Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia

Abstract

Mitochondrial fission catalyzed by dynamin-related protein 1 (Drp1) is necessary for mitochondrial biogenesis and maintenance of healthy mitochondria. However, excessive fission has been associated with multiple neurodegenerative disorders, and we recently reported that mice with smaller mitochondria are sensitized to ischemic stroke injury. Although pharmacological Drp1 inhibition has been put forward as neuroprotective, the specificity and mechanism of the inhibitor used is controversial. Here, we provide genetic evidence that Drp1 inhibition is neuroprotective. Drp1 is activated by dephosphorylation of an inhibitory phosphorylation site, Ser637. We identify Bb2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bb2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bb2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca 21 homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bb2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bb2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bb2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

“…However, inhibiting DRP1 remains an ongoing challenge. Indeed, it has been found that the deletion of a neuron-specific DRP1 activator, Bβ2 (a mitochondria-localized protein phosphatase 2A regulatory subunit), in vivo ameliorated excessive stroke damage [ 216 ]. Interestingly, DRP1 also participates in processes other than mitochondrial fission in vascular tissues following ischemic injury, such as ischemia-induced autophagy, apoptosis, and metabolic pathways [ 217 ].…”

The Multifaceted Roles of Zinc in Neuronal Mitochondrial Dysfunction

“…The mechanism by which DRP1 interacts with Zip1-MCU to allow mitochondrial zinc influx is unclear. Furthermore, whether excess zinc interferes with this mitochondrial surveillance mechanism has not yet been demonstrated in neurons, although it is an intriguing topic of future study due to the extent that DRP1 activation and mitophagy have been implicated in the pathology of various neurodegenerative diseases [ 235 ], such as AD [ 234 , 248 ], PD [ 249 , 250 , 251 ], HD [ 252 , 253 ], ALS [ 254 ], and ischemia [ 255 , 256 ].…”

Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1–Drp1 pathway

“…Dynamin-related protein 1 (Drp1) is a key protein that regulates mitochondrial fission after brain ischemia 19 . Many studies have shown that downregulating Drp1 can induce neuroprotection after stroke 20,21 . To explore the potential molecular mechanisms of CB1 receptor activation, in the present study, we used oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO) in vitro and in vivo, respectively, as brain IRI models and examined whether the CB1 agonist ACEA protects ischemic brain tissue via the CB1-Drp1 pathway by inhibiting mitochondrial fission.…”