Current Molecular Medicine - Volume 17, Issue 9, 2017

Mitochondria are the sole semiautonomous organelles of the human cell and play a very important role in not only energy production but also in apoptosis, metabolism and cell signaling. They are also known to be major producers of ROS and RNS free radicals during ATP production. These free radicals in excessive amount may damage the mitochondrial DNA as well as proteome resulting in accumulation of misfolded proteins which may prove deleterious to their functioning and are known to be involved in disease pathology. To maintain healthy proteome, mitochondria have developed as quality control machinery in semiautonomous manner, where cellular proteins such as proteases and heat shock proteins are used for quality control. The present review discusses various aspects of mitochondrial protein quality control operating at outer or inner membrane as well as intermembranal space. The various pathways involved in mitochondrial unfolded protein response have been discussed along with their implications in cancer and various neurodegenerative diseases.

In metabolic diseases such as obesity, metabolic syndrome and type II diabetes, the over-expression of uncoupling proteins (UCPs) in a response to increased reactive oxygen species (ROS) generation by mitochondrial respiratory complexes, and to the excess of free fatty acid (FFA) supply from adipose tissue, may protect cells from oxidative stress, lipotoxicity and in turn from death. UCPs by reducing superoxide anion and H2O2 generation trigger several signals to cell for their adaptation to the lipotoxic microenvironment. In mitochondria, a decrease of cytochrome c (cyt c) and proapoptotic protein release promotes cell survival and proliferation. The altered lipid metabolism also affects cardiolipin susceptibility to the peroxidation, a process involved in the dissociation of cyt c from mitochondrial inner membrane and its release, a key step of apoptosis. Therefore, UCPs by attenuating ROS generation and lipotoxicity may downregulate programmed cell death, a well-known physiological process controlling cell proliferation contributing to uncontrolled cell proliferation and tumorigenesis. In addition, tumor cells over-expressed UCPs, by inhibiting ROS generation acquire resistance to death during pharmacological treatment with oxidative stress drug inducers. Therefore, the aim of this review is to discuss recent findings regarding the role that UCPs play in cell survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote cell proliferation.

VCP/p97/Cdc48, a member of the ATPases associated with diverse cellular activities (AAA) family, is necessary for the endoplasmic-reticulum-associated protein degradation (ERAD) pathway to maintain protein homeostasis. Overwhelming proteotoxic stress drove cancer cells to enhance VCP/p97/Cdc48-associated ERAD to maintain protein homeostasis for survival, demonstrating that VCP/p97/Cdc48 expression was positively correlated with cancer prognosis. More studies revealed that targeting VCP/p97/Cdc48 could be a potential target in cancer therapy. CB-5083, a novel inhibitor of VCP/p97/Cdc48, is in clinical trials as the first VCP/p97/Cdc48- inhibiting drug for cancer therapy. Here, we discuss the relationship between VCP/p97/Cdc48, ERAD, protein homeostasis and cancer therapy.

Graphene and graphene oxide topography have an effect on the fate of stem cells such as adhesion, differentiation, and proliferation. This overview clearly shows that a new design and manipulation of associated graphene oxide stem cell culture platforms are of paramount importance as a focus in stem cell to tissue engineering applications. This overview also proposes that a film of graphene oxide is an efficient platform to modulate structure and function of multipotent mesenchymal stem/stromal cells (MSCs) and in special human adipose tissue derived mesenchymal stromal/stem cells (AT-MSCs). The implication of graphene oxide on osteogenesis, neurogenesis, oligodendrogenesis, adipogenic and epithelial differentiation is also discussed. Graphene oxide toxicity on stem cells and the importance of GO application on ATMSCs differentiation and proliferation are final topics that are being discussed.

Background: Four-and-a-half LIM domains protein 1 (FHL1) mutations are associated with human myopathies. However, the function of this protein in skeletal development remains unclear. Methods: Whole-mount in situ hybridization and embryo immunostaining were performed. Results: Zebrafish Fhl1A is the homologue of human FHL1. We showed that fhl1A knockdown causes defective skeletal muscle development, while injection with fhl1A mRNA largely recovered the muscle development in these fhl1A morphants. We also demonstrated that fhl1A knockdown decreases the number of satellite cells. This decrease in satellite cells and the emergence of skeletal muscle abnormalities were associated with alterations in the gene expression of myoD, pax7, mef2ca and skMLCK. We also demonstrated that fhl1A expression and retinoic acid (RA) signalling caused similar skeletal muscle development phenotypes. Moreover, when treated with exogenous RA, endogenous fhl1A expression in skeletal muscles was robust. When treated with DEAB, an RA signalling inhibitor which inhibits the activity of retinaldehyde dehydrogenase, fhl1A was downregulated. Conclusion: fhl1A functions as an activator in regulating the number of satellite cells and in skeletal muscle development. The role of fhl1A in skeletal myogenesis is regulated by RA signaling.

Purpose: Dysfunction or death of retinal pigment epithelial (RPE) cells is a common pathogenesis of various types of retinal degenerative diseases. Recent reports indicated that ROCK pathway inhibitors regulate cell proliferation or apoptosis in a celltype- dependent manner. Here, we aim to investigate the effect of ROCK inhibitor Y- 27632 on the human retinal pigment epithelium (RPE) in vitro. Methods: Cell proliferation and apoptosis were analyzed by CCK-8 and flow cytometry respectively. Cell proliferation markers were detected by immunofluorescence and western blot. Cell morphology was evaluated using scanning electron microscopy. The topography and biomechanical properties of living cells were assessed using atomic force microscope (AFM). In addition, cytoskeleton and epithelial-mesenchymal transition (EMT) markers were detected by western blot and immunofluorescence. Results: 30μM Y-27632 significantly promoted cell proliferation and decreased apoptosis. Compared with control group, human retinal pigment epithelial cell line ARPE-19 cells treated with 30μM Y-27632 exhibited significantly decreased cytomembrane roughness (Ra: 41.04±1.63nm vs. 24.41±0.75nm, P<0.01; Rq: 51.56±2.03nm vs. 30.81±0.95nm, P<0.01) and increased elasticity modulus (16.66±0.83KPa vs. 32.55±1.48KPa, P<0.01). In addition, the inhibition of ROCK activity by Y-27632 caused cell elongation and reorganization of microfilaments and microtubules of cytoskeletons. Conclusion: Taken together, our data demonstrated that Y-27632 could alter biomechanical properties and reorganized cytoskeletons to promote RPE cell survival. These results are an important step toward the future application of Y-27632 in retinal degenerative diseases.