Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although there are many etiologies for diabetic nephropathy (DN), one common characteristic of all cases involves mitochondrial oxidative stress and consequent bioenergetic dysfunction. As the predominant low-molecular-weight, intramitochondrial thiol reductant, the mitochondrial glutathione (mtGSH) pool plays important roles in how this organelle adapts to the chronic hyperglycemia and redox imbalances associated with DN. This review will summarize information about the processes by which this important GSH pool is regulated and how manipulation of these processes can affect mitochondrial and cellular function in the renal proximal tubule. Mitochondria in renal proximal tubular (PT) cells do not appear to synthesize GSH de novo but obtain it by transport from the cytoplasm. Two inner membrane organic anion carriers, the dicarboxylate carrier (DIC; Slc25a10) and 2-oxoglutarate carrier (OGC; Slc25a11) are responsible for this transport. Genetic modulation of DIC or OGC expression in vitro in PT cells from diabetic rats can alter mitochondrial function and susceptibility of renal PT cells to oxidants, with overexpression leading to reversion of bioenergetic conditions to a non-diabetic state and protection of cells from injury. These findings support the mtGSH carriers as potential therapeutic targets to correct the underlying metabolic disturbance in DN.
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PMID:Mitochondrial Glutathione in Diabetic Nephropathy. 2623 84

Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment.
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PMID:The 2-oxoglutarate carrier promotes liver cancer by sustaining mitochondrial GSH despite cholesterol loading. 2894 94