Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.
Despite great promises of cellulose nanofibers for water treatment, current technologies have lacked the exclusive use of cellulose nanofibers (CNF) in high-flux filters having an affinity for a desired contaminant. To tackle this, we prepared porous and functionalized filters via solvent exchange, supercritical drying, and freeze-drying of cationic CNF and compared them to conventional CNF filters obtained by the paper-making process. Porosity and pore size were evaluated in the dry state qualitatively and quantitatively via scanning electron microscopy and mercury intrusion porosimetry, respectively. The permeance of water and a solution containing a negatively charged model molecule (humic acid) through these filters was measured at various pressures and correlated to the filters' structure. As compared to the CNF filters made via paper-making, the porosity, pore size, and permeance were increased after processing via solvent exchange, supercritical drying, and freeze-drying routes. Those filters which were prepared via freeze-drying displayed the highest permeance reported so far for CNF filters, which is about an order of magnitude higher than the permeance of CNF filters made via paper-making and having the same grammage. While the permeability was clearly affected by the processing technique, the functional filters showed a comparable adsorption capacity for humic acid. The filtration of a humic acid solution provided an initial removal of nearly 100% without noticeable reduction in flow. Considering the diluted concentration of HA in natural waters, we expect that large volumes of HA solution could be treated with the present CNF filters, with the possibility to regenerate these filters for multiple utilizations. The present concept of utilizing functional cellulose nanofibers in highly permeable filters working on the adsorption principle may be extended to encompass removal of other water contaminants for a better supply of clean water.
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