Journal article
AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission
The Journal of neuroscience, Vol.38(38), pp.8233-8242
09/19/2018
DOI: 10.1523/JNEUROSCI.0649-18.2018
PMCID: PMC6146498
PMID: 30093535
Abstract
Mitochondrial fission and fusion impact numerous cellular functions and neurons are particularly sensitive to perturbations in mitochondrial dynamics. Here we describe that male mice lacking the mitochondrial A-kinase anchoring protein 1 (AKAP1) exhibit increased sensitivity in the transient middle cerebral artery occlusion model of focal ischemia. At the ultrastructural level, AKAP1
−/−
mice have smaller mitochondria and increased contacts between mitochondria and the endoplasmic reticulum in the brain. Mechanistically, deletion of AKAP1 dysregulates complex II of the electron transport chain, increases superoxide production, and impairs Ca
2+
homeostasis in neurons subjected to excitotoxic glutamate. Ca
2+
deregulation in neurons lacking AKAP1 can be attributed to loss of inhibitory phosphorylation of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) at the protein kinase A (PKA) site Ser637. Our results indicate that inhibition of Drp1-dependent mitochondrial fission by the outer mitochondrial AKAP1/PKA complex protects neurons from ischemic stroke by maintaining respiratory chain activity, inhibiting superoxide production, and delaying Ca
2+
deregulation. They also provide the first genetic evidence that Drp1 inhibition may be of therapeutic relevance for the treatment of stroke and neurodegeneration.
SIGNIFICANCE STATEMENT
Previous work suggests that activation of dynamin-related protein 1 (Drp1) and mitochondrial fission contribute to ischemic injury in the brain. However, the specificity and efficacy of the pharmacological Drp1 inhibitor mdivi-1 that was used has now been discredited by several high-profile studies. Our report is timely and highly impactful because it provides the first evidence that genetic disinhibition of Drp1 via knock-out of the mitochondrial protein kinase A (PKA) scaffold AKAP1 exacerbates stroke injury in mice. Mechanistically, we show that electron transport deficiency, increased superoxide production, and Ca
2+
overload result from genetic disinhibition of Drp1. In summary, our work settles current controversies regarding the role of mitochondrial fission in neuronal injury, provides mechanisms, and suggests that fission inhibitors hold promise as future therapeutic agents.
Details
- Title: Subtitle
- AKAP1 Protects from Cerebral Ischemic Stroke by Inhibiting Drp1-Dependent Mitochondrial Fission
- Creators
- Kyle H Flippo - Department of Pharmacology and Iowa Neuroscience InstituteAswini Gnanasekaran - Department of Pharmacology and Iowa Neuroscience InstituteGuy A Perkins - National Center for Microscopy and Imaging ResearchAhmad Ajmal - Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242Ronald A Merrill - Department of Pharmacology and Iowa Neuroscience InstituteAudrey S Dickey - Department of Neurology, Duke University, Durham, North Carolina 27708, andSusan S Taylor - Department of Pharmacology, University of California, San Diego, California 92093G. Stanley McKnight - Department of Pharmacology, University of Washington, Seattle, Washington 98195Anil K Chauhan - Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242Yuriy M Usachev - Department of Pharmacology and Iowa Neuroscience InstituteStefan Strack - Department of Pharmacology and Iowa Neuroscience Institute
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.38(38), pp.8233-8242
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.0649-18.2018
- PMID
- 30093535
- PMCID
- PMC6146498
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 09/19/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984040015502771
Metrics
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