Short-lived mammals (shrew, mouse) have a less robust metal-responsive transcription factor than humans and bats

Abstract

Non-essential “heavy” metals such as cadmium tend to accumulate in an organism and thus are a particular threat for long-lived animals. Here we show that two unrelated, short-lived groups of mammals (rodents and shrews, separated by 100 Mio years of evolution) each have independently acquired mutations in their metal-responsive transcription factor (MTF-1) in a domain relevant for robust transcriptional induction by zinc and cadmium. While key amino acids are mutated in rodents, in shrews an entire exon is skipped. Rodents and especially shrews are unique regarding the alterations of this region. To investigate the biological relevance of these alterations, MTF-1s from the common shrew (Sorex araneus), the mouse, humans and a bat (Myotis blythii), were tested by cotransfection with a reporter gene into cells lacking MTF-1. Whereas shrews only live for 1.5–2.5 years, bats, although living on a very similar insect diet, have a lifespan of several decades. We find that bat MTF-1 is similarly metal-responsive as its human counterpart, while shrew MTF-1 is less responsive, similar to mouse MTF-1. We propose that in comparison to most other mammals, the short-lived shrews and rodents can afford a “lower-quality” system for heavy metal homeostasis and detoxification.

Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging

“…Here, we provide evidence for a potential role of gene expression response to heavy metals in healthy aging. Our work perfectly fits with the observation that short-lived mammals have a less active MTF-1 (display defects in heavy [37] metal response) than the longer lived humans and bats [71] and supports the hypothesis that an efficient metal homeodynamic process is a key aspect of longevity.…”

“…In liver and kidney, Cd import and sequestration predominate, while fibroblasts avoid Cd accumulation and induce MTs when needed. Consistent with this model, MTF-1 from longer-lived species is more efficient at inducing MTs in vitro [71].…”

Genomic Redistribution of Metal-Response Transcription Factor-1 (MTF-1) in Cadmium Resistant Cells

“…MTF-1 was revealed to be a zinc finger containing a transcription factor able to activate metal-responsive genes in mice [ 7 ]. A human homolog was discovered with high sequence conservation to the mouse MTF-1 [ 5 ], which is also conserved in flies, fish, and mammals [ 8 , 9 ]. MTF-1 is essential for normal metal homeostasis and for the cellular response to heavy metals [ 10 ].…”