Mitochondrial Mechanisms During Ischemia and Reperfusion

Introduction

The mitochondrion keeps a continuous workflow for oxidation of energy substances that are obtained from the blood to produce adenosine triphosphate (ATP) for cellular functions. Neural cells consume this energy derived from the ATP hydrolysis for maintaining ionic gradients across plasma membranes. During ischemia, oxygen supply and ATP production are rapidly impaired, followed by exhaustion of energy substances. This condition blocks mitochondrial respiration and glycolytic activity, two major energy metabolism events. Restoration of the local blood flow after an ischemic event for short term immediately reinitiates the energy production when ATP and other energy substances/metabolites recover mostly in parallel. Although recovery of energy demand prevails in all the postischemic tissues regardless of the regional sensitivity difference to ischemic insults, complete restoration of the ATP content may be delayed to several hours later.

During ischemic reperfusion, alterations in mitochondrial dynamics occur and lead to acute cell death. This disruption of mitochondrial Ca ²⁺ homeostasis may impair ATP-producing mitochondrial respiration and cause energy deficiency in postischemic cells. Regulation of the phosphate receptors, voltage-dependent anion channels, Na ⁺ /Ca ²⁺ exchanger, and mitochondrial permeability transition pore (mPTP), which were precisely controlled, plays significant and dual roles in reperfusion injury.

Calcium is involved in the maintenance of electrical potential of inner mitochondrial membrane. In hypoxic and ischemic conditions, the inefficient Na ⁺ /K ⁺ ATPase activity causes accumulation of sodium in the cytoplasm, which drives Ca ²⁺ influx through the Na ⁺ /Ca ²⁺ exchanger contributing to the accumulation of intracellular Ca ²⁺ . The intracellular concentration affects mitochondrial calcium dynamics. Mitochondrial respiratory activity is restored during early reperfusion when intracellular calcium is still increased. Mitochondrial calcium increase is then reversed within the first hour after reperfusion. A delayed local increase may be restricted in some ischemia-susceptible regions at as long as 24 h after reperfusion. This event can lead to ATP loss and energy deficiency, contributing to the progression of ischemic reperfusion injury. Characterization of the molecular basis for reduced mitochondrial activity and its involvement in ischemia-induced changes has helped to understand the mitochondrial mechanisms during ischemia and reperfusion.

Adenosine Triphosphate and Energy Metabolisms

Mitochondria from ischemic brains show a decreased ability for ATP generation. This is correlated to a reduced capacity for respiratory activity and cell death in the acute phase of ischemia. In the adult brain after ischemia, glycogen is rapidly consumed by aerobic glycolysis, generating ATP and pyruvate. Resynthesizing of ATP in the reperfusion period required a certain time in all the affected tissues, although there may be differences between an ischemia-susceptible region and an ischemia-resistant region. The ability and maintenance for relatively high ATP concentrations in cells has indicated integrity of tissue after ischemia and an operative intracellular control against ischemic cell death and brain injury. The late reductions of ATP in ischemia-susceptible regions may indicate the disrupted mitochondrial functions ( Fig. 47.1 ).

Besides, measurements of other energy-related metabolites such as glucose provide evidence for mitochondrial activity and energy metabolism during blood flow recirculation. Reduction of glucose oxidation in the ischemic brain compared with normal brain persists within the first several hours. Evidences show that an increased energy requirement in the brain tissue can result in elevated glucose utilization. However, the coupling of blood flow to glucose utilization can be significantly varied among different brain areas in different physical and pathologic conditions. In postischemic brains, the generalized reductions of glucose metabolism are associated with the low local energy requirements in short term, and do not seem to result from a loss of metabolic capacity due to changes of blood flow in the affected tissue. Studies also suggest that the continuous reductions in the requirement for ATP are associated with long-term changes in the brain that has been subjected to ischemic insults.

Within the first few hours of reperfusion, pyruvate is reduced, suggesting a reduced aerobic glycolytic activity. This activity catalyzed by the pyruvate dehydrogenase complex, was inhibited to limit glucose oxidation after ischemia, accounting for the reduction in energy-producing mitochondrial function during the first few hours of reperfusion. Through anaerobic glycolysis, pyruvate is catalyzed to lactate, with generation of NAD ⁺ . The lactate level is of significant prognostic value for outcome after neonatal hypoxic-ischemic injury. Moreover, the inability to survive the accumulated oxidative stress in postischemic tissue may prolong the exposure of some neurons to oxidative damage as the reperfusion period progresses.

However, during the first few hours of reperfusion, decreased energy demands prevail in the ischemic brain, indicated by an oxidative metabolism reduction. Tissue slices reveal an attenuated metabolic response to chemical depolarization and an impairment of mitochondrial function. Although at this time the brain tissue tends to recover normal function, the mitochondria-associated problem fails to respond to increases in energy requirements. Mitochondrial deficiency due to impaired mitochondrial function leads to further deleterious changes and potentially compromises secondary injury of ischemia-susceptible neurons in the long term.