Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

Guzy, Robert D.; Hoyos, Beatrice; Robin, Emmanuel; Chen, Hong; Liu, Liping; Mansfield, Kyle D.; Simon, M. Celeste; Hämmerling, Ulrich; Schumacker, Paul T.

doi:10.1016/j.cmet.2005.05.001

Cited by 1,363 publications

(1,145 citation statements)

References 30 publications

Supporting

Mentioning

1,081

Contrasting

Unclassified

Order By: Relevance

“…HIF1 has been referred to as the "master regulator of oxygen homeostasis" 7 , but it is regulated by many factors aside from hypoxia, including oncogenes, growth factors and free radicals [27][28][29] . Free radicals are chemical species that contain unpaired electrons; of particular importance here are oxygen-containing radicals, such as the superoxide anion (O 2 -).…”

Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

“…It has been reported that mitochondrial complex III may be important in this pathway. Cells in which complex III activity has been knocked down through RNA interference-mediated reduction of expression of one of the protein subunits of this complex show decreased reactive oxygen species formation and decreased HIF1α expression levels 29 . When H 2 O 2 is added back, the knockdown cells regain the ability to stabilize HIF1α under hypoxia.…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

See 1 more Smart Citation

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

View full text Add to dashboard Cite

Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

show abstract

Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

View full text Add to dashboard Cite

show abstract

“…Intriguingly, some studies reported that increased mitochondrial ROS, through various mechanisms, might finally lead to the apoptosis resistance of PASMCs during hypoxia,54, 55 and, for example, a study showed that increased ROS/mitochondrial ROS and dynamin‐related protein‐1 had a positive feedback loop that finally resulted in the apoptosis resistance of PASMCs by affecting the mitochondrial fission 56. However, other studies showed that increased mitochondrial ROS could directly cause mitochondrial damage, resulting in the apoptosis of cells 45, 57.…”

Section: Discussionmentioning

confidence: 99%

Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Dysfunction

Chen

Wang

Dong

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundPulmonary arterial remodeling, a main characteristic of hypoxic pulmonary hypertension, can gradually reverse once oxygen has been restored. Previous studies documented that apoptosis increased markedly during the reversal of remodeled pulmonary arteries, but the types of cells and mechanisms related to the apoptosis have remained elusive. This study aimed to determine whether pulmonary artery smooth muscle cell (PASMC)‐specific apoptosis was involved in the reoxygenation‐induced reversal of hypoxic pulmonary arterial remodeling and elucidate the underlying mechanism.Methods and ResultsHypoxic pulmonary hypertension was induced in adult male Sprague‐Dawley rats (n=6/group) by chronic hypobaric hypoxia. and the hypoxic pulmonary hypertension rats were then transferred to a normoxia condition. During reoxygenation, hypoxia‐induced pulmonary arterial remodeling gradually reversed. The reversal of remodeled pulmonary arteries was associated with increased H2O2 and with changes in lung expression of cleaved caspase3/PARP, Bax, and Bcl‐2, consistent with increased apoptosis. The PASMC apoptosis, in particular, increased remarkably during this reversal. In vitro, reoxygenation induced the apoptosis of cultured rat primary PASMCs accompanied by increased mitochondrial reactive oxygen species, mitochondrial dysfunction, and the release of cytochrome C from mitochondria to cytoplasm. Clearance of reactive oxygen species alleviated mitochondrial dysfunction as well as the release of cytochrome C and, finally, decreased PASMC apoptosis.ConclusionsReoxygenation‐induced apoptosis of PASMCs is implicated in the reversal of hypoxic pulmonary arterial remodeling, which may be attributed to the mitochondrial reactive oxygen species–mediated mitochondrial dysfunction.

show abstract

“…For respiratory chain complex III, the semiquinone at center ''o'' of the Q-cycle (being stabilized by antimycin A treatment) has been identified as an additional site of mitochondrial superoxide production (36), which in contrast to complex I releases superoxide to the intermembrane space (37,38). While under conditions of inhibited electron transfer (e.g., under conditions of cytochrome c release), all these sites are potentially relevant, the relevance of the latter site under the conditions of uninhibited electron flow is still a matter of discussion (39,40). Additionally to the sites within mitochondrial respiratory chain, several flavoproteins in the mitochondrial matrix space, like the a-lipoamide dehydrogenase moiety of the a-ketoglutarate dehydrogenase complex (41,42) or the electron transfer flavoprotein of the b-oxidation pathway (37), are further candidate sites for mitochondrial superoxide production.…”

Section: Mitochondrial Formation Of Ros and Neurodegenerationmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

View full text Add to dashboard Cite

The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

show abstract

Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing

Cited by 1,363 publications

References 30 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial Dysfunction

Mitochondrial involvement in neurodegenerative diseases

Contact Info

Product

Resources

About