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MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS
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2014
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Doherty.pdf
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Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disorder,
characterized by T cell and B cell dysfunction. SLE mitochondria have been
shown to be dysfunctional with increased mass, mitochondrial potential,
decreased ATP, elevated reactive oxygen species (ROS) and reactive nitrogen
species (RNS) concentrations, and altered Ca2+ stores. Drug treatments that
target the mitochondria have shown efficacy in treating SLE. Here we have
investigated electron transport chain (ETC) activity in SLE, to better understand
the causes of mitochondrial dysfunction in SLE.
We have found that mitochondrial complexes I and IV of the ETC have
elevated respiration in SLE compared to healthy controls after both overnight
resting and anti-CD3/CD28 stimulation. We have also shown that SLE complex I
is resistant to NO inhibition of respiration. SLE peripheral blood lymphocytes
(PBL) have increased S-nitrosylation (SNO) while immunoprecipitated complex I
had decreased SNO of proteins compared to healthy controls. The drug Nacetylcysteine (NAC) was able to inhibit complex I activity in SLE, and was found
to reduce the amount of complex I protein NDUFS3 after 15 minutes as
measured by western blotting.
These results have led us to the conclusion that SLE mitochondrial
complex I is in an active form which is resistant to SNO and is driving the
production of ROS and RNS that are associated with SLE. The drug NAC is able
to inhibit complex I respiration which may have therapeutic efficacy by reducing
the ROS and RNS stress in SLE.