• 2018-07
  • 2018-10
  • 2018-11
  • br ECM in mammary gland


    ECM in mammary gland development
    ECM in breast cancer progression
    Introduction Mitochondria are double-membrane organelles of which structure is characterized by containing lipid bilayers in almost eukaryotic cells. The two main compartments of the mitochondria are separated by the inter mitochondrial membrane (IMM) and the outer mitochondrial membrane (OMM).The inter membrane space (IMS) intensely folded into cristae. Different Tenovin-6 harbor 10–1000 mitochondria. Mitochondria are composed of approximately 1100 proteins, which are encoded by genes located in both the mitochondrial genomes (mtDNA) and the nuclear genomes. Yet, most of the mitochondrial proteomes are encoded by the nuclear genomes, synthesized in the cytosol and imported into mitochondria. Mitochondria possess their own genome, which encodes 13 polypeptides of the electron transport chain (ETC), 22 tRNAs and 2 rRNAs required for their synthesis. Organismal lives in a sophisticated and unstable environment, and different adverse environmental conditions can induce varying degrees of mitochondrial stress. Different mitochondrial stress may cause mitochondrial dysfunction in different degrees. Mitochondrial dysfunction is one of the major pathological factors in neurological disorders. Thus, it’s meaningful to discuss the molecular mechanisms of the mitochondrial UPRmt.
    Communication between mitochondria and nucleus In order to quickly adapt to changeable conditions, mitochondria evolve to well-integrated organelles communicated with other cell compartments. Under stress conditions, the signal conduction can be achieved from the misfolded or unfolded mitochondrial proteins within the matrix to the nucleus. Mitochondrial retrograde signaling or mitochondrion to nucleus communication has been discovered by Butow and Avadhani laboratories. Maintenance of protein homeostasis, the mitochondrial retrograde response increases nucleus encoded mitochondrial proteases and chaperones synthesis to facilitate protein folding or clearance of defective proteins in response to decreased mitochondrial activity, which is essential for organism functionality and survival. Recent works have not completely defined UPRmt extensively in mammals, but two potential signal transduction pathways may involve in retrograde response. One is mitochondrial membrane potential. The retrograde response can be triggered by low membrane potential, and blocked via restoring the membrane potential in rho and cox4 null yeast. The other one is cytosolic calcium accumulation. Assembling calcium within cytosolic causes activation of calcineurin and subsequently transcription factors. Under accumulation of misfolded or unfold proteins conditions, protein kinase R (PKR) is activated and elevates levels of phosphorylated-JNK, which promotes the transcription factor c-Jun bind to the activation protein-1 (AP-1) element, then activates the transcription of CHOP. There exist two mitochondrial unfolded protein response elements (MURE1 and MURE2) adjacent to CHOP binding site which present in promoters of UPRmt responsive genes. Interestingly, activation of UPRmt via JNK/c-jun pathway requires ClpP protease that could be a potential factor for inducing the UPRmt. During mitochondrial stress, cytosolic calcium homeostasis disruption activates the transcription factors of C/EBP homologous protein (CHOP), extracellular signal-regulated kinase 1 (ERK1), and nuclear factor kappa B (NF-κB). NF-κB activation is independently of the traditional repressor IκBα, but dependent on the inhibitor IκBβ dephosphorylation, inducing NF-κB outward from the cytoplasm to the nucleus. Activation of these transcription factors turn on the expression of UPRmt target genes, including the mitochondrial chaperones HSP60, HSP10 and mtDnaJ encoded by the nuclear genome. Furthermore, upon mitochondrial stress additional proteases ClpP, Yme1L1, Lon and PMPCB, the import component TIMM17A and the enzymes NDUFB2, endonuclease G and thioredoxin 2 are all upregulated.