RT Journal Article
SR Electronic
T1 Deletion of a Neuronal Drp1 Activator Protects against Cerebral Ischemia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3119
OP 3129
DO 10.1523/JNEUROSCI.1926-19.2020
VO 40
IS 15
A1 Kyle H. Flippo
A1 Zhihong Lin
A1 Audrey S. Dickey
A1 Xinchang Zhou
A1 Nirav A. Dhanesha
A1 Grant C. Walters
A1 Yujia Liu
A1 Ronald A. Merrill
A1 Robert Meller
A1 Roger P. Simon
A1 Anil K. Chauhan
A1 Yuriy M. Usachev
A1 Stefan Strack
YR 2020
UL http://www.jneurosci.org/content/40/15/3119.abstract
AB 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 Bβ2, a mitochondria-localized protein phosphatase 2A (PP2A) regulatory subunit, as a neuron-specific Drp1 activator in vivo. Bβ2 KO mice of both sexes display elongated mitochondria in neurons and are protected from cerebral ischemic injury. Functionally, deletion of Bβ2 and maintained Drp1 Ser637 phosphorylation improved mitochondrial respiratory capacity, Ca2+ homeostasis, and attenuated superoxide production in response to ischemia and excitotoxicity in vitro and ex vivo. Last, deletion of Bβ2 rescued excessive stroke damage associated with dephosphorylation of Drp1 S637 and mitochondrial fission. These results indicate that the state of mitochondrial connectivity and PP2A/Bβ2-mediated dephosphorylation of Drp1 play a critical role in determining the severity of cerebral ischemic injury. Therefore, Bβ2 may represent a target for prophylactic neuroprotective therapy in populations at high risk of stroke.SIGNIFICANCE STATEMENT With recent advances in clinical practice including mechanical thrombectomy up to 24 h after the ischemic event, there is resurgent interest in neuroprotective stroke therapies. In this study, we demonstrate reduced stroke damage in the brain of mice lacking the Bβ2 regulatory subunit of protein phosphatase 2A, which we have shown previously acts as a positive regulator of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). Importantly, we provide evidence that deletion of Bβ2 can rescue excessive ischemic damage in mice lacking the mitochondrial PKA scaffold AKAP1, apparently via opposing effects on Drp1 S637 phosphorylation. These results highlight reversible phosphorylation in bidirectional regulation of Drp1 activity and identify Bβ2 as a potential pharmacological target to protect the brain from stroke injury.