Peroxisomal Biogenesis in Ischemic Brain

Abstract

Aims: Peroxisomes are highly adaptable and dynamic organelles, adjusting their size, number, and enzyme composition to changing environmental and metabolic demands. We determined whether peroxisomes respond to ischemia, and whether peroxisomal biogenesis is an adaptive response to cerebral ischemia. Results: Focal cerebral ischemia induced peroxisomal biogenesis in peri-infarct neurons, which was associated with a corresponding increase in peroxisomal antioxidant enzyme catalase. Peroxisomal biogenesis was also observed in primary cultured cortical neurons subjected to ischemic insult induced by oxygen-glucose deprivation (OGD). A catalase inhibitor increased OGD-induced neuronal death. Moreover, preventing peroxisomal proliferation by knocking down dynamin-related protein 1 (Drp1) exacerbated neuronal death induced by OGD, whereas enhancing peroxisomal biogenesis pharmacologically using a peroxisome proliferator-activated receptor-alpha agonist protected against neuronal death induced by OGD. Innovation: This is the first documentation of ischemia-induced peroxisomal biogenesis in mammalian brain using a combined in vivo and in vitro approach, electron microscopy, high-resolution laser-scanning confocal microscopy, and super-resolution structured illumination microscopy. Conclusion: Our findings suggest that neurons respond to ischemic injury by increasing peroxisome biogenesis, which serves a protective function, likely mediated by enhanced antioxidant capacity of neurons. Antioxid. Redox Signal. 22, 109-120.

The peroxisome: an update on mysteries 2.0

“…Understanding neuroprotective mechanisms associated with cerebral ischemia is a prerequisite for the development of future therapeutic inventions. In mice, peroxisome proliferation was observed after focal cerebral ischemia induced by middle cerebral artery occlusion suggesting a protective response (Young et al 2015 ). For mechanistic studies, the authors induced ischemic injury in cortical neuron cultures by oxygen–glucose deprivation, and similar to the in vivo situation, neurons responded with peroxisome proliferation.…”

“…When peroxisome division was impeded by Drp1-knockdown or when catalase activity was inhibited with 3-amino-1,2,4-triazole, increased neuronal cell death was observed in response to the ischemic insult. In contrast, administration of PPARα agonists had a protective effect on neuron survival rates (Young et al 2015 ). The authors concluded that peroxisomes might exhibit protective functions against oxidative or metabolic stress induced after ischemia–reperfusion injury which might be targeted as therapy for neuroprotection after stroke.…”

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

“…proteins, are also regulating peroxisomal dynamics [148][149][150]. Remarkably, aberrant Snitrosylation of DRP1 induces its GTPase activity, which is associated with mitochondria fission in AD and HD [151].…”

ESCRT-III is required for scissioning new peroxisomes from the endoplasmic reticulum

“…They are induced in metazoans in response to fats, hypolipidemic agents, and nongenotoxic carcinogens as well as during development and differentiation ( Weller et al, 2003 ). Peroxisome proliferation is linked to their varied functions including, for example, in response to cirrhosis of the liver ( De Craemer et al, 1993 ), after ischemia in the brain ( Young et al, 2015 ), in developing cardiomyocytes ( Colasante et al, 2015 ), in protecting the auditory canal against sound-induced hearing loss from reactive oxygen species ( Delmaghani et al, 2015 ), in epithelial cells to modulate the innate immune system ( Dixit et al, 2010 ; Odendall et al, 2014 ), in macrophages to assist in clearance of microbial pathogens ( Di Cara et al, 2017 ), and as regulatory sites for the mammalian target of rapamycin (mTOR) pathway ( Zhang et al, 2013 , 2015 ; Tripathi and Walker, 2016 ). In many of these examples, the proliferation of peroxisomes appears to be in response to metabolic need or as part of a stress response to deal with increased levels of harmful molecules, particularly reactive oxygen species, produced through insult or injury.…”