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Abstract: Mitochondria are the major supplier of cellular energy in the form of ATP. Defects in normal ATP production due to dysfunctions in mitochondrial gene expression are responsible for many mitochondrial and aging related disorders. Mitochondria carry their own DNA genome which is transcribed by relatively simple transcriptional machinery consisting of the mitochondrial RNAP (mtRNAP) and one or more transcription factors. The mtRNAPs are remarkably similar in sequence and structure to single-subunit bacteriophage T7 RNAP but they require accessory transcription factors for promoter-specific initiation. Comparison of the mechanisms of T7 RNAP and mtRNAP provides a framework to better understand how mtRNAP and the transcription factors work together to facilitate promoter selection, DNA melting, initiating nucleotide binding, and promoter clearance. This review focuses primarily on the mechanistic characterization of transcription initiation by the yeast Saccharomyces cerevisiae mtRNAP (Rpo41) and its transcription factor (Mtf1) drawing insights from the homologous T7 and the human mitochondrial transcription systems. We discuss regulatory mechanisms of mitochondrial transcription and the idea that the mtRNAP acts as the in vivo ATP “sensor” to regulate gene expression. This article is part of a Special Issue entitled: Mitochondrial Gene Expression. [Copyright &y& Elsevier]

Metal-responsive transcription factor 1 (MTF1) participates in redox homeostasis and heavy metals detoxification via regulating the expression of metal responsive genes. However, the exact role of MTF1 in Cd-induced cerebral toxicity remains unclear. Herein, we explored the mechanism of Cd-elicited cerebral toxicity through modulating MTF1/MTs pathway in chicken cerebrum exposed to different concentrations of Cd (35 mg, 70 mg, and 140 mg/kg CdCl 2) via diet. Notably, cerebral tissues showed varying degrees of microstructural changes under Cd exposure. Cd exposure significantly up-regulated the expression of metal transporters (DMT1, ZIP8, and ZIP10) with concomitant elevated Cd level, as determined by ICP-MS. Cd significantly altered other cerebral biometals concentrations (particularly, Zn, Fe, Se, Cr, Mo, and Pb) and redox balance, resulting in increased cerebral oxidative stress. More importantly, Cd exposure suppressed MTF1 mRNA and nuclear protein levels and its target metal-responsive genes, notably metallothioneins (MT1 and MT2), and Fe and Cu transporter genes (FPN1, ATOX1, and XIAP). Moreover, Cd disrupted the regulation of expression of selenoproteome (particularly, GPxs and SelW), and cerebral Se level. Overall, our data revealed that molecular mechanisms associated with Cd-induced cerebral damage might include over-expression of DMT1, ZIP8 and ZIP10, and suppression of MTF1 and its main target metal-responsive genes as well as several selenoproteins. Environmentally relevant hazardous neurotoxic metal Cd uptake in neurons/nerve cells is mediated by over-expression of membrane metal transporters (DMT1, ZIP8, and ZIP10). Once inside the cerebral cells, Cd perturbed cerebral ionic homeostasis as well as redox balance and thereby induced oxidative stress. Meanwhile, Cd and/or Cd-mediated oxidative stress triggered the transcription factor MTF1 to translocate into the nucleus and thereby suppressing MTF1 and its major target metal-responsive genes (MT1, MT2, ATOX1, and FPN1), leading to neuronal damage. Moreover, Cd disrupted the regulation of the expression of cerebral selenoproteins. Above these pathways simultaneously induced dose-dependent cerebral toxicity. [Display omitted] • The MTF1 is the potential molecular target of Cd-induced cerebral toxicity. • Cd-induced overexpression of DMT1, ZIP8 and ZIP10 mediated cerebral Cd influx. • Cd induced oxidative stress by affecting bio-metals and redox homeostasis. • Cd induced cerebral toxicity via suppressing the MTF1-MTs cellular defense system. • Cd modulated cerebral selenoproteins regulation, more particularly GPxs and SelW. Cadmium modulated MTF1-MTs regulatory axis. [ABSTRACT FROM AUTHOR]