Mitochondrial Dysfunction in Ischemia/Stroke

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are current articles and published clinical studies documenting the
strong link between Mitochondrial Dysfunction and Ischemia/Stroke.
PLoS One. 2012
Reperfusion promotes mitochondrial dysfunction
following focal cerebral ischemia in rats.
BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia.
METHODS: Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis.
RESULTS: Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+) increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period.
CONCLUSIONS: Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+)-induced mitochondrial swelling. The mechanism of this swelling may be mediated by the upregulation of the Cyclophilin D protein, the destruction of the mitochondrial membrane potential and the generation of excessive reactive oxidative species.
Acta Anaesthesiol Scand. 2013 Feb
Cerebral energy metabolism during induced mitochondrial dysfunction.
BACKGROUND: In patients with traumatic brain injury as well as stroke, impaired cerebral oxidative energy metabolism may be an important factor contributing to the ultimate degree of tissue damage. We hypothesize that mitochondrial dysfunction can be diagnosed bedside by comparing the simultaneous changes in brain tissue oxygen tension (PbtO(2)) and cerebral cytoplasmatic redox state. The study describes cerebral energy metabolism during mitochondrial dysfunction induced by sevoflurane in piglets.
METHODS: Ten piglets were included, seven in the experimental group (anesthetized with sevoflurane) and three in the control group (anesthetized with midazolam). PbtO(2) and cerebral levels of glucose, lactate, and pyruvate were monitored bilaterally. The biochemical variables were obtained by intracerebral microdialysis.
RESULTS: All global variables were within normal range and did not differ significantly between the groups except for blood lactate that was slightly higher in the experimental group. Mitochondrial dysfunction was observed in the group of animals initially anesthetized with sevoflurane. Cerebral glucose was significantly lower in the experimental group than in the control group whereas lactate and lactate/pyruvate ratio were significantly higher. Pyruvate and tissue oxygen tension remained within normal range in both groups. Changes of intracerebral variables indicating mitochondrial dysfunction were present already from the very start of the monitoring period.
CONCLUSION: Intracerebral microdialysis revealed mitochondrial dysfunction by marked increases in cerebral lactate and lactate/pyruvate ratio simultaneously with normal levels of pyruvate and a normal PbtO(2). This metabolic pattern is distinctively different from cerebral ischemia, which is characterized by simultaneous decreases in PbtO(2) and intracerebral pyruvate.
Molecules. 2012 Nov 9
By improving regional cortical blood flow, attenuating
mitochondrial dysfunction and sequential apoptosis galangin acts as
a potential neuroprotective agent after acute ischemic stroke.
Ischemic stroke is a devastating disease with a complex pathophysiology. Galangin is a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, which has been widely used as an antioxidant agent. However, its effects against ischemic stroke have not been reported and its related neuroprotective mechanism has not really been explored. In this study, neurological behavior, cerebral infarct volumes and the improvement of the regional cortical blood flow (rCBF) were used to evaluate the therapeutic effect of galangin in rats impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia.

Furthermore, the determination of mitochondrial function and Western blot of apoptosis-related proteins were performed to interpret the neuroprotective mechanism of galangin. The results showed that galangin alleviated the neurologic impairments, reduced cerebral infarct at 24 h after MCAO and exerted a protective effect on the mitochondria with decreased production of mitochondrial reactive oxygen species (ROS).

These effects were consistent with improvements in the membrane potential level (Dym), membrane fluidity, and degree of mitochondrial swelling in a dose-dependent manner. Moreover, galangin significantly improved the reduced rCBF after MCAO. Western blot analysis revealed that galangin also inhibited apoptosis in a dose-dependent manner concomitant with the up-regulation of Bcl-2 expression, down-regulation of Bax expression and the Bax/Bcl-2 ratio, a reduction in cytochrome c release from the mitochondria to the cytosol, the reduced expression of activated caspase-3 and the cleavage of poly(ADP-ribose) polymerase (PARP).

All these data in this study demonstrated that galangin might have therapeutic potential for ischemic stroke and play its protective role through the improvement in rCBF, mitochondrial protection and inhibiting caspase-dependent mitochondrial cell death pathway for the first time.
Journal of Toxicology
Volume 2011 (2011)
Oxidative Toxicity in Neurodegenerative Diseases:
Role of Mitochondrial Dysfunction and Therapeutic Strategies
Besides fluorine, oxygen is the most electronegative element with the highest reduction potential in biological systems. Metabolic pathways in mammalian cells utilize oxygen as the ultimate oxidizing agent to harvest free energy. They are very efficient, but not without risk of generating various oxygen radicals. These cells have good antioxidative defense mechanisms to neutralize these radicals and prevent oxidative stress. However, increased oxidative stress results in oxidative modifications in lipid, protein, and nucleic acids, leading to mitochondrial dysfunction and cell death. Oxidative stress and mitochondrial dysfunction have been implicated in many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and stroke-related brain damage.

Research has indicated mitochondria play a central role in cell suicide. An increase in oxidative stress causes mitochondrial dysfunction, leading to more production of reactive oxygen species and eventually mitochondrial membrane permeabilization. Once the mitochondria are destabilized, cells are destined to commit suicide. Therefore, antioxidative agents alone are not sufficient to protect neuronal loss in many neurodegenerative diseases.

Combinatorial treatment with antioxidative agents could stabilize mitochondria and may be the most suitable strategy to prevent neuronal loss. This review discusses recent work related to oxidative toxicity in the central nervous system and strategies to treat neurodegenerative diseases.
Journal of Neurochemistry (2009)
Volume: 109 Suppl 1, Issue
Oxidative stress and mitochondrial dysfunction
as determinants of ischemic neuronal death and survival.
Mitochondria are the powerhouse of the cell. Their primary physiological function is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Reactive oxygen species generated from mitochondria have been implicated in acute brain injuries such as stroke and neurodegeneration.

Recent studies have shown that mitochondrially-formed oxidants are mediators of molecular signaling, which is implicated in the mitochondria-dependent apoptotic pathway that involves pro- and antiapoptotic protein binding, the release of cytochrome c, and transcription-independent p53 signaling, leading to neuronal death. Oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves phosphatidylinositol 3-kinase/Akt and downstream signaling, which lead to neuronal survival.

Genetically modified mice or rats that over-express or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
Stroke 2001
Mitochondrial Disease and Stroke
Background and Purpose: It is well known that some mitochondrial disorders are responsible for ischemic cerebral infarction in young patients. Our purpose was to determine, in this prospective ongoing study, whether ischemic stroke is the only manifestation of a mitochondrial disorder in young patients.
Methods: Patients aged ≤50 years, admitted to the Stroke Unit from January 1999 to May 2000 with a diagnosis of ischemic stroke of unknown origin, were included in the study. All of them had full biochemical and hematologic tests, neuroimaging studies, transesophageal echocardiography, and extracranial and transcranial Doppler sonography. Patent foramen ovale was ruled out. Lactic acid concentrations were measured after anaerobic exercise of the forearm, and a morphological, biochemical, and molecular study after biceps muscle biopsy was performed.
Results: Of the 18 patients so far included, 3 (17%) presented lactic acid hyperproduction after physical exercise, and 6 (33%) showed deficit of the mitochondrial respiratory chain complexes. The molecular analyses have confirmed mitochondrial mutations at base pairs 3243 (characteristic of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes [MELAS]), 4216, and 15 928.
Conclusions: These results suggest that ischemic stroke may be the only manifestation or the initial manifestation of a mitochondrial disorder.
Vol. 254, No. 19. Issue of October 10
Reversal of Ischemic Mitochondrial Dysfunction
Liver ischemia in intact rats is associated with a series of alterations in mitochondrial structure and function that include: a complete loss of respiratory control; a loss of adenine nucleotide translocase activity; decreases in, at least, the heme portions of cytochromes aa and c + cl; a decrease in dinitrophenol activated ATPase; a loss of the ability of dinitrophenol to stimulate 02 uptake; a decrease in the content of one nfr = 83,000 protein band; and lastly, changes in mitochondrial ultrastructure characterized by swelling, loss of a tightly folded and contorted inner membrane, and the appearance of amorphous matrix densities. After 3 h of ischemia, none of these alterations are restored upon reestablishment of liver blood flow.
An identical sequence of mitochondrial alterations occurs in ischemic liver tissue that has been pretreated with chlorpromazine. However, in the chlorpromazine-treated animals all of these mitochondrial alterations are completely reversible even after 3 h of ischemia. The inability to restore mitochondrial function during reperfusion in the absence of chlorpromazine, therefore, cannot be the direct consequence of any of these alterations. Rather, it would seem to be the metabolic consequence of reperfusion itself. In the same way, these mitochondrial alterations cannot be the cause of the irreversibility of the cellular deterioration and death during the reperfusion period. The mechanisms for theeffects of ischemia on mitochondrial structure and function and the ability to reverse these changes