What Trump Can Learn from Prime Minister Modi

The Texas Orato

Clinical implications of augmenter of liver regeneration in cancer: A systematic review

Background/Aim: Hepatocellular carcinoma is a substantial healthcare burden with high prevalence and poor prognosiS. As such, efforts are continually made to uncover molecules relevant in cancer biology, that are exploitable as targets for therapy. The mitochondrion is the powerhouse of the cell and exhibits altered functionality in the malignant state, including aberrant regulation of apoptosis and cellular respiration. Augmenter of liver regeneration (ALR) is a multifunctional mitochondrial protein that demonstrates antioxidative and anti-apoptotic properties and plays a key role in liver regeneration. Materials and Methods: The present study systematically reviews the available literature on the role of ALR in cancer. Results: Systematic search of PubMed resulted in 12 studies discussing ALR in multiple types of cancer. More specifically, ALR appears to be up-regulated in malignant cells and tissueS. Furthermore, treatment of cells with exogenous ALR shows an anti-apoptotic effect while silencing or inhibiting ALR decreases cell and tumor survival. Conclusion: ALR clearly plays a role in cancer biology and demonstrates potential as a therapeutic target. Hepatocellular carcinoma (HCC) is a common oncologic condition with a poor prognosis that poses as a global burden on medical care (1). Between 2002 and 2012 the mortality rate of HCC rose by 34.8% in the United States and liver cancer, with HCC estimated as 70 to 90% of cases, was considered to be the second leading cause of cancer-related deaths among males on a global scale in 2012 (2, 3). Considering the metabolic aspect of several known risk factors for HCC, such as obesity, diabetes, and non-alcoholic fatty liver disease, a common underlying feature of mitochondrial dysfunction is of growing interest in molecular oncology. The regulation of specific mitochondrial proteins is of particular interest, as these proteins demonstrate potential as therapeutic targets for HCC (4). Augmenter of liver regeneration (ALR) is one particular protein of interest that localizes in the intermembrane space of the mitochondria of humans and has a prokaryotic homolog, Erv1, sharing 42% identical amino acid residueS. ALR/Erv1 has been known to contribute to mitochondrial biogenesis and function as a sulfhydryl oxidase in mitochondrial disulfide relay systems (5). It functions to oxidize the import receptor Mia40, both of which conjunctively import small translocase inner membrane (Tim) proteins through an oxidative-folding pathway (6). In turn, cytochrome c (cyt c), which constitutes an important member of the electron transport chain, oxidizes ALR through locomotion of electrons via FAD, thus connecting this redox regulated import pathway to electron transport (5, 7). During specific unfavorable conditions, cells must reprogram to undergo apoptosis during which cyt c activates a series of activated-caspase pathways that lead to cell suicide (8). It is a trademark of cancer cells to down-regulate apoptotic mechanisms and alter mitochondrial respiratory function, resulting in uncontrolled growth and eventual metastasis of cancerous cellS. ALR manifests anti-oxidative and anti-apoptotic properties and is known to support liver regeneration in cases of hepatic injury (9). Considering these properties, early investigations have suggested a role for ALR in cancer (particularly hepatocellular) pathogenesis, growth and progression. In this study, we systematically review the literature discussing ALR in cancer. Clinical implications including oncogenesis and targeted therapy are explored

Substrate specificity of the TIM22 mitochondrial import pathway revealed with small molecule inhibitor of protein translocation

The TIM22 protein import pathway mediates the import of membrane proteins into the mitochondrial inner membrane and consists of two intermembrane space chaperone complexes, the Tim9-Tim10 and Tim8-Tim13 complexes. To facilitate mechanistic studies, we developed a chemical-genetic approach to identify small molecule agonists that caused lethality to a tim10-1 yeast mutant at the permissive temperature. One molecule, MitoBloCK-1, attenuated the import of the carrier proteins including the ADP/ATP and phosphate carriers, but not proteins that used the TIM23 or the Mia40/ Erv1 translocation pathways. MitoBloCK-1 impeded binding of the Tim9-Tim10 complex to the substrate during an early stage of translocation, when the substrate was crossing the outer membrane. As a probe to determine the substrate specificity of the small Tim proteins, MitoBloCK-1 impaired the import of Tim22 and Tafazzin, but not Tim23, indicating that the Tim9-Tim10 complex mediates the import of a subset of inner membrane proteins. MitoBloCK-1 also inhibited growth of mammalian cells and import of the ADP/ATP carrier, but not TIM23 substrates, confirming that MitoBloCK-1 can be used to understand mammalian mitochondrial import and dysfunction linked to inherited human disease. Our approach of screening chemical libraries for compounds causing synthetic genetic lethality to identify inhibitors of mitochondrial protein translocation in yeast validates the generation of new probes to facilitate mechanistic studies in yeast and mammalian mitochondria

Role of twin Cys-Xaa\u3csub\u3e9\u3c/sub\u3e-Cys motif cysteines in mitochondrial import of the cytochrome c oxidase biogenesis factor Cmc1

