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ObjectiveWe describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A (TNFRSF1A) gene causing TNF receptor–associated periodic syndrome (TRAPS) with renal AA amyloidosis.MethodsCase series of affected family members. We further investigated the plasma metabolome of these patients in comparison with healthy controls using mass spectrometry.ResultsIn all symptomatic family members, we detected the previously undescribed variant c.332A>G (p.Q111R) in the TNFRSF1A gene. Canakinumab proved an effective treatment option leading to remission in all treated patients. One patient with suspected renal amyloidosis showed near normalization of proteinuria under treatment. Analysis of the metabolome revealed 31 metabolic compounds to be upregulated and 35 compounds to be downregulated compared with healthy controls. The most dysregulated metabolites belonged to pathways identified as arginine biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, and cysteine and methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission.ConclusionWe present a novel mutation in the TNFRSF1A gene associated with amyloidosis. Canakinumab is an effective treatment for individuals with this new likely pathogenic variant. Alterations in the metabolome were most prominent in the pathways related to arginine biosynthesis, tryptophan metabolism, and metabolism of cysteine and methionine, and seemed to be unaffected by treatment with canakinumab. Further investigation is needed to determine the role of these metabolomic changes in the pathophysiology of TRAPS.

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 elusive1–5. Here we show that Caenorhabditis elegans nuclear transcription factor Y, beta subunit (NFYB-1), a subunit of the NF-Y transcriptional complex6–8, 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. Tharyan et al. identify NFYB-1 as a regulator of mitochondrial function that represses lysosomal prosaposin. The NFYB-1–prosaposin signalling axis coordinates lysosomal-to-mitochondria signalling via cardiolipin to enhance cellular mitochondrial function and longevity in C. elegans.

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 3′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.

Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also highly plastic, and remodelled in response to stress, growth, neural and metabolic inputs. The evolutionarily conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle biology during development, but whether it plays a role during ageing is unknown. Here we investigated the role of C. elegans miR-1 in muscle function in response to proteostatic stress during adulthood. mir-1 deletion results in improved mid-life muscle motility, pharyngeal pumping, and organismal longevity under conditions of polyglutamine repeat proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6VIA as a direct target downregulated via its 3’UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. In summary, our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during ageing.

In most eukaryotic cells mitochondria are essential organelles involved in a great variety of cellular functions. One of the physiological processes linked to mitochondria is aging, a gradual process of damage accumulation that eventually promotes cell death. Aging depends on a balance between mitochondrial biogenesis, function and degradation. It has been previously shown that Tor1, Sch9 and Ras2 are activated in response to nutrient availability and regulate cell growth and division. A deficiency in any of these genes promotes lifespan extension and cell protection during oxidative and heat shock stress. In this work we report that in Saccharomyces cerevisiae, the uncharacterized mitochondrial protein Slm35 is functionally linked with the TOR signaling pathway. A Δtor1Δslm35 strain shows a severe decrease in lifespan and is unable to contend with oxidative and heat shock stresses. Specifically, this mutant shows decreased catalase activity indicating a misregulation of ROS scavenging mechanisms. In this study we show that Slm35 is also relevant for mitochondrial network dynamics and mitophagy. The results presented here suggest that Slm35 plays an important role connecting mitochondrial function with cytosolic responses and cell adaptation to stress and aging.

Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles, and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly, however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together, these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.