The Alterations in Mitochondrial Dynamics Following Cerebral Ischemia/Reperfusion Injury

Abstract

Cerebral ischemia results in a poor oxygen supply and cerebral infarction. Reperfusion to the ischemic area is the best therapeutic approach. Although reperfusion after ischemia has beneficial effects, it also causes ischemia/reperfusion (I/R) injury. Increases in oxidative stress, mitochondrial dysfunction, and cell death in the brain, resulting in brain infarction, have also been observed following cerebral I/R injury. Mitochondria are dynamic organelles, including mitochondrial fusion and fission. Both processes are essential for mitochondrial homeostasis and cell survival. Several studies demonstrated that an imbalance in mitochondrial dynamics after cerebral ischemia, with or without reperfusion injury, plays an important role in the regulation of cell survival and infarct area size. Mitochondrial dysmorphology/dysfunction and inflammatory processes also occur after cerebral ischemia. Knowledge surrounding the mechanisms involved in the imbalance in mitochondrial dynamics following cerebral ischemia with or without reperfusion injury would help in the prevention or treatment of the adverse effects of cerebral injury. Therefore, this review aims to summarize and discuss the roles of mitochondrial dynamics, mitochondrial function, and inflammatory processes in cerebral ischemia with or without reperfusion injury from in vitro and in vivo studies. Any contradictory findings are incorporated and discussed.

Keywords: fission; fusion; ischemia; mitochondria; reperfusion.

Figure 1

Under the physiological condition, mitochondrial dynamic is a process for the balance between fission and fusion to provide cellular homeostasis and cell survival. Mitochondrial fission is the process for the division of mitochondria. Mitochondrial fission enables mitochondria to segregate dysfunctional mitochondria. Mitochondrial fission is mediated by Drp1 and Fis1, which are essential for mitochondrial division. In addition, mitochondrial fission is associated with the mitophagy process, which is the process that separates and removes damaged mitochondria by a phagosome. Mitochondrial fusion involves the processes of sharing the mitochondrial matrix or metabolites. Mfn1, Mfn2, and OPA1 play roles in mitochondrial fusion. The long form of OPA-1 interacts with cardiolipin of the adjacent mitochondria to promote inner mitochondrial fusion. Drp1, dynamin-related protein-1; Fis1, mitochondrial fission 1 protein; Mfn1, mitofusin1; Mfn2, mitofusin2; OPA1, optic atrophy protein1.

Figure 2

A schematic diagram representing the alteration of mitochondrial dynamic balance during pathology. Several diseases are related to the disruption of fusion, fission, and mitophagy in mitochondria. Cerebral ischemia, cardiovascular disease, and Huntington’s disease increased mitochondrial fission via increased oxidative stress, inflammation, and calcium overload. Charcot–Marie–Tooth disease and dominant optic atrophy increased mitochondria fusion by stimulated mitochondrial membrane depolarization and ATP depletion. Parkinson’s disease also increased mitophagy. ATP, adenosine triphosphate; ΔΨm, mitochondrial membrane potential. (This figure was created with BioRender.com).

Figure 3

The differences in mitochondrial dynamic alteration after ischemia with or without reperfusion (both in vitro and in vivo studies). In in vitro studies, an increase in mitochondrial fission occurred in OGD (ischemic) condition. Mitochondrial fusion was increased during the early phase of OGD/reoxygenation and decreased after late phase of OGD/reoxygenation. In in vivo studies, a decrease in mitochondrial fusion occurred in cerebral ischemia. An increase in mitochondrial fission and the reduction in mitochondrial fusion were observed after cerebral ischemia/reperfusion. These impaired mitochondrial dynamics caused brain apoptosis and consequently caused neuronal cell death. OGD, oxygen glucose deprivation. (This figure was created with BioRender.com).

Figure 4

A summary of evidence in the interventions for the alterations in mitochondrial dynamics following ischemia/reperfusion: in vitro and in vivo studies. An increase in mitochondrial fission and a decrease in mitochondrial fusion were observed after cerebral ischemia/reperfusion. The upregulation of the Mfn2, exercise, inhibition of Drp1, and inhibition of P38 MAPK caused a decrease in mitochondrial fission, neuronal death, and neurological deficit. A reduction of AKAP1, which is an endogenous Drp1 inhibitor, increased mitochondrial fission, leading to an increase in brain infarct volume. AKAP-1, A-kinase anchoring protein 1; Drp1, dynamin-related protein-1; MAPK, major mitogen-activated protein kinases; Mfn2, mitofusin2; OPA1: optic atrophy protein1; s-OPA1, short optic atrophy protein1.