Hypoxic-Ischemic Injury in the Developing Brain: The Role of Reactive Oxygen Species Originating in Mitochondria

Ten, Vadim S.; Starkov, Anatoly A.

doi:10.1155/2012/542976

Cited by 94 publications

(74 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…One of the better-characterized ways in which liver cells adapt to starvation is through phosphorylation-mediated inhibition of pyruvate dehydrogenase (Huang et al, 2003), which reduces mitochondrial utilization of pyruvate and has been proposed to increase ROS production (Ten and Starkov, 2012). We recently reported that electrons derived from NADH and FADH 2 follow separate routes along the mETC, and that this is important for metabolic adaptation to starvation, with an increase in the rate of FADH 2 oxidization occurring at the expense of the NADH route (Lapuente-Brun et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

ROS-Triggered Phosphorylation of Complex II by Fgr Kinase Regulates Cellular Adaptation to Fuel Use

et al. 2014

View full text Add to dashboard Cite

SUMMARY Electron flux in the mitochondrial electron transport chain is determined by the superassembly of mitochondrial respiratory complexes. Different superassemblies are dedicated to receive electrons derived from NADH or FADH2, allowing cells to adapt to the particular NADH/FADH2 ratio generated from available fuel sources. When several fuels are available, cells adapt to the fuel best suited to their type or functional status (e.g., quiescent versus proliferative). We show that an appropriate proportion of superassemblies can be achieved by increasing CII activity through phosphorylation of the complex II catalytic subunit FpSDH. This phosphorylation is mediated by the tyrosine-kinase Fgr, which is activated by hydrogen peroxide. Ablation of Fgr or mutation of the FpSDH target tyrosine abolishes the capacity of mitochondria to adjust metabolism upon nutrient restriction, hypoxia/reoxygenation, and T cell activation, demonstrating the physiological relevance of this adaptive response.

show abstract

Section: Resultsmentioning

confidence: 99%

ROS-Triggered Phosphorylation of Complex II by Fgr Kinase Regulates Cellular Adaptation to Fuel Use

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In our study, RET also provided the greatest rate in H 2 O 2 release equivalent to around 3.5% of total oxygen consumption, which is very close to what observed for the mitochondria from adult rat brain 26 . Therefore, in postischemic tissue, RET is active and may render injury to the tissue found in several models of tissue ischemia 18,33 .…”

Section: Discussionmentioning

confidence: 99%

Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury

Степанова

Kahl

Konràd

et al. 2017

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Ischemic stroke is one of the most prevalent sources of disability in the world. The major brain tissue damage takes place upon the reperfusion of ischemic tissue. Energy failure due to alterations in mitochondrial metabolism and elevated production of reactive oxygen species (ROS) is one of the main causes of brain ischemia-reperfusion (IR) damage. Ischemia resulted in the accumulation of succinate in tissues, which favors the process of reverse electron transfer (RET) when a fraction of electrons derived from succinate is directed to mitochondrial complex I for the reduction of matrix NAD+. We demonstrate that in intact brain mitochondria oxidizing succinate, complex I became damaged and was not able to contribute to the physiological respiration. This process is associated with a decline in ROS release and a dissociation of the enzyme's flavin. This previously undescribed phenomenon represents the major molecular mechanism of injury in stroke and induction of oxidative stress after reperfusion. We also demonstrate that the origin of ROS during RET is flavin of mitochondrial complex I. Our study highlights a novel target for neuroprotection against IR brain injury and provides a sensitive biochemical marker for this process.

show abstract

“…Mitochondrial dysfunction is the most fundamental mechanism of cell damage in cerebral ischemia-reperfusion injury as it has critical roles in the apoptotic pathway in ischemic injury (34). Ischemia-reperfusion impairs mitochondrial function and leads to an increase of mitochondrial membrane permeability, resulting in release of cytochrome c, caspase-3 activation and apoptotic cell death (34).…”

Section: Discussionmentioning

confidence: 99%

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

Gao

Zhai

et al. 2017

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Stroke, characterized by a disruption of blood supply to the brain, is a major cause of morbidity and mortality worldwide. Although humanin, a 24-amino acid polypeptide, has been identified to have multiple neuroprotective functions, the level of humanin in plasma has been demonstrated to decrease with age, which likely limits the effects against stroke injury. A potent humanin analogue, S14G-humanin (HNG), generated by replacement of Ser14 with glycine, has been demonstrated to have 1,000-fold stronger biological activity than humanin. The present study established an in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model using SH-SY5Y neuroblastoma cells to mimic the in vivo ischemia/reperfusion injury in stroke. Adding HNG (0-10 µg/l) to SH-SY5Y cells to different extents blocked OGD/R-induced reduction of cell viability and antioxidative capacity, as well as decreased the elevated apoptosis rate induced by OGD/R, with the most evident effects at 1 µg/l HNG. Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) signaling was attenuated in OGD/R processes, yet reactivated with HNG treatment. FLLL32 (5 µM), a specific inhibitor of the signal, abolished effects of HNG on anti-apoptosis and antioxidation in OGD/R processes. Co-treatment with HNG and FLLL32 failed to interrupt upregulation of cytochrome c, B-cell lymphoma 2-associated X protein and cleaved caspase-3 provoked by OGD/R. Similar to FLLL32, Jak2/Stat3 signaling activated by HNG was also repressed by inhibitor of phosphoinositide 3-kinase (PI3K; 10 µM LY294002) or protein kinase B (AKT; 5 µM MK-2206 2HCl). These data collectively indicated that HNG has neuroprotective effects against OGD/R by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway, suggesting that HNG may be a promising agent in the management of stroke.

show abstract

Hypoxic-Ischemic Injury in the Developing Brain: The Role of Reactive Oxygen Species Originating in Mitochondria

Cited by 94 publications

References 87 publications

ROS-Triggered Phosphorylation of Complex II by Fgr Kinase Regulates Cellular Adaptation to Fuel Use

ROS-Triggered Phosphorylation of Complex II by Fgr Kinase Regulates Cellular Adaptation to Fuel Use

Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

Contact Info

Product

Resources

About