GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy

Abstract

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.

Only one carbon difference determines the pro‐apoptotic activity of α‐tocopheryl esters

“…GRP78 also maintains mitochondrial functionality by reducing Ca 2+ efflux from the ER to mitochondria and by managing misfolded mitochondrial proteins and mitochondrial steroidogenesis [49][50][51]. Recently, it has been proposed that GRP78 overexpression aids neuroprotection by triggering the mitophagy process [52]. Our real-time PCR and western blotting results confirm that GRP78 activity is higher in B16F1 cells than mouse 3T3-Swiss albino cells (Fig.…”

Role of PERK‐mediated pathway in the effect of mild hypothermia after cerebral ischaemia/reperfusion

“…In addition, GRP78 has been shown to bind ions of Са 2+ , by blocking the activation of ER‐associated proapoptotic factors, such as BIK and caspase‐7 36 . There is an evidence of neuroprotective properties of the GRP78 protein 37 . In this study, a much higher level of GRP78 expression was observed in the hypothermia group than in the normothermic ischaemia/reperfusion group.…”

“…36 There is an evidence of neuroprotective properties of the GRP78 protein. 37 In this study, a much higher level of GRP78 expression was observed in the hypothermia group than in the normothermic ischaemia/reperfusion group. This may indicate that GRP78 expression is facilitated by hypothermia-induced neuroprotection in the hippocampal region during cerebral ischaemia/reperfusion.…”

Targeting neuronal mitophagy in ischemic stroke: an update

“…The latter hypothesis lacks a clear definition in ischemic stroke and the roles of mitophagy in cerebral ischemia may vary across experimental models ( Table 1 ). In fact, previous studies propose that different compounds or gene manipulations confer neuroprotection with reduced mitophagy in ischemic brains [ 65 , 66 , 85 ]. Bnip3 knockout attenuates ischemic brain injury and mitophagy induction [ 12 ], but the gene plays a more complex role in regulating apoptosis and lysosomal function [ 86 , 87 ].…”