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Mol Brain. 2016 Aug 2;9(1):75. doi: 10.1186/s13041-016-0257-8.

Acute upregulation of neuronal mitochondrial type-1 cannabinoid receptor and it's role in metabolic defects and neuronal apoptosis after TBI.

Author information

1
Department of Neurosurgery, First affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou, 310006, China. xuzhenhangzhou@yeah.net.
2
Department of Surgery, First affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou, 310006, China.
3
Central laboratory, First affiliated Hospital of Zhejiang Chinese Medicine University, 54 Youdian Lane, Hangzhou, 310006, China.
4
Department of Neurosurgery, Huzhou Central Hospital, 198 Hongqi Lane, Huzhou, 313003, China.

Abstract

Metabolic defects and neuronal apoptosis initiated by traumatic brain injury (TBI) contribute to subsequent neurodegeneration. They are all regulated by mechanisms centered around mitochondrion. Type-1 cannabinoid receptor (CB1) is a G-protein coupled receptor (GPCR) enriched on neuronal plasma membrane. Recent evidences point to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes (mtCB1) and the activation of mtCB1 influences aerobic respiration via inhibiting mitochondrial cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/complex I pathway. The expression and role of neuronal mtCB1 under TBI are unknown. Using TBI models of cultured neurons, wild type and CB1 knockout mice, we found mtCB1 quickly upregulated after TBI. Activation of mtCB1 promoted metabolic defects accompanied with ATP shortage but protected neurons from apoptosis. Selective activation of plasma membrane CB1 showed no effects on neuronal metabolism and apoptosis. Activation of mtCB1 receptors inhibited mitochondrial cAMP/PKA/complex I and resulted in exacerbated metabolic defects accompanied with a higher ratio of ATP reduction to oxygen consumption decrease as well as neuronal apoptosis. Further research found the remarkable accumulation of protein kinase B (AKT) on neuronal mitochondria following TBI and the activation of mtCB1 upregulated mitochondrial AKT/complex V activity. Upregulation of mitochondrial AKT/complex V activity showed anti-apoptosis effects and alleviated ATP shortage in metabolic defects. Taken together, we have identified mtCB1 quickly upregulate after TBI and a dual role the mtCB1 might play in metabolic defects and neuronal apoptosis initiated by TBI: the inhibition of mitochondrial cAMP/PKA/complex I aggravates metabolic defects, energy insufficiency as well as neuronal apoptosis, but the coactivation of mitochondrial AKT/complex V mitigates energy insufficiency and neuronal apoptosis.

KEYWORDS:

Apoptosis; Metabolic defects; Mitochondrial type-1 cannabinoid receptor; Traumatic brain injury

PMID:
27485212
PMCID:
PMC4971620
DOI:
10.1186/s13041-016-0257-8
[Indexed for MEDLINE]
Free PMC Article

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