MitomiRs, chloromiRs and modelling of the microRNA inhibition.

MicroRNAs are non-coding parts of nuclear and mitochondrial genomes, preventing the weakest part of the genetic regulatory networks from being expressed and preventing the appearance of a too many attractors in these networks. They have also a great influence on the chromatin clock, which ensures the updating of the genetic regulatory networks. The post-transcriptional inhibitory activity by the microRNAs, which is partly unspecific, is due firstly to their possibly direct negative action during translation by hybridizing tRNAs, especially those inside the mitochondrion, hence slowing mitochondrial respiration, and secondly to their action on a large number of putative m-RNA targets like those involved in immunetworks; We show that the circuits in the core of the interaction graphs are responsible for the small number of dedicated attractors that correspond to genetically controlled functions, partly due to a general filtering by the microRNAs. We analyze this influence as well as their impact on important functions like the control by the p53 network over the apoptosis/proliferation system and the homeostasis of the energy metabolism. In this last case, we show the role of two kinds of microRNAs, both involved in the control of the mitochondrial genome: (1) nuclear microRNAs, called mitoMirs, inhibiting mitochondrial genes and (2) putative mitochondrial microRNAs inhibiting the tRNAs functioning.

MitomiRs delineating the intracellular localization of microRNAs at mitochondria.

Mitochondria play a crucial role in energetic metabolism, signaling pathways, and overall cell viability. Mitochondrial dysfunctions are known to cause a wide range of human diseases that affect tissues especially those with high energetic requirements, such as skeletal muscle, heart, kidney, and central nervous system, while being involved in cancer, aging, and metabolic processes. At the same time, the microRNA (miRNA) gene family has been demonstrated to be involved in most cellular processes through modulation of proteins critical for cellular homeostasis. Given the broad scope of reactivity profiles and the ability of miRNAs to modify numerous proteomic and genomic processes, new emphasis is being placed on the influence of miRNAs at the mitochondrial level. Recently, the localization of miRNAs in mitochondria was characterized in different species. This raises the idea that those miRNAs, noted "mitomiRs," could act as "vectors" that sense and respond dynamically to the changing microenvironment of mitochondria at the cellular level. Reciprocally, we present the involvement of mitochondria in small RNA biogenesis. With the aim of deciphering the significance of this localization, we discuss the putative mechanism of import of miRNAs at mitochondria, their origin, and their hypothetical roles within the organelle.

microRNAs in diseases: from candidate to modifier genes.

Until recently, the search for genetic factors predisposing or causing Mendelian diseases focused almost exclusively on protein coding sequences. As essential components of the regulatory system of gene expression, microRNAs (miRNAs) hold great promises into elucidating a number of inherited diseases. The herein review focuses on the genetic variations, whether copy number variation (CNV) or single nucleotide polymorphism (SNP), alternatively at the levels of the miRNA gene itself and of its target genes. We consider miRNA as the candidate gene, or the regulator of a disease-causing gene, or the modifier gene. The best paradigms of the field are presented in both monogenic diseases and complex traits. The computational tools, which are essential into identifying miRNAs and characterizing miRNA targets, are overviewed.

Role of cyclins in epithelial response to oxidants.

Oxidants are involved in a large variety of pulmonary diseases. Among the various cell types that compose the respiratory system, the epithelial cells appear to be a major target for oxidative stress. When cells are exposed to DNA-damaging agents such as oxidants, a feedback control is activated that acts as a brake on the cell cycle to inhibit entry into the S phase until DNA repair is completed. Progression through the G1 phase and the G1-S transition involves sequential assembly and activation of key regulators of the cell cycle machinery, the cyclin-dependent kinases (CDKs). Activity of the CDKs is regulated by several mechanisms, which include the CDK inhibitors (CKIs). The CKI p21(CIP1) appears to play an important role in the response of epithelial cells to oxidants.

Restoring effects of vitamin A on surfactant synthesis in nitrofen-induced congenital diaphragmatic hernia in rats.

Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Besides pulmonary hypoplasia, the pathophysiology of CDH also includes surfactant deficiency. Vitamin A (vit A) is important for various aspects of lung development. We hypothesized that antenatal treatment with vit A would stimulate lung surfactant synthesis in experimental CDH induced in rats by maternal ingestion of the herbicide nitrofen (2,4-dichloro-phenyl-p-nitrophenyl-ether) on Day 12. Fetuses were assigned to six experimental groups: (1) controls from rats that received olive oil, the vehicle; (2) fetuses from rats that received olive oil on Day 12 and vit A orally (15,000 IU) on Day 14; (3) nitrofen (N)-exposed fetuses without diaphragmatic hernia (N/no DH); (4) N/no DH from rats given vit A on Day 14; (5 ) nitrofen-exposed fetuses with DH (N/+DH); (6) N/+DH from rats given vit A on Day 14. Fetuses were delivered by C-section at Day 21. Lung DNA content was lowered in the nitrofen group as compared with the controls group, but increased by subsequent vit A treatment. Lung surfactant disaturated phosphatidylcholine was reduced in the N/+DH group and restored to control level by vit A. The expression level of surfactant proteins (SP) -A and -C was decreased in vit A-treated control rats and in nitrofen-exposed fetuses with or without DH. Vit A restored SP-A and -C mRNA expression to control levels in N/+DH. SP-B expression was lowered in N/no DH and increased by vit A in this group. The proportion of type II cells assessed by SP-B immunolabeling was lowered in N/+DH and restored by vit A treatment. We conclude that antenatal treatment with vit A restores lung maturation in nitrofen-induced hypoplastic lungs with CDH. These findings point out vit A as a potential therapeutical agent for correcting surfactant deficiency in CDH.

Role of secondary structure in discrimination between constitutive and inducible activators.

We have examined structural differences between the proto-oncogene c-Myb and the cyclic AMP-responsive factor CREB that underlie their constitutive or signal-dependent activation properties. Both proteins stimulate gene expression via activating regions that articulate with a shallow hydrophobic groove in the KIX domain of the coactivator CREB-binding protein (CBP). Three hydrophobic residues in c-Myb that are conserved in CREB function importantly in cellular gene activation and in complex formation with KIX. These hydrophobic residues are assembled on one face of an amphipathic helix in both proteins, and mutations that disrupt c-Myb or CREB helicity in this region block interaction of either factor with KIX. Binding of the helical c-Myb domain to KIX is accompanied by a substantial increase in entropy that compensates for the comparatively low enthalpy of complex formation. By contrast, binding of CREB to KIX entails a large entropy cost due to a random coil-to-helix transition in CREB that accompanies complex formation. These results indicate that the constitutive and inducible activation properties of c-Myb and CREB reflect secondary structural characteristics of their corresponding activating regions that influence the thermodynamics of formation of a complex with CBP.