The Mia40 import pathway facilitates the import and oxidative folding of cysteine-rich protein substrates into the mitochondrial intermembrane space. Here we describe the in vitro and in organello oxidative folding of Cmc1, a twin CX9C-containing substrate, which contains an unpaired cysteine. In vitro, Cmc1 can be oxidized by the import receptor Mia40 alone when in excess or at a lower rate by only the sulfhydryl oxidase Erv1. However, physiological and efficient Cmc1 oxidation requires Erv1 and Mia40. Cmc1 forms a stable intermediate with Mia40 and is released from this interaction in the presence of Erv1. The three proteins are shown to form a ternary complex in mitochondria. Our results suggest that this mechanism facilitates efficient formation of multiple disulfides and prevents the formation of non-native disulfide bonds

Proteasome inhibition stabilizes tau inclusions in oligodendroglial cells that occur after treatment with okadaic acid

Tau-positive inclusions in oligodendrocytes are consistent neuropathological features of corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementias with Parkinsonism linked to chromosome 17. Here we show by immunohistochemistry that tau-positive oligodendroglial inclusion bodies also contain the small heat-shock protein (HSP) αB-crystallin but not H HSP70. To study the molecular mechanisms underlying inclusion body formation, we engineered an oligodendroglia cell line (OLN-t40) to overexpress the longest human tau isoform. Treatment of OLN-t40 cells with okadaic acid (OA), an inhibitor of protein phosphatase 2A, caused tau hyperphosphorylation and a decrease in the binding of tau to microtubules. Simultaneously, tau-positive aggregates that also stained with the amyloid-binding dye thioflavin-S as well as with antibodies to tau and αB-crystallin were detected. However, they were only transiently expressed and were degraded within 24 hr. When the proteasomal apparatus was inhibited by carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132) after OA treatment, the aggregates were stabilized and were still detectable after 18 hr in the absence of OA. Incubation with MG-132 alone inhibited tau proteolysis and led to the induction of HSPs, including αB-crystallin and to its translocation to the perinuclear region, but did not induce the formation of thioflavin-S-positive aggregates. Hence, although tau hyperphosphorylation induced by protein phosphatase inhibition contributes to pathological aggregate formation, only hyperphosporylation of tau followed by proteasome inhibition leads to stable fibrillary deposits of tau similar to those observed in neurodegenerative diseases

A small molecule inhibitor of redox-regulated protein translocation into mitochondria

The mitochondrial disulfide relay system of Mia40 and Erv1/ALR facilitates import of the small translocase of the inner membrane (Tim) proteins and cysteine-rich proteins. A chemical screen identified small molecules that inhibit Erv1 oxidase activity, thereby facilitating dissection of the disulfide relay system in yeast and vertebrate mitochondria. One molecule, mitochondrial protein import blockers from the Carla Koehler laboratory (MitoBloCK-6), attenuated the import of Erv1 substrates into yeast mitochondria and inhibited oxidation of Tim13 and Cmc1 in in vitro reconstitution assays. In addition, MitoBloCK-6 revealed an unexpected role for Erv1 in the carrier import pathway, namely transferring substrates from the translocase of the outer membrane complex onto the small Tim complexes. Cardiac development was impaired in MitoBloCK-6-exposed zebrafish embryos. Finally, MitoBloCK-6 induced apoptosis via cytochrome c release in human embryonic stem cells (hESCs) but not in differentiated cells, suggesting an important role for ALR in hESC homeostasis

Osm1 facilitates the transfer of electrons from Erv1 to fumarate in the redox-regulated import pathway in the mitochondrial intermembrane space

Prokaryotes have aerobic and anaerobic electron acceptors for oxidative folding of periplasmic proteins. The mitochondrial intermembrane space has an analogous pathway with the oxidoreductase Mia40 and sulfhydryl oxidase Erv1, termed the mitochondrial intermembrane space assembly (MIA) pathway. The aerobic electron acceptors include oxygen and cytochrome c, but an acceptor that can function under anaerobic conditions has not been identified. Here we show that the fumarate reductase Osm1, which facilitates electron transfer from fumarate to succinate, fills this gap as a new electron acceptor. In addition to microsomes, Osm1 localizes to the mitochondrial intermembrane space and assembles with Erv1 in a complex. In reconstitution studies with reduced Tim13, Mia40, and Erv1, the addition of Osm1 and fumarate completes the disulfide exchange pathway that results in Tim13 oxidation. From in vitro import assays, mitochondria lacking Osm1 display decreased import of MIA substrates, Cmc1 and Tim10. Comparative reconstitution assays support that the Osm1/fumarate couple accepts electrons with similar efficiency to cytochrome c and that the cell has strategies to coordinate expression of the terminal electron acceptors. Thus Osm1/ fumarate is a new electron acceptor couple in the mitochondrial intermembrane space that seems to function in both aerobic and anaerobic conditions