, but not citrate, from succinate. The results indicate that liver mitochondria export a larger number of metabolites from a wider range of substrates than do islet or heart mitochondria. This may reflect the multiple roles of the liver in body metabolism versus the specialized roles of the islet cell and heart.

Amino Acids↗
PubMed2002

Effect of Ca(2+) and Mg(2+) on the Mn-superoxide dismutase from rat liver and heart mitochondria.

The manganese superoxide dismutase (Mn-SOD) converts superoxide anions to hydrogen peroxide plus oxygen, providing the first line of defense against oxidative stress in mitochondria. Heart mitochondria exhibited higher Mn-SOD activity than liver mitochondria. In mitochondria from both tissues Mn-SOD activity decreased after incubation at low oxygen concentration (hypoxic mitochondria). The effects of free Ca(2+) ([Ca(2+)](f)) and free Mg(2+) ([Mg(2+)](f)) on normoxic and hypoxic mitochondria from either organ were tested. In normoxic mitochondria from either tissue, both [Ca(2+)](f) and [Mg(2+)](f) activated the enzyme, although [Mg(2+)](f) was less efficient as an activator and the effect was lower in heart than in liver mitochondria. When added simultaneously, high [Ca(2+)](f) and [Mg(2+)](f) exhibited additive effects which were more pronounced in heart mitochondria and were observed regardless of whether mitochondria had been incubated under normal or low oxygen. The data suggest that [Ca(2+)](f) plays a role in regulating Mn-SOD in concert with the activation of aerobic metabolism.

Animals↗
PubMed1984

Effect of hypnorm, chloralosane and pentobarbital on the ultrastructure of the inner membrane of rat heart mitochondria.

Rat heart mitochondria were isolated from four groups of animals treated in a different way. The animals of the first group were killed after decapitation (D-group) without previous anaesthesia. The three other groups of animals were anaesthetised with different anaesthetics. The second group (N-group) was anaesthetised with nembutal (sodium pentobarbital), the third group with chloralosane (C-group) and the fourth group with hypnorm (H-group). From these three anaesthetics only nembutal is known to interact with mitochondria. After retrograde perfusion and excision of the heart, mitochondria were prepared from the ventricles by standard methods. After freeze-fracturing the mitochondrial suspension, the intramembrane particle dimension and density on both fracture faces of the inner mitochondrial membrane were measured. The intramembrane particle diameter on the P-face of the inner membrane of the N-group mitochondria was significantly different from D-, C- and H-group mitochondria. Also the density and diameter of the intramembrane particles on the mitochondrial inner membrane of D-group mitochondria compared to C- and H-group mitochondria were significantly different at the 95% level of confidence. Between C- and H-group mitochondria no differences of these parameters were observed. From these results it is clear that, depending on the pretreatment of the animals, a different substructure of the inner membrane of heart mitochondria is obtained.

Animals↗
PubMed1993

Conditions for glutamate dehydrogenase activity in heart mitochondria.

Although heart mitochondria contain glutamate dehydrogenase, it has not been thought to play a role in their metabolism. We investigated this matter to define the conditions under which it is active. We found modest activity in the presence of glutamate and malate and a continuous source of ADP when pyruvate is added. This increases several fold as the osmolarity is increased from 296 to 370 mosM. At the higher osmolarity ammonia formation is brief, associated with a lower intramitochondrial alpha-ketoglutarate from citrate does not make up for the drop in glutamate conversion to alpha-ketoglutarate. Mitochondrial content of nucleotides and CoA compounds are not altered by pyruvate addition. The rate of glutamate deamination by GDH in sonicated heart mitochondria agrees with the rate of ammonia formation in intact mitochondria in the presence of pyruvate (20 nmol/min/mg of mitochondrial protein). We conclude pyruvate lowers mitochondrial oxalacetate which decreases alpha-ketoglutarate formation by transamination. The lower mitochondria alpha-ketoglutarate level permits glutamate deamination until alpha-ketoglutarate reaches a level that inhibits the forward reaction. Further proof of the key role of alpha-ketoglutarate is seen with aminooxyacetate which blocks transamination. In its presence ammonia formation occurs at the same rate (18 nm/min/mg of mitochondrial protein), is not dependent upon pyruvate, and does not stop after a couple of minutes. Leucine, which decreases alpha-ketoglutarate inhibition of GDH, also results in ammonia formation, further supporting the concept of regulation by alpha-ketoglutarate. The higher osmolarity increases GDH activity by increasing alpha-ketoglutarate transport from mitochondria.

