Effect of the non-steroidal anti-inflammatory drugs on the acyl-CoA synthetase activity toward medium-chain,long-chain and polyunsaturated fatty acids in mitochondria of mouse liver and brain

Effect of eleven non-steroidal anti-inflammatory drugs on the acyl-CoA synthetase activities toward octanoic, palmitic, arachidonic and docosahexaenoic acids was evaluated in mouse liver and brain mitochondria. The drugs tested were aspirin, salicylic acid, diflunisal, mefenamic acid, indomethacin, etodolac, ibuprofen, ketoprofen, naproxen, loxoprofen, flurbiprofen. In mouse liver mitochondria, diflunisal and mefenamic acid exhibited the inhibitory activities not only for octanoic acid (IC₅₀?=?78.7 and 64.7 µM) and but also for palmitic acid (IC₅₀?=?236.5 and 284.4 µM), respectively. Aspirin was an inhibitor for the activation of octanoic acid only (IC₅₀?=?411.0 µM). In the brain, mefenamic acid and diflunisal inhibited strongly palmitoyl-CoA formation (IC₅₀?=?57.3 and 114.0 µM), respectively. The activation of docosahexaenoic acid in brain was sensitive to inhibition by diflunisal and mefenamic acid compared with liver.     

A New Series of S-Adenosyl-L-Methionine Synthetase Inhibitors

Abstract

A new series of epithio and epoxy amino acid analogues of L-methionine or L-methoxinine were examined as potential inhibitors of the enzyme S-adenosylmethionine (AdoMet) syn-thetase. The kinetic behaviour of these compounds was studied using recombinant rat liver S-adenosyl-L-methionine sythetase (α-isoform) fractionated from E. coli, transformed with the plasmid pSSRL-T7N. All the compounds tested were competitive inhibitors with respect to L-methionine and the (2S, 4S)-2-amino-4,5-epoxy pentanoic acid was found to be a very potent inhibitor of the enzyme compared to those already reported for AdoMet synthetase from other mammalian tissues.     

Cigarette smoke metabolically promotes cancer,via autophagy and premature aging in the host stromal microenvironment

Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora of different human cancer subtypes, including breast cancers. The prevailing view is that cigarette smoke acts as a mutagen and DNA damaging agent in normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on the normal stromal microenvironment have been largely ignored. Here, we propose a new mechanism by which carcinogen-rich cigarette smoke may promote cancer growth, by metabolically “fertilizing” the host microenvironment. More specifically, we show that cigarette smoke exposure is indeed sufficient to drive the onset of the cancer-associated fibroblast phenotype via the induction of DNA damage, autophagy and mitophagy in the tumor stroma. In turn, cigarette smoke exposure induces premature aging and mitochondrial dysfunction in stromal fibroblasts, leading to the secretion of high-energy mitochondrial fuels, such as L-lactate and ketone bodies. Hence, cigarette smoke induces catabolism in the local microenvironment, directly fueling oxidative mitochondrial metabolism (OXPHOS) in neighboring epithelial cancer cells, actively promoting anabolic tumor growth. Remarkably, these autophagic-senescent fibroblasts increased breast cancer tumor growth in vivo by up to 4-fold. Importantly, we show that cigarette smoke-induced metabolic reprogramming of the fibroblastic stroma occurs independently of tumor neo-angiogenesis. We discuss the possible implications of our current findings for the prevention of aging-associated human diseases and, especially, common epithelial cancers, as we show that cigarette smoke can systemically accelerate aging in the host microenvironment. Finally, our current findings are consistent with the idea that cigarette smoke induces the “reverse Warburg effect,” thereby fueling “two-compartment tumor metabolism” and oxidative mitochondrial metabolism in epithelial cancer cells.     

Genetically distinct Dutch-domesticated Clarias gariepinus used in aquaculture in southern Africa

Clarias gariepinus, a catfish species widely distributed in Africa including South Africa, is naturally absent from the Western Cape and the coastal Eastern Cape provinces. Because of its potential as an aquaculture species it has been widely used in aquaculture ventures in South Africa, specifically a stock known as Dutch catfish, a domesticated strain developed in the Netherlands. Mitochondrial DNA markers indicate that this stock is genetically distinct from the natural populations of C. gariepinus in South Africa. It could potentially pose a threat to South Africa's natural biodiversity if these fish were to escape from aquaculture farms, or was deliberately introduced into inland waters.     

Maternal inheritance of mitochondrial DNA

Maternal inheritance of mitochondrial DNA (mtDNA) is generally observed in many eukaryotes. Sperm-derived paternal mitochondria and their mtDNA enter the oocyte cytoplasm upon fertilization and then normally disappear during early embryogenesis. However, the mechanism underlying this clearance of paternal mitochondria has remained largely unknown. Recently, we showed that autophagy is required for the elimination of paternal mitochondria in Caenorhabditis elegans embryos. Shortly after fertilization, autophagosomes are induced locally around the penetrated sperm components. These autophagosomes engulf paternal mitochondria, resulting in their lysosomal degradation during early embryogenesis. In autophagy-defective zygotes, paternal mitochondria and their genomes remain even in the larval stage. Therefore, maternal inheritance of mtDNA is accomplished by autophagic degradation of paternal mitochondria. We also found that another kind of sperm-derived structure, called the membranous organelle, is degraded by zygotic autophagy as well. We thus propose to term this allogeneic (nonself) organelle autophagy as allophagy.     

The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation

Mitochondrial homeostasis is critical to cellular homeostasis, and mitophagy is an important mechanism to eliminate mitochondria that are superfluous or damaged. Multiple events can be involved in the recognition of mitochondria by the phagophore, and the key one is the priming of the mitochondria with specific molecular signatures. PARK2/Parkin is an E3 ligase that can be recruited to depolarized mitochondria and is required for mitophagy caused by respiration uncoupling. PARK2 induces ubiquitination of mitochondrial outer membrane proteins, which are subsequently degraded by the proteasome. Why these PARK2-mediated priming events are necessary for mitophagy to occur is not clear. We propose that they are needed to prevent a default pathway that would be inhibitory to mitophagy. In the default pathway depolarized and fragmented mitochondria undergo a dramatic three-dimensional conformational change to become mitochondrial spheroids. This transformation requires mitofusins; however, PARK2 inhibits this process by causing mitofusin ubiquitination and degradation. The spherical transformation may prevent recognition of the damaged mitochondria by the autophagosome, and PARK2 ensures that no such transformation occurs in order to promote mitophagy. Whether the formed mitochondrial spheroids functionally represent an alternative mitigation to mitophagy or an adverse consequence in the absence of PARK2 has yet to be determined.