Genetic reduction of mitochondrial complex I function does not lead to loss of XXXX neurons in  vivo.

@entity5212 @entity137 @entity67834 @entity19 @entity935 @entity191 @entity51 @entity528
UNASSIGNED: Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic @entity528 in @entity191 . However, loss of complex I activity by  systemic deletion of the @entity67834 gene, one of the subunits comprising complex I, does not cause dopaminergic @entity528 in culture. Here, we generated @entity19 with conditional @entity67834 knockout in dopaminergic neurons ( @entity67834 conditional knockout @entity19 [cKO]) to examine the effect of complex  I  inhibition on dopaminergic neuron function and survival during aging and on @entity5212 ( @entity5212 ) treatment in  vivo. @entity67834 cKO @entity19 did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or @entity935 -dependent @entity51 over the 24-month life span. These @entity19 were just as susceptible to @entity5212 as control @entity19 . However, compared with control @entity19 , @entity67834 cKO @entity19 exhibited an age-dependent reduction of @entity935 in the striatum and increased a-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible @entity67834 knockout @entity19 ( @entity67834  inducible knockout) in which @entity67834 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on @entity5212 sensitivity of dopaminergic neurons. The @entity67834 inducible knockout @entity19 exhibited similar sensitivity to @entity5212 as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to @entity935 loss and the development of a-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic @entity528 during the normal life span of @entity19 . Furthermore, mitochondrial complex I inhibition does not underlie @entity5212 @entity137 in  vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic @entity528 during aging nor does it contribute to @entity935 neuron @entity137 in the @entity5212 model of @entity191 . These findings suggest the existence of alternative mechanisms of dopaminergic @entity528 independent  of mitochondrial complex I inhibition.
