Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α). The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. Reverse transcription-polymerase chain reaction analysis confirmed the presence of 5-HT2A, 5-HT2B, and 5-HT2C receptor mRNA in RPTC. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 3–10 μM) increased PGC-1α levels, expression of mitochondrial proteins ATP synthase β and NADH dehydrogenase (ubiquinone) 1β subcomplex 8 (NDUFB8), MitoTracker Red staining intensity, cellular respiration, and ATP levels through a 5-HT receptor and PGC-1α-dependent pathway. Similar effects were observed with the 5-HT2 agonist m-chlorophenylpiperazine and were blocked by the 5-HT2 antagonist 8-[3-(4-fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (AMI-193). In addition, DOI accelerated the recovery of mitochondrial function after oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor-mediated mitochondrial biogenesis, and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury.

RNA-dependent RNA polymerases (RdRPs) represent a distinctive yet versatile class of nucleic acid polymerases encoded by RNA viruses for the replication and transcription of their genome. The structure of the RdRP is comparable to that of a cupped right hand consisting of fingers, palm, and thumb subdomains. Despite the presence of a common structural core, the RdRPs differ significantly in the mechanistic details of RNA binding and polymerization. The present review aims at exploring these incongruities in light of recent structural studies of RdRP complexes with diverse cofactors, RNA moieties, analogs, and inhibitors.

Biotin is an indispensable adipogenic agent, and its ability to coordinate carbohydrate, lipid, and amino acid metabolism sensitizes insulin signaling in adipocytes. This enables the organism to adapt and survive under nutrient stress by synthesis and storage of lipids. Biotin deficiency mimics insulin resistance with alterations in cellular intermediary metabolism. Though the mechanism of lipogenesis is well established across cell types, considering its predisposition to accumulate only lipids, it is necessary to elucidate the mechanism that minimizes the effects of biotin on adipocyte protein synthesis. In order to determine the differential metabolic phenotype by biotin, the primary cultures of adipocytes were induced to differentiate in the presence and absence of excess biotin. Serum pre-incubated with avidin was used to limit biotin availability in cultured cells. Biotin restricts cellular signaling associated with protein synthesis without altering total protein content. The decline in autophagy elicits endoplasmic reticulum stress to inhibit protein synthesis by eIF2α phosphorylation possibly via accumulation of misfolded/long-lived proteins. Furthermore, the compensatory increase in Unc51 like autophagy activating kinase 1 possibly competes with eukaryotic initiation factor 4E-binding protein 1 and ribosomal p70 S6kinase phosphorylation by mechanistic targets of rapamycin complex 1 to uncouple its effect on protein synthesis. In conclusion, autophagy inhibition by biotin uncouples protein synthesis to promote lipogenesis by eliciting endoplasmic reticulum stress and differential phosphorylation of mechanistic targets of rapamycin complex 1 substrates.