Role of Myc/Mondo transcriptional network in metabolism and lifespan regulation

The transcriptional complex MondoA/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in C. elegans. How do these pathways converge on this complex, and what are the upstream signals involved? This work sought to understand the upstream signals that regulate MML-1 localization, transcription, and longevity, using combined genetic, biochemical, omics, and light microscopy approaches. We found that an overall reduction in glucose metabolism decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as strong positive regulators of MML-1 function. Upon knockdown, hexokinases reduce MML-1 nuclear localization and cause its redistribution to mitochondria and lipid droplets (LD). Interestingly, although both hexokinases decrease MML-1 nuclear function, we provide evidence that they do so through distinct mechanisms. On the one hand, we found that under hxk-1 knockdown, there is an increase in fatty acid metabolism, and pharmacological and genetic inhibition of mitochondrial -oxidation could rescue MML-1 localization. On the other hand, we found that oxoglutarate dehydrogenase complex (OGDC) and the pentose phosphate pathway (PPP) are important for decreasing MML 1 localization and function under hxk-2 knockdown. Analysis of the MML-1 interactome in different longevity backgrounds revealed that MML-1 associates with varying proteins from distinct cellular compartments, suggesting a role for MML-1 in integrating diverse organellar signals to the transcriptional response. In particular, we found many mitochondrial proteins, including the mitochondrial pyruvate carrier MPC-1 and the long-chain fatty acid acyl-CoA synthetase ACS-13, which is associated with both mitochondria and lipid droplets. Both candidates showed a degree of cellular co-localization and functional interaction with MML-1, suggesting that these proteins could cooperate with MML-1 in connecting metabolism and transcription

NFYB-1 regulates mitochondrial function and longevity via lysosomal prosaposin

Mitochondria are multidimensional organelles whose activities are essential to cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive(1-5). Here we show that Caenorhabditis elegans nuclear transcription factor Y, beta subunit (NFYB-1), a subunit of the NF-Y transcriptional complex(6-8), is a crucial regulator of mitochondrial function. Identified in RNA interference (RNAi) screens, NFYB-1 loss leads to perturbed mitochondrial gene expression, reduced oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, decreased mitochondrial cardiolipin levels and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of lysosomal prosaposin, a regulator of glycosphingolipid metabolism. Limiting prosaposin expression unexpectedly restores cardiolipin production, mitochondrial function and longevity in the nfyb-1 background. Similarly, cardiolipin supplementation rescues nfyb-1 phenotypes. These findings suggest that the NFYB-1-prosaposin axis coordinates lysosomal to mitochondria signalling via lipid pools to enhance cellular mitochondrial function and organismal health

miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact proteotoxicity and muscle function during aging

Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also plastic, and remodeled in response to stress, growth, neural and metabolic inputs. The conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle development, but whether it plays a role during aging is unknown. Here we investigated Caenorhabditis elegans miR-1 in muscle function in response to proteostatic stress. mir-1 deletion improved mid-life muscle motility, pharyngeal pumping, and organismal longevity upon polyQ35 proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6V1A as a direct target downregulated via its 30 UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. Our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during aging

Population structure and connectivity in the Mediterranean sponge Ircinia fasciculata are affected by mass mortalities and hybridization

Este artículo contiene 13 páginas, 6 figuras, 4 tablas.Recent episodes of mass mortalities in the Mediterranean Sea have been reported for the closely related marine sponges Ircinia fasciculata and Ircinia variabilis that live in sympatry. In this context, the assessment of the genetic diversity, bottlenecks and connectivity of these sponges has become urgent in order to evaluate the potential effects of mass mortalities on their latitudinal range. Our study aims to establish (1) the genetic structure, connectivity and signs of bottlenecks across the populations of I. fasciculata and (2) the hybridization levels between I. fasciculata and I. variabilis. To accomplish the first objective, 194 individuals of I. fasciculata from 12 locations across the Mediterranean were genotyped at 14 microsatellite loci. For the second objective, mitochondrial cytochrome c oxidase subunit I sequences of 16 individuals from both species were analyzed along with genotypes at 12 microsatellite loci of 40 individuals coexisting in 3 Mediterranean populations. We detected strong genetic structure along the Mediterranean for I. fasciculata, with high levels of inbreeding in all locations and bottleneck signs in most locations. Oceanographic barriers like the Almeria-Oran front, North-Balearic front and the Ligurian-Thyrrenian barrier seem to be impeding gene flow for I. fasciculata, adding population divergence to the pattern of isolation by distance derived from the low dispersal abilities of sponge larvae. Hybridization between both species occurred in some populations that might be increasing genetic diversity and somewhat palliating the genetic loss caused by population decimation in I. fasciculata.This research was funded by the Spanish Government project MARSYMBIOMICS CTM2013-43287-P and the Catalan Government Grant 2014SGR-336 for Consolidated Research Groups.Peer reviewe