Biomedical subjects

N S Chandel

Publications and source records attributed to N S Chandel.

21 records · Page 2Linked to original sources

PubMed1997

Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria.

Mitochondrial physiology is disrupted in either apoptosis or necrosis. Here, we report that a wide variety of apoptotic and necrotic stimuli induce progressive mitochondrial swelling and outer mitochondrial membrane rupture. Discontinuity of the outer mitochondrial membrane results in cytochrome c redistribution from the intermembrane space to the cytosol followed by subsequent inner mitochondrial membrane depolarization. The mitochondrial membrane protein Bcl-xL can inhibit these changes in cells treated with apoptotic stimuli. In addition, Bcl-xL-expressing cells adapt to growth factor withdrawal or staurosporine treatment by maintaining a decreased mitochondrial membrane potential. Bcl-xL expression also prevents mitochondrial swelling in response to agents that inhibit oxidative phosphorylation. These data suggest that Bcl-xL promotes cell survival by regulating the electrical and osmotic homeostasis of mitochondria.

Anti-Bacterial Agents↗

PubMed1997

Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes.

We previously reported that hepatocytes exhibit a reversible suppression of respiration during prolonged hypoxia (PO2 = 20 torr for 3-5 h). Also, isolated bovine heart cytochrome c oxidase undergoes a reversible decrease in apparent Vmax when incubated under similar conditions. This study sought to link the hypoxia-induced changes in cytochrome oxidase to the inhibition of respiration seen in intact cells. Hepatocytes incubated at PO2 = 20 torr exhibited decreases in respiration and increases in [NAD(P)H] after 2-3 h that were reversed upon reoxygenation (PO2 = 100 torr). Respiration during hypoxia was also inhibited when N,N,N',N'-tetramethyl-p-phenylenediamine (0.5 mM) and ascorbate (5 mM) were used to reduce cytochrome c, suggesting that cytochrome oxidase was partially inhibited. Similarly, liver submitochondrial particles revealed a 44% decrease in the apparent Vmax of cytochrome oxidase after hypoxic incubation. In hepatocytes loaded with tetramethylrhodamine ethyl ester (10 nM) to quantify mitochondrial membrane potential, acute hypoxia (<30 min) produced no change in fluorescence, consistent with the absence of an acute change in respiration. However, fluorescence increased during acute reoxygenation after prolonged hypoxia, suggesting an increase in potential. The control exhibited by NADH over mitochondrial respiration was not altered during hypoxia. Thus, changes in the Vmax of cytochrome oxidase during prolonged hypoxia correlate with the changes in respiration and mitochondrial potential. This suggests that the oxidase functions as an oxygen sensor in the intact hepatocyte.

ATP Synthetase Complexes↗

PubMed1996

Molecular oxygen modulates cytochrome c oxidase function.

This study sought to determine whether molecular oxygen interacts with cytochrome c oxidase to modify its catalytic activity. Such an interaction could explain the observation that mitochondria incubated under low O2 concentrations exhibit a reversible suppression of State 3 respiration. Oxidized bovine heart cytochrome c oxidase was incubated in oxygen concentrations of <50 microM for 4 h. The enzyme exhibited a reversible decrease in Vmax after incubation, compared with control enzyme incubated at higher oxygen concentrations. This change was accompanied by a small increase in the apparent Km of the enzyme for both cytochrome c and oxygen, although the optical absorption spectra of oxidized, cycling, or reduced enzyme were not affected. Spectroscopy studies after 4 h of incubation revealed that heme a3 was 33% reduced during cycling at [O2] = 25 microM whereas enzyme at [O2] = 135 microM was only 18% reduced, suggesting that the site of inhibition occurred at the electron transfer step between heme a3 and O2. These results provide a mechanistic explanation for the observation that intact cells or mitochondria exhibit a reversible inhibition of respiration during prolonged exposure to [O2] <25 mM, by demonstrating that the catalytic activity of cytochrome c oxidase function is similarly inhibited, possibly through an allosteric effect of molecular O2 on the enzyme.

Animals↗