Seth, Rohit
Zinc deficiency induces apoptosis via mitochondrial p53- and
caspase-dependent pathways in human neuronal precursor cells.
Journal of Trace Elements in Medicine and Biology.
Abstract
Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo
and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured
human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to
the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading
to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green
fluorescence ratio. Disruption of mitochondrial membrane integrity was accompanied by efflux of the
apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant
increase in reactive oxygen species (ROS) after 24 h of zinc deficiency. Measurement of caspase cleavage,
mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in
zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear
structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were
also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin-
, established that these alterations were largely dependent on p53. Together these data identify a cascade
of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading
to apoptosis during zinc deficiency.
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