Adenosine Diphosphate↗
PubMed1985

A combination of methods for the preparation of highly intact mitoplasts from beef heart mitochondria.

Beef heart mitochondria are noted for difficulty of fractionation compared to mitochondria from other tissues. A method that would give the desired efficiency while leaving the inner membrane intact did not seem to be available. Four variables, alone and in all possible combinations, were evaluated for their effectiveness in fractionation. These variables were treatment with digitonin, hypotonic swelling, phospholipase A2 predigestion, and addition of high concentrations of EDTA. The efficiency of fractionation was evaluated by electron microscopy and marker enzyme assays. Highly intact mitoplasts were obtained when the mitochondria were treated with digitonin together with intense hypotonic swelling, or moderate hypotonic swelling and phospholipase A2 predigestion, or EDTA addition and phospholipase predigestion. The enzyme GTP:AMP phosphotransferase was found to be located exclusively in the matrix compartment.

Adenylate Kinase↗
PubMed1989

Studies on mitochondrial Ca2+-transport and matrix Ca2+ using fura-2-loaded rat heart mitochondria.

Rat heart mitochondria were incubated for 5 min at 30 degrees C and at approx. 40 mg protein.ml-1 and in the presence of 10 microM fura-2/AM. This allowed the entrapment of free fura-2 within the mitochondrial matrix and its use as a probe for Ca2+, but without affecting the apparent viability of the mitochondria. Parallel measurements of the activities of the intramitochondrial Ca2+-sensitive enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase, allowed an assessment of their sensitivity to measured free Ca2+ within intact mitochondria incubated under different conditions; the enzymes responded to matrix Ca2+ over the approximate range 0.02-2 microM with half-maximal effects at about 0.3-0.6 microM Ca2+. Effectors of Ca2+-transport across the inner membrane (e.g., Na+, Mg2+, Ruthenium red, spermine) did not appear to affect these ranges, but did bring about expected changes in Ca2+ distribution across this membrane. Significantly, when mitochondria were incubated in the presence of physiological concentrations of both Na+ and Mg2+, and at low extramitochondrial Ca2+ (less than 400 nM), there was a gradient of Ca2+ (in:out) of less than unity; at higher extramitochondrial [Ca2+] (but still within the physiological range) the gradient was greater than unity indicating a highly cooperative nature of transmission of the Ca2+ signal into the matrix under such conditions.

Animals↗
PubMed1987

Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria.

Rat heart mitochondria became permeabilized to sucrose when incubated with 100 nmol of Ca2+/mg of protein in the presence of Pi. Ca2+ chelation with EGTA restored impermeability to sucrose, which became entrapped in the matrix space. t-Butylhydroperoxide markedly promoted permeabilization in the presence of Ca2+ but not in its absence, and Ca2+-plus-t-butylhydroperoxide-induced permeabilization was reversed by EGTA. The data suggest that Ca2+ and oxidative stress synergistically promote the reversible opening of an inner membrane pore.

Animals↗
PubMedDate not supplied

[Uncoupled oxidation in rat heart mitochondria].

Isolated heart mitochondria possessing a high phosphorylation efficiency with pyruvate and malate as substrates oxidize NADH and ascorbate unassociated with ADP phosphorylation. This uncoupled pathway is expressed partially when succinate or NAD-linked substrates are oxidized. The uncoupled oxidation is likely to be the result of the presence of a mitochondrial population with the high-permeable inner membrane in intact tissues. The nature and origin of a uncoupled respiratory system and its role in the thermoproduction of endotherms are discussed.

Animals↗
PubMed1979

[The effect of carbocromen on the respiratory function of rat heart mitochondria].

