In the eye of the storm: mitochondrial damage during heart and brain ischaemia

Borutaitė, Vilmantė; Toleikis, Adolfas; Brown, Guy C.

doi:10.1111/febs.12353

Cited by 65 publications

(69 citation statements)

References 140 publications

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“…The reason for decline in state III respiration may be due to deficiency in supply of respiratory substrates. This may occur due to compromise of ETC components and oxygen to produce ATP (Borutaite et al 2013). Previous studies targeting mitochondrial dysfunction have shown a decrease in state III respiration following anoxia which is in agreement to our finding (Rosenberg et al 1989).…”

Section: Discussionsupporting

confidence: 93%

Characterization of mitochondrial bioenergetics in neonatal anoxic model of rats

Samaiya

Krishnamurthy

2015

J Bioenerg Biomembr

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Neonatal anoxia at the time of birth can lead to mitochondrial dysfunction and further neurodevelopmental abnormalities. The present study investigated the mitochondrial bioenergetics and associated sensorimotor changes in the anoxic neonatal rats. Rat pups after 30 h to birth (2 days) were subjected to anoxia of two episodes (10 min in each) at a time interval of 24 h by passing 100 % N2 into an enclosed chamber. Brain mitochondrial respiration was measured using clark type oxygen electrode. A significant decrease in brain respiratory control ratio (RCR; State III/IV respiration) at all-time points, complex I (24 h) and complex II (30 min, 6 and 24 h) enzyme activities indicated loss of mitochondrial integrity and function A significant increase in levels of nitric oxide was observed after second anoxic episode at all-time points. A significant change in sensorimotor activity in terms of increased reflex latency was observed 24 h after second episode in this model, which is an indication of loss of subcortical maturation. All the above changes were observed after second but not after the first anoxic exposure. Therefore, this anoxic model shows significant changes in mitochondrial bioenergetics, nitric oxide levels and sensorimotor effects after second episode of anoxia. This model may be helpful to evaluate mitochondrial targeted pharmacological intervention for the treatment of anoxia.

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Section: Discussionsupporting

confidence: 93%

Characterization of mitochondrial bioenergetics in neonatal anoxic model of rats

Samaiya

Krishnamurthy

2015

J Bioenerg Biomembr

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“…28 Complex I activity is suppressed during ischemia so enhancing its activity is a potential treatment strategy. 29,30 In this in vivo study, we found ketones improved mitochondrial complex I activity in the penumbra. To restore the mitochondrial function in the penumbra, ketones save it from irreversible damage as evidenced by the reduction in infarct volume.…”

Section: Discussionmentioning

confidence: 54%

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Yin

Han

Tang

et al. 2015

J Cereb Blood Flow Metab

125

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Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD + /NADH ratio. In this study, we investigated whether mitochondrial NAD + -dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD + -dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.

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“…Neuronal apoptosis has emerged as a key deleterious factor in cerebral ischemia and is a result of complex pathophysiological cascades (Balduini et al, 2012;Hofmeijer and van Putten, 2012;Wang et al, 2014). Nowadays it is well established that mitochondrial damage plays an important role in ischemia-induced neuronal apoptosis (Borutaite et al, 2013;Calo et al, 2013;Sanderson et al, 2013). Under ischemia condition, abnormal mitochondrial membrane permeabilization subsequently causes the down-regulation of mitochondrial membrane potential (MMP) and the release of cytochrome c from mitochondria into the cytoplasm, further activating downstream apoptosis pathway (Jordan et al, 2011).…”

Section: Introductionmentioning

confidence: 99%