Mitochondrial dysfunction: A major player in hepatic development, function, and senescence.

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The relationship between accelerated postnatal catch-up growth and premature ageing is one of the important discoveries in biology. Recent studies by our laboratory and others has demonstrated that maternal protein restriction (MPR, 8% protein) during pregnancy in rats followed by rapid catch-up growth leads to premature hepatic senescence, dysmetabolism, and decreased longevity. In contrast, if there is no catch-up growth (due to maintenance of an 8% protein diet throughout life), longevity is not hindered. Recently we have demonstrated that these MPR offspring with catch-up growth exclusively exhibit higher hepatic p66Shc, a critical adapter protein involved in mitochondrial dysfunction, oxidative stress, and senescence. However, the underlying mechanisms remain elusive. We have also demonstrated that MPR offspring with catch-up growth exclusively exhibit changes in hepatic postranslational histone modifications and microRNAs (i.e. miR-140, miR-203-a-p, miR-193b) which can directly or indirectly influence p66Shc expression, mitochondrial function, and senescence. Therefore, the overall hypothesis is that postnatal catch-up growth in MPR offspring impairs hepatic development, function, and senescence via epigenetic mechanisms.  To address this, the first objective will employ chromatin immunoprecipitation (ChIP) to examine the posttranslational histone modifications in the proximal promoter of p66shc in MPR offspring with and without catch-up growth. We will also address if mimics or inhibitors of miR-140 influence the epigenetic regulation of hepatic p66Shc in vitro using cultured neonatal hepatocytes. For our second objective, using neonatal hepatocytes treated with mimics or inhibitors of miR-203a-p, we will address if alterations in miR-203a-p levels influences hepatic p66Shc expression and downstream mitochondrial function using the Seahorse XFe24 analyzer.  Finally, given Cyclin D1, an important component of the cell cycle, has been implicated in (i) premature senescence and (ii) is inversely related to miR-193b expression in these MPR offspring, our third objective is to directly implicate the role of miR-193b on mitochondrial function and senescence in the liver. To examine this relationship further, we will assess if mimics or inhibitors of miR-193b in vitro alters Cyclin D1 expression, mitochondrial function, and ultimately the cell cycle/senescence in neonatal rat liver cells. Collectively, these studies would further implicate how a poor in utero environment epigenetically impairs mitochondrial activity leading to altered hepatic development, function, and ageing. In addition, by using this MPR regime as a unique and highly relevant model of premature senescence, we can further elucidate how better management of low birth weight offspring can improve longevity in mammals which has major implications on the livestock industry (e.g. improved meat quality).