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.
Highlights
Metabolic defects are common pathological processes after traumatic brain injury (TBI) and relate to subsequent brain atrophy and cognitive dysfunction [1]
The CB1 receptors are identified as typical plasma membrane G-protein coupled receptor (GPCR), recent evidences have pointed to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes and their activation influences mitochondrial cyclic adenosine monophosphate accumulation, protein kinase A (PKA) activity, complex I activity and mitochondrial respiration [7]
Our results present clear evidence that at least two pathways are the downstream targets of mtCB1 and play a dual role in metabolic defects and neuronal apoptosis after TBI
Summary
Metabolic defects are common pathological processes after traumatic brain injury (TBI) and relate to subsequent brain atrophy and cognitive dysfunction [1]. Metabolic defects following TBI are not the results of ischemia or metabolic substrate insufficiency and the underlying mechanisms are not definitely clarified. TBI initiates a number of biochemical processes which lead to Endocannabinoids are implicated in a broad range of neurobiological processes including neuronal survival after cerebral ischemia or trauma [5, 6]. CB1 receptors are the most abundant G-protein coupled receptor (GPCR) in mammalian brain and account for most of the biological actions of cannabinoid drugs. The CB1 receptors are identified as typical plasma membrane GPCRs, recent evidences have pointed to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes and their activation influences mitochondrial cyclic adenosine monophosphate (cAMP) accumulation, protein kinase A (PKA) activity, complex I activity and mitochondrial respiration [7]
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