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.

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

“…The action of PGC-1a is also related to control of oxidative stress. 26 Overproduction of ROS, a by-product of mitochondrial electron transport chain, has been implicated in acute brain injuries such as ischemia. 26 Our results showed that fructose exacerbated the effects of TBI on the levels of 4HNE, as indicative of increased lipid peroxidation and neuronal damage.…”

“…26 Overproduction of ROS, a by-product of mitochondrial electron transport chain, has been implicated in acute brain injuries such as ischemia. 26 Our results showed that fructose exacerbated the effects of TBI on the levels of 4HNE, as indicative of increased lipid peroxidation and neuronal damage. It could be argued that the high oxygen supply necessitated for the delivery of anesthesia could influence the outcome of the brain injury by altering cerebral metabolism and ROS levels.…”

“…PGC-1a can interact with brain-derived neurotrophic factor (BDNF) 25 and reactive oxygen species (ROS) in the regulation of brain plasticity. 26 We also determined the effects of fructose and TBI on mitochondrial functions by assessing the oxygen consumption rate (OCR). In addition, BDNF signaling is crucial for maintaining energy metabolism and cognitive function.…”

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

“…AMPactivated protein kinase, which guards against deficient ATP regeneration by upregulating catabolic pathways including glycolysis, 30 likely contributes to the upregulation of MCTs in response to hypoxia and increased activity-dependent energy demand in the brain, such as observed for MCT1 and MCT4 in heart and skeletal muscle on chronic stimulation or exercise. 31 The transcriptional coactivator PGC-1α (peroxisome proliferatoractivated receptor-γ (PPARγ) coactivator-1α), a master regulator of reactive oxygen species scavenging enzymes and of mitochondrial biogenesis in brain, 32 may also participate. Thus, PGC-1α 33 is known to upregulate MCTs in other tissues, and so does PPARα, 34 which mediates adaptive responses to energy restriction and induces the formation of ketone bodies.…”

Neuroprotection requires the functions of the RNA-binding protein HuR

“…To restrict our analyses to putative HuR targets, we examined whether the human homologs of these 61 mRNAs were identified to physically interact with HuR in PAR-CLiP 36,37 assays deposited in the DoRiNA 38 database; based on phenotypic relevance, we selected six such mRNAs. These included mRNAs encoding for: (a) major energy sensors involved in oxidative metabolism such as Ppargc1a (aka PGC1α), which is a master regulator of ROS-scavenging enzymes, and mitochondrial biogenesis, previously shown to counteract cerebral ischemia; 39 and NQO1 (NAD(P)H dehydrogenase, quinone 1), a major antioxidant whose dysfunction associates with many disease states and cancer; 40 (b) pleiotropic controllers involved in cell survival and cell stress such as Myc 41 and Cirbp (cold-inducible RNA-binding protein); 42 and (c) factors involved in neuronal polarity and plasticity such as semaphorin 3a (Sema3a) and Gja1 (connexin-43). 43 One gene that associated with Elavls but was not identified in DoRiNA (Prkar2a) was also selected because of the relevance of protein kinase A signals to neuronal excitation.…”