Roles of oxidative stress, apoptosis, PGC-1α and mitochondrial biogenesis in cerebral ischemia

Abstract

The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS) as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α). PGC1-α is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-α is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.

Keywords: antioxidant enzyme; apoptosis; ischemia; mitochondrial biogenesis; oxidative stress; peroxisome proliferative activated receptor-γ co-activator 1α.

Figure 1

Schematic overview of selected cellular events in the ischemic brain. The ischemic event begins with reduced blood flow to the area supplied by the occluded arteries. The lack of oxygen, glucose, and other nutrients leads to an ischemic cascade culminating in cell death. EAA = excitatory amino acid; ATP = adenosine triphosphate; CBF = cerebral blood flow; nNOS = neuronal nitric oxide synthase; NO = nitric oxide; ↑ and ↓ denote increase and decrease, respectively.

Figure 2

Proposed role of PGC-1α in ischemic condition. ROS overproduction may stimulate the activation of PGC-1α signaling pathway, further triggering upregulation of mitochondrial proteins, including UCP2 and SOD2, in ischemic neurons. PGC-1α also regulates NRF-1, NRF-2 and Tfam expression as well as mitochondrial biogenesis that may have protective effects in ischemic condition. PGC-1α = peroxisome proliferative activated receptor-γ co-activator 1α; UCP2 = uncoupling protein 2; SOD2 = superoxide dismutase 2; NRFs = Nuclear respiratory factors; Tfam = Mitochondrial transcription factor A; ↑ and ↘ denote increase and decrease, respectively.