Actively phosphorylating mitochondria are more resistant to lactic acidosis than inactive mitochondria

1999 ◽  
Vol 277 (2) ◽  
pp. C288-C293 ◽  
Author(s):  
M. Tonkonogi ◽  
K. Sahlin
Keyword(s):  
Lactic Acid ◽  
Lactic Acidosis ◽  
Energy Production ◽  
Reaction Medium ◽  
Mitochondrial Oxygen Consumption ◽  
Physiological Conditions ◽  
Skeletal Muscle Mitochondria ◽  
Potassium Lactate ◽  
Menten Constant ◽  
Aerobic Energy Production

Oxidative phosphorylation of isolated rat skeletal muscle mitochondria after exposure to lactic acidosis in either phosphorylating or nonphosphorylating states has been evaluated. Mitochondrial respiration and transmembrane potential (ΔΨm) were measured with pyruvate and malate as the substrates. The addition of lactic acid decreased the pH of the reaction medium from 7.5 to 6.4. When lactic acid was added to nonphosphorylating mitochondria, the subsequent maximal ADP-stimulated respiration decreased by 27% compared with that under control conditions ( P < 0.05), and the apparent Michaelis-Menten constant ( K m) for ADP decreased to 10 μM vs. 20 μM ( P< 0.05) in controls. In contrast, maximal respiration and ADP sensitivity were not affected when mitochondria were exposed to acidosis during active phosphorylation in state 3. Acidosis significantly increased mitochondrial oxygen consumption in state 4 (post-state 3), irrespective of when acidosis was induced. This effect of acidosis was attenuated in the presence of oligomycin. The addition of lactic acid during state 4 respiration decreased ΔΨm by 19%. The ratio between added ADP and consumed oxygen (P/O) was close to the theoretical value of 3 in all conditions. The addition of potassium lactate during state 3 (i.e., medium pH unchanged) had no effect on the parameters measured. It is concluded that lactic acidosis has different effects when induced on nonphosphorylating vs. actively phosphorylating mitochondria. On the basis of these results, we suggest that the influence of lactic acidosis on muscle aerobic energy production depends on the physiological conditions at the onset of acidity.

Increased concentrations of Pi and lactic acid reduce creatine-stimulated respiration in muscle fibers

2002 ◽  
Vol 92 (6) ◽  
pp. 2273-2276 ◽  
Author(s):  
B. Walsh ◽  
T. Tiivel ◽  
M. Tonkonogi ◽  
K. Sahlin
Keyword(s):  
Skeletal Muscle ◽  
Lactic Acid ◽  
Lactic Acidosis ◽  
High Intensity ◽  
Respiratory Function ◽  
Fiber Bundles ◽  
Ph Values ◽  
Skeletal Muscle Mitochondria ◽  
Rat Soleus Muscle ◽  
Skinned Fiber Bundles

We tested the hypothesis that the respiratory function of skeletal muscle mitochondria is impaired by lactic acidosis and elevated concentrations of Pi. The rate of respiration of chemically skinned fiber bundles from rat soleus muscle was measured at [Pi] (brackets denote concentration) and pH values similar to those at rest (3 mM Pi, pH 7.0) and high-intensity exercise (20 mM Pi, pH 6.6). Respiration was measured in the absence of ADP and after sequential additions of 0.1 mM ADP, 20 mM creatine (Cr; V˙Cr), and 4 mM ADP. Respiration at 0.1 mM ADP increased after addition of Cr. However,V˙Cr was 23% lower ( P < 0.05) during high-intensity conditions than during resting conditions.V˙Cr was also reduced when Pi or H+ was increased separately ( P < 0.05). Respiration in the absence of ADP and after additions of 0.1 mM ADP and 4 mM ADP was not affected by changes in [Pi] or [H+]. The response was similar, irrespective of when acidosis was induced (i.e., quiescent or actively respiring mitochondria). In conclusion, Cr-stimulated respiration is impaired by increases in [H+] and [Pi] corresponding to those in exercising muscle. Although the reduced Cr-stimulated respiration could be compensated for by increased [ADP], this might have implications for intracellular homeostasis.

scholarly journals Reversible ATP-induced inactivation of branched-chain 2-oxo acid dehydrogenase

1980 ◽  
Vol 192 (1) ◽  
pp. 155-163 ◽  
Author(s):  
R Odessey
Keyword(s):  
Skeletal Muscle ◽  
Liver Mitochondria ◽  
Initial Activity ◽  
Rat Skeletal Muscle ◽  
Kidney Mitochondria ◽  
Physiological Conditions ◽  
Acid Dehydrogenase ◽  
Skeletal Muscle Mitochondria ◽  
Branched Chain

