Brown G 2014 Abstract MiP2014

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Complex I inhibition in microglia and inflammatory neuronal loss.
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Brown GC
Mitochondr Physiol Network 19.13 - MiP2014

Brown GC (2014)

Event: MiP2014

Brain inflammation may contribute to neuronal loss in infectious, ischemic, traumatic and neurodegenerative brain pathologies. We and others have shown that: a) brain inflammation induces the expression in microglia and astrocytes of inducible nitric oxide synthase (iNOS), which produces high levels of NO, b) NO derivatives peroxynitrite and S-nitrosothiols inactivate mitochondrial Complex I, resulting in a stimulation of oxidant production by mitochondria, c) oxidant production by microglia contributes to their inflammatory activation, and d) activated microglia can cause neuronal loss by eating them alive [1-4]. Thus, we were interested in whether activated microglia may inhibit their mitochondrial Complex I, resulting in sustained activation and phagocytosis of live neurons.

There is evidence that in Parkinson’s disease and general brain aging mitochondrial Complex I is inhibited in affected parts of the brain. Rotenone is an environmental toxin and Complex I inhibitor that can cause activation of microglia and a Parkinson’s like pathology in rodents. We, therefore, tested whether it could cause microglia to phagocytose live neurons.

We found that low nanomolar levels of rotenone could indeed activate microglial phagocytosis and cause neurons to phagocytose co-cultured neurons [5]. Removal of microglia or inhibition of phagocytic signalling prevented rotenone-induced neuronal loss, leaving viable neurons [5].

Low levels of brain inflammation during ageing may cause partial inhibition of Complex I, resulting in oxidant production which sustains inflammation, and induces microglia to phagocytose synapses and cell bodies of live neurons. This process may be exacerbated in Parkinson’s disease and prevented by blocking inflammation or phagocytic signalling.


O2k-Network Lab: UK Cambridge Brown GC


Labels: Pathology: Aging;senescence, Parkinson's  Stress:Oxidative stress;RONS 

Tissue;cell: Nervous system 

Enzyme: Complex I 



Event: C1, Oral  MiP2014 

Affiliation

Dep Biochemistry, Univ Cambridge, UK. - gcb3@cam.ac.uk

References

  1. Borutaite V, Brown GC (2006) S-nitrosothiol inhibition of mitochondrial complex I causes a reversible increase in mitochondrial hydrogen peroxide production. Biochim Biophys Acta 1757: 562-6.
  2. Vilalta A, Brown GC (2014) Deoxyglucose prevents neurodegeneration in culture by eliminating microglia. J Neuroinflammation 11: 58.
  3. Neher JJ, Emmrich JV, Fricker M, Mander PK, Thery C, Brown GC (2013) Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci 110: E4098-107.
  4. Brown GC, Neher JJ (2014) Microglial phagocytosis of live neurons. Nat Rev Neurosci 15: 209-16.
  5. Emmrich J, Hornik T, Neher J, Brown GC (2013) Rotenone induces neuronal death by microglial phagocytosis of neurons. FEBS J. 280: 5030-8.