Mitochondria: Oxygen sinks rather than sensors?

Abstract

At the cellular level, oxygen partial pressure (pO2) is sensed by a family of protein hydroxylases. These enzymes transmit the information about the current pO2 directly to hypoxia-inducible transcription factors (HIFs) in the form of covalently attached hydroxy groups which regulate abundance and activity of the HIFs. In addition to this highly specific and direct mechanism of oxygen sensing, mitochondria were repeatedly proposed to sense oxygen and to transmit the signal in the form of a side product of the electron transport chain, i.e. the reactive oxygen species (ROS). However, the exact correlation between pO2 and ROS production, the precise downstream targets of ROS, and how ROS regulate these targets at the molecular level, are questions that remain unanswered. Supported by recent novel data, an alternative model is discussed which is based on the redirection of oxygen towards the protein hydroxylase oxygen sensors. Under conditions of changes in oxygen usage, e.g. following changes in mitochondrial function or cellular metabolism, oxygen redirection would provide an elegant explanation for HIF regulation under apparently constant external oxygen concentrations. SummaryAt the cellular level, oxygen partial pressure (pO 2 ) is sensed by a family of protein hydroxylases. These enzymes transmit the information about the current pO 2 directly to hypoxia-inducible transcription factors (HIFs) in the form of covalently attached hydroxy groups which regulate abundance and activity of the HIFs. In addition to this highly specific and direct mechanism of oxygen sensing, mitochondria were repeatedly proposed to sense oxygen and to transmit the signal in the form of a side product of the electron transport chain, i.e. the reactive oxygen species (ROS). However, the exact correlation between pO 2 and ROS production, the precise downstream targets of ROS, and how ROS regulate these targets at the molecular level, are questions that remain unanswered. Supported by recent novel data, an alternative model is discussed which is based on the redirection of oxygen towards the protein hydroxylase oxygen sensors. Under conditions of changes in oxygen usage, e.g. following changes in mitochondrial function or cellular metabolism, oxygen redirection would provide an elegant explanation for HIF regulation under apparently constant external oxygen concentrations. 3 Oxygen sensing in health and diseaseThe transcriptional regulator hypoxia-inducible factor (HIF) is central to physiological and pathological processes involved in the adaptation to decreased oxygen availability. More than 70 direct target genes are known up to date and expression of probably far more than 200 genes is directly or indirectly increased by HIF [1,2]. Understanding this orchestrated response to low oxygen is important to medical progress because many major diseases of developed countries, including solid tumor growth, stroke, infarction, microbial infections, rheumatoid arthritis and chronic ulcerations, are associated with impaired oxygen suppl...

Over-expression of hypoxia-inducible factor 1 alpha in ovarian clear cell carcinoma

“…Previous studies showed that tumor hypoxia could lead to chemoresistance, directly due to the lack of oxygen availability, and indirectly due to the alteration in the proteome and genome, angiogenesis and pH changes [24]. Since HIF-1α is the key molecule regulated by tumor hypoxia, HIF-1a deregulation in tumor cells may confer resistance in these cells [16,17]. The significantly higher HIF-1α expression identified in clear cell carcinoma compared with other histological types suggests that the mechanism of intrinsic chemo resistance in ovarian clear cell carcinoma may be mediated by tumor hypoxia.…”

“…Stabilized HIF-1α protein heterodimerizes with HIF-1β to form the HIF-1 and binds to target DNA at the hypoxic response element. More than 70 target genes are increased by HIF-1 [16,17]. Previous studies showed that HIF-1α is associated with tumor growth, metastasis and survival of cancer patients [18][19][20].…”

Peroxisomal Localization of Hypoxia-Inducible Factors and Hypoxia-Inducible Factor Regulatory Hydroxylases in Primary Rat Hepatocytes Exposed to Hypoxia-Reoxygenation

“…A potential mechanism for targeting HIF hydroxylases to other organelles may involve the oxygen-redirection hypothesis, 58 which states that inhibition of mitochondrial respiration may lead to subcellular redirection of O 2 from mitochondria to nonrespiratory O 2 -dependent compartments. In hepatocytes, the peroxisome represents one such compartment, constituting ϳ1% of total cell volume, yet consuming up to 30% of the O 2 in resting liver.…”

Determination and Modulation of Prolyl‐4‐Hydroxylase Domain Oxygen Sensor Activity

“…Indeed, the increase in ROS in junD -/-cells leads to a decrease in PHD activity and hence to HIF-1α accumulation (Gerald et al, 2004). Apart from direct interference of ROS with the active center of oxygen sensing protein hydroxylases, also the re-direction of oxygen from mitochondria towards the protein hydroxylases might contribute to these effects (Hagen et al, 2003;Wenger, 2006).…”