The branched chain 2-oxo acid dehydrogenase from rat skeletal muscle, heart, kidney and liver mitochondria can undergo a reversible activation-inactivation cycle in vitro. Similar results were obtained with the enzyme from kidney mitochondria of pig and cow. The dehydrogenase is markedly inhibited by ATP and the inhibition is not reversed by removing the nucleotide. The non-metabolizable ATP analogue adenosine 5′-[beta gamma-imido] triphosphate can block the effect of ATP when added with the nucleotide, but has no effect by itself, nor can it reverse the inhibition in mitochondria preincubated with ATP. These findings suggest that the branched chain 2-oxo acid dehydrogenase undergoes a stable modification that requires the splitting of the ATP gamma-phosphate group. In skeletal muscle mitochondria the rate of inhibition by ATP is decreased by oxo acid substrates and enhanced by NADH. The dehydrogenase can be reactivated 10-20 fold by incubation at pH 7.8 in a buffer containing Mg2+ and cofactors. Reactivation is blocked by NaF (25 mM). The initial activity of dehydrogenase extracted from various tissues of fed rats varies considerably. Activity is near maximal in kidney and liver whereas the dehydrogenase in heart and skeletal muscle is almost completely inactivated. These studies emphasize that comparisons of branched chain 2-oxo acid dehydrogenase activity under various physiological conditions or in different tissues must take into account its state of activation. Thus the possibility exists that the branched chain 2-oxo acid dehydrogenase may be physiologically regulated via a covalent mechanism.

scholarly journals Tumor Lactic Acidosis: Protecting Tumor by Inhibiting Cytotoxic Activity Through Motility Arrest and Bioenergetic Silencing

2020 ◽  
Vol 10 ◽  
Author(s):  
Angelika J. Fischbeck ◽  
Svenja Ruehland ◽  
Andreas Ettinger ◽  
Kerstin Paetzold ◽  
Ilias Masouris ◽  
...  
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Lactic Acidosis ◽  
Tumor Cell ◽  
Cytotoxic Activity ◽  
Adoptive T Cell Therapy ◽  
Normal Medium ◽  
Granule Exocytosis ◽  
Prolonged Contact

Adoptive T cell therapy (ACT) is highly effective in the treatment of hematologic malignancies, but shows limited success in solid tumors. Inactivation of T cells in the tumor milieu is a major hurdle to a wider application of ACT. Cytotoxicity is the most relevant activity for tumor eradication. Here, we document that cytotoxic T cells (CTL) in lactic acidosis exhibited strongly reduced tumor cell killing, which could be compensated partly by increasing the CTL to tumor cell ratio. Lactic acid intervened at multiple steps of the killing process. Lactic acid repressed the number of CTL that performed lytic granule exocytosis (degranulation) in tumor cell co-culture, and, additionally impaired the quality of the response, as judged by the reduced intensity of degranulation and lower secretion of cytotoxins (perforin, granzyme B, granzyme A). CTL in lactic acid switched to a low bioenergetic profile with an inability to metabolize glucose efficiently. They responded to anti-CD3 stimulation poorly with less extracellular acidification rate (ECAR). This might explain their repressed granule exocytosis activity. Using live cell imaging, we show that CTL in lactic acid have reduced motility, resulting in lower field coverage. Many CTL in lactic acidosis did not make contact with tumor cells; however, those which made contact, adhered to the tumor cell much longer than a CTL in normal medium. Reduced motility together with prolonged contact duration hinders serial killing, a defining feature of killing potency, but also locally confines cytotoxic activity, which helps to reduce the risk of collateral organ damage. These activities define lactic acid as a major signaling molecule able to orchestrate the spatial distribution of CTL inside inflamed tissue, such as cancer, as well as moderating their functional response. Lactic acid intervention and strategies to improve T cell metabolic fitness hold promise to improve the clinical efficacy of T cell–based cancer immunotherapy.

scholarly journals Erroneously High Lactate: A Guide to Diagnosing Ethylene Glycol Poisoning

2019 ◽  
Vol 4 (2) ◽  
pp. 1-3
Author(s):  
Mayanka Kamboj ◽  
Harini Bejjanki ◽  
Saraswathi Gopal ◽  
Rupam Ruchi
Keyword(s):  
Lactic Acid ◽  
Lactic Acidosis ◽  
Ethylene Glycol ◽  
Critically Ill Patients ◽  
Poor Prognosis ◽  
Acid Level ◽  
Lactic Acid Level ◽  
Analytical Interference ◽  
Ethylene Glycol Poisoning ◽  
High Lactate

A high lactic acid level in critically ill patients is a marker of poor prognosis. However, lactic acidosis in ethylene glycol (EG) poisoning should be interpreted cautiously as analytical interference is observed with EG metabolites.

Distribution of pulmonary vascular resistance during lactic acid infusion in dogs

1990 ◽  
Vol 68 (4) ◽  
pp. 1328-1336 ◽  
Author(s):  
K. W. Presberg ◽  
J. I. Sznajder ◽  
J. Melendres ◽  
T. Lewis ◽  
C. Abrahams ◽  
...  
Keyword(s):  
Lactic Acid ◽  
Lactic Acidosis ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Light And Electron Microscopy ◽  
Balloon Occlusion ◽  
Longitudinal Distribution ◽  
Acid Infusion ◽  
Systemic Artery ◽  
Systemic Vein

We sought to determine the longitudinal distribution of pulmonary vascular resistance (PVR) in acute lactic acidosis utilizing pulmonary artery and vein balloon occlusion techniques (Holloway et al. J. Appl. Physiol. 54: 840-851, 1983). In anesthetized dogs, both a systemic vein (I-V) infusion and systemic artery (I-A) infusion of L-lactic acid were studied to control for potential effects of factors other than pH on PVR. During progressive I-A infusion (n = 9) to a pH of 6.94 +/- 0.06 there was no significant change in PVR or its distribution. In contrast, I-V infusion (n = 9) to a pH of 7.08 +/- 0.09 increased median PVR from 3.6 to 21.7 mmHg.1(-1).min (P less than 0.001), due to an increase in middle segment resistance (0.0-15.4 mmHg.1(-1).min, P less than 0.02). Examination by light and electron microscopy demonstrated pulmonary capillary obstruction with hemolyzed erythrocyte (RBC) membranes with I-V infusion, but representative I-A animals did not demonstrate these findings. Conceivably, the systemic vascular bed filtered the fragmented RBC membranes in the I-A model, but this microvascular obstruction with altered RBCs and RBC fragments caused the pulmonary hypertension observed in the I-V infusion. We conclude that lactic acidosis does not increase pulmonary vascular tone in dogs, a finding compatible with most previous studies in which observed increases in PVR may be attributed to other effects from I-V acid infusion on circulating blood elements.

Renal cell cancer (RCC): Use of metformin in the setting of renal impairment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15551-e15551
Author(s):  
Nwabugwu Ochuwa ◽  
Kevin Finkel ◽  
Fangqian Ouyang ◽  
Robert J. Amato
Keyword(s):  
Lactic Acid ◽  
Lactic Acidosis ◽  
Renal Impairment ◽  
Demographic Data ◽  
Cell Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Significant Difference ◽  
Life Threatening ◽  
Student’S T ◽  
Amp Activated Protein Kinase

e15551 Background: Metformin is a biguanide that is widely used to treat type-2 diabetes and prediabetic syndromes. It has been found to inhibit RCC cell proliferation through activation of AMP-activated protein kinase (AMPK) and downstream inhibition of mammalian target of rapamycin (mTOR). Metformin is associated with potentially life threatening lactic acidosis (LA), but a clear link has not been established. We evaluated the occurrence of lactic acidosis in metformin-treated RCC patients with renal impairment. Methods: A retrospective study of 65 RCC patients treated with 250 to 2000 mg of metformin daily was conducted. Demographic data including age, gender, and ethnic background were collected. Data were collected on median metformin dose, eGFR, dialysis status, lactic acid, BUN, Na, K, Cl, and CO2 values. Results: Median metformin dose was 1000 mg daily in each group. Fifteen patients (23%) had elevated lactic acid >4. The mean eGFR for patients with elevated lactic acid of >4 vs. <4is comparable (p=0.98). The two populations were significantly different at the BUN baseline level: patients with lactic acids >4 have statistically significant smaller median baseline BUN level (median of 19.0 vs. 19.5; Wilcoxon two-sample p=0.03). Moreover, there is a marginally significant difference in age between these 2 groups (Mean of 58 vs. 62.8, Student's t-test p=0.07). Conclusions: Regardlessof lactic acid elevation, patients did not experience lactic acidosis. Complete data will be presented. [Table: see text]

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