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2015 ; 470
(1
): 65-76
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Transition metals activate TFEB in overexpressing cells
#MMPMID26251447
Peņa KA
; Kiselyov K
Biochem J
2015[Aug]; 470
(1
): 65-76
PMID26251447
show ga
Transition metal toxicity is an important factor in the pathogenesis of numerous
human disorders, including neurodegenerative diseases. Lysosomes have emerged as
important factors in transition metal toxicity because they handle transition
metals via endocytosis, autophagy, absorption from the cytoplasm and exocytosis.
Transcription factor EB (TFEB) regulates lysosomal biogenesis and the expression
of lysosomal proteins in response to lysosomal and/or metabolic stresses. Since
transition metals cause lysosomal dysfunction, we proposed that TFEB may be
activated to drive gene expression in response to transition metal exposure and
that such activation may influence transition metal toxicity. We found that
transition metals copper (Cu) and iron (Fe) activate recombinant TFEB and
stimulate the expression of TFEB-dependent genes in TFEB-overexpressing cells. In
cells that show robust lysosomal exocytosis, TFEB was cytoprotective at moderate
levels of Cu exposure, decreasing oxidative stress as reported by the expression
of heme oxygenase-1 (HMOX1) gene. However, at high levels of Cu exposure,
particularly in cells with low levels of lysosomal exocytosis, activation of
overexpressed TFEB was toxic, increasing oxidative stress and mitochondrial
damage. Based on these data, we conclude that TFEB-driven gene network is a
component of the cellular response to transition metals. These data suggest
limitations and disadvantages of TFEB overexpression as a therapeutic approach.
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