Rat heart mitochondria were isolated by a slightly modified method of Sordahl. The influence of carbocromen (Intensaín) on the respiratory function of the tightly coupled or uncoupled mitochondria was tested in the presence of the respiratory substrates pyruvate, alpha-ketoglutarate, D,L-palmitoylcarnitine, L-palmitoylcarnitine, and D,L-acetylcarnitine. Carbocromen (0.089--0.89 mmol/l) did not change the P/O ratio, but reduced the rate of oxygen consumption (QO2) of the coupled mitochondria by about 20% when palmitoylcarnitine was used as respiratory substrate. With ADP in excess (5 mmol/l) carbocromen decreased QO2 in state ST3 by about 35%. This drug induced reduction of QO2 is still much more evident in uncoupled mitochondria (18% with 0.045 mmol/l carbocromen, 70% with 0.89 mmol/l carbocromen). In the presence of pyruvate as substrate the respiratory function of the coupled and uncoupled mitochondria remained nearly unchanged after adding the drug. It is discussed that carbocromen could interact with the complex enzyme dependent transport of long-chain fatty acids through the mitochondrial membrane.

Adenosine Diphosphate↗
PubMed1984

[Kinetic differences in the oxidative phosphorylation system of control and ischemia-damaged heart mitochondria].

Rabbit heart mitochondria isolated with or without rotenone (M + R and M -R, respectively) were studied. It was shown with the use of pHmetry that the Vmax of oxidative phosphorylation decreased during ischemia (autolysis for 0.5 h at 37 degrees C) in both preparations of the mitochondria to the same extent. The Km for ADP was unchanged in M - R, but rose significantly in M + R. Carnitine reduced the ischemia -increased Km value. The data suggest the inhibition of adenine nucleotide translocase by longchain acyl-Co A, whose level was found to be elevated by 52% in M + R during ischemia.

Animals↗
PubMed2001

Effects of desmin gene knockout on mice heart mitochondria.

In heart tissue from mice lacking the intermediate filament (IF) desmin, mitochondria show an abnormal shape and distribution (Thornell et al., 1997). In the present study we have isolated heart mitochondria from desmin null (D-/-) and control (D+/+) mice, and analyzed their composition by SDS-PAGE, immunoblotting, and enzyme measurements. We found both in vitro and in situ that the conventional kinesin, the microtubule-associated plus-end directed motor, was frequently associated with D+/+ heart mitochondria, but not with D-/- heart mitochondria, suggesting that the positioning of mitochondria in heart is a dynamic event involving the IF desmin, the molecular motor kinesin, and, most likely, the microtubules (MT) network. Furthermore, an increased capacity in energy production was found, as indicated by a threefold higher creatine kinase activity in heart mitochondria from D-/- compared to D+/+ mice. We also observed a significantly lower amount of cytochrome c in heart mitochondria from D-/- mice, and a relocalization of Bcl-2, which may indicate an apoptotic condition in the cell leading to the earlier reported pathological events, such as cardiomyocytes degeneration and calcinosis of the heart (Thornell et al., 1997).

Animals↗
PubMedDate not supplied

The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines.

The molecular mechanism of the anthracycline-dependent development of cardiotoxicity is still far from being clear. However, it is generally accepted, that mitochondria play a significant role in triggering this organ specific injury. The results presented in this study demonstrate that, in contrast to liver mitochondria, isolated heart mitochondria shuttle single electrons to adriamycin, giving rise to oxygen radical formation via autoxidation of adriamycin semiquinones. This one electron reduction of anthracyclines is catalyzed by the exogenous NADH dehydrogenase associated with complex I of heart mitochondria, an enzyme which is lacking in liver mitochondria. Upon addition of NADH heart mitochondria generate significant amounts of adriamycin semiquinones while liver mitochondria were ineffective. Adriamycin semiquinones undergo both autoxidation leading to superoxide radical release and complex reactions under formation of adriamycin aglycone. Due to the high lipophilicity adriamycin aglycones accumulate in the inner mitochondrial membrane where they interfere with electron carriers of the respiratory chain. Adriamycin aglycone semiquinones emerging from an interaction with complex I were found to trigger homolytic cleavage of H2O2 which results in the formation of hydroxyl radicals. As demonstrated in this study the activation of adriamycin by the exogenous NADH dehydrogenase of cardiac mitochondria initiates a cascade of reaction steps leading to the establishment of oxidative stress. Our experiments suggest the exogenous NADH dehydrogenase of heart mitochondria to play a key role in the cardiotoxicity of adriamycin. This organ-specific enzyme initiates a sequence of one electron transfer reactions ending up in the establishment of oxidative stress.

Animals↗