Dataset Information

Mitochondrial respiratory function induces endogenous hypoxia.

ABSTRACT: Hypoxia influences many key biological functions. In cancer, it is generally believed that hypoxic condition is generated deep inside the tumor because of the lack of oxygen supply. However, consumption of oxygen by cancer should be one of the key means of regulating oxygen concentration to induce hypoxia but has not been well studied. Here, we provide direct evidence of the mitochondrial role in the induction of intracellular hypoxia. We used Acetylacetonatobis [2-(2'-benzothienyl) pyridinato-kN, kC3'] iridium (III) (BTP), a novel oxygen sensor, to detect intracellular hypoxia in living cells via microscopy. The well-differentiated cancer cell lines, LNCaP and MCF-7, showed intracellular hypoxia without exogenous hypoxia in an open environment. This may be caused by high oxygen consumption, low oxygen diffusion in water, and low oxygen incorporation to the cells. In contrast, the poorly-differentiated cancer cell lines: PC-3 and MDAMB231 exhibited intracellular normoxia by low oxygen consumption. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content reduced intracellular hypoxia, indicating that intracellular oxygen concentration is regulated by the consumption of oxygen by mitochondria. HIF-1? was activated in endogenously hypoxic LNCaP and the activation was dependent on mitochondrial respiratory function. Intracellular hypoxic status is regulated by glucose by parabolic dose response. The low concentration of glucose (0.045 mg/ml) induced strongest intracellular hypoxia possibly because of the Crabtree effect. Addition of FCS to the media induced intracellular hypoxia in LNCaP, and this effect was partially mimicked by an androgen analog, R1881, and inhibited by the anti-androgen, flutamide. These results indicate that mitochondrial respiratory function determines intracellular hypoxic status and may regulate oxygen-dependent biological functions.

SUBMITTER: Prior S

PROVIDER: S-EPMC3931703 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mitochondrial respiratory function induces endogenous hypoxia.

Prior Sara S Kim Ara A Yoshihara Toshitada T Tobita Seiji S Takeuchi Toshiyuki T Higuchi Masahiro M

PloS one 20140221 2

Hypoxia influences many key biological functions. In cancer, it is generally believed that hypoxic condition is generated deep inside the tumor because of the lack of oxygen supply. However, consumption of oxygen by cancer should be one of the key means of regulating oxygen concentration to induce hypoxia but has not been well studied. Here, we provide direct evidence of the mitochondrial role in the induction of intracellular hypoxia. We used Acetylacetonatobis [2-(2'-benzothienyl) pyridinato-k ...[more]

PMID: 24586439

Similar Datasets

Project description:Key pointsSleep apnoea increases susceptibility to opioid-induced respiratory depression (OIRD). Endogenous opioids are implicated as a contributing factor in sleep apnoea. Rats exposed to sleep-phase chronic intermittent hypercapnic hypoxia (CIHH) for 7 days exhibited exaggerated OIRD to systemic fentanyl both while anaesthetized and artificially ventilated and while conscious and breathing spontaneously, implicating heightened CNS inhibitory efficacy of fentanyl. CIHH also induced tonic endogenous opioid suppression of neural inspiration. Sleep-related episodes of hypercapnic hypoxia, as in sleep apnoea, promote hypersensitivity to OIRD, with tonic respiratory depression by endogenous opioids implicated as a potential underlying cause.AbstractSleep apnoea (SA) increases opioid-induced respiratory depression (OIRD) and lethality. To test the hypothesis that this results from chronic intermittent bouts of hypercapnic hypoxia (CIHH) accompanying SA, we compared OIRD across continuously normoxic control rats and rats exposed to sleep-phase (8 h/day) CIHH for 1 week. OIRD sensitivity was first assessed in anaesthetized (urethane/α-chloralose), vagotomized and artificially ventilated rats by recording phrenic nerve activity (PNA) to index neural inspiration and quantify PNA burst inhibition to graded doses (0, 2, 20, 50 μg kg-1 , i.v.) of the synthetic opioid fentanyl. Fentanyl dose-dependently reduced PNA burst frequency (P = 0.0098-0.0001), while increasing the duration of burst quiescence at 50 μg kg-1 (P < 0.0001, n = 5-6/group/dose). CIHH shifted the fentanyl dose-phrenic burst frequency response curve to the left (P = 0.0163) and increased the duration of burst quiescence (P < 0.0001). During fentanyl recovery, PNA burst width was increased relative to baseline in normoxic and CIHH rats. Systemic naloxone (1 mg kg-1 , i.v.) reversed fentanyl-induced PNA arrest in both groups (P = 0.0002), and increased phrenic burst amplitude above baseline (P = 0.0113) in CIHH rats only. Differential sensitivity to anaesthesia as a cause of CIHH-related OIRD hypersensitivity was excluded by observing in conscious spontaneously breathing rats that fentanyl at 20 μg kg-1 (i.v.), which silenced PNA in anaesthetized rats, differentially increased breathing variability in normoxic versus CIHH rats (P = 0.0427), while significantly reducing breathing frequency (P < 0.0001) and periodicity (P = 0.0003) in CIHH rats only. Findings indicate that CIHH increased OIRD sensitivity, with tonic inspiratory depression by endogenous opioids as a likely contributing cause.

Dataset Information

Mitochondrial respiratory function induces endogenous hypoxia.

Publications

Mitochondrial respiratory function induces endogenous hypoxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets