Our results suggest a central role of mitochondrial complex I (C-I) impairment in the development of bioenergetic failure after acute I/R brain injury. Here, we used a mouse model of middle cerebral artery occlusion (MCAO) to investigate acute I/R-induced changes of mitochondrial function, focusing on the molecular and biochemical mechanisms of primary and secondary energy failure. 11, 13, 14 However, despite intensive research, the molecular mechanisms of mitochondria damage in I/R remain to be elucidated. 11, 12 Mitochondrial electron transport chain (ETC) enzymes are known to become rapidly over-reduced in the absence of oxygen and to be damaged by subsequent reoxygenation. 11, 12 In fact, data indicate that secondary energy failure after transient ischemia might be the result of delayed mitochondrial damage, likely because of oxidative stress. 9, 10 This sequence of events has been confirmed by several laboratories, which have also ruled out microcirculatory failure or changes in substrate availability as the cause of the secondary energy depletion and cell death. 7, 8Īfter reperfusion, there is a transient restoration of bioenergetic state, which is followed by a second phase of energy depletion (secondary energy failure) leading to delayed tissue damage.
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5, 6 The lack of oxygen resulting from ischemia leads to impaired mitochondrial ATP production (primary energy failure), collapse of the mitochondrial membrane potential, and, consequently, activation of intrinsic cell death pathways. 4 Mitochondria play a key role in ischemic brain injury, both through impairment of mitochondrial ATP production with bioenergetic dysfunction and oxidative stress and by mediating cell death pathways.
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The loss of cerebral blood flow leads to decreased oxygen levels, impairment of mitochondrial oxidative phosphorylation and energy failure in the ischemic area, initiating a sequence of pathophysiological events that after reoxygenation lead to ischemia/reperfusion (I/R) damage. 3 This highlights the need for a broader understanding of tissue injury mechanisms to develop more effective treatments.
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2 However, because of a narrow therapeutic time window and potential contraindications, only 3% to 5% of stroke patients are able to benefit from these interventions.
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1 Despite decades of research, tissue-type plasminogen activator and endovascular devices are the only available treatment options. Stroke remains a leading cause of death and disability worldwide.