Beyond protein synthesis and autophagy, emerging evidence has implicated mTORC1 in regulating protein folding and proteasomal degradation as well, highlighting its prominent role in cellular proteome homeostasis or proteostasis. In addition to growth signals, mTORC1 senses and responds to a wide array of stresses, including energetic/metabolic stress, genotoxic stress, oxidative stress, osmotic stress, ER stress, proteotoxic stress, and psychological stress. Whereas growth signals unanimously stimulate mTORC1, stresses exert complex impacts on mTORC1, most of which are repressive. mTORC1 suppression, as (...) a generic adaptive strategy, empowers cell survival under various stressful conditions. In this essay, we provide an overview of the emerging role of mTORC1 in proteostasis, the distinct molecular mechanisms through which mTORC1 reacts to diverse stresses, and the schemes exploited by cancer cells to circumvent stress‐induced mTORC1 suppression. Hence, acting as a stress sensor, mTORC1 intimately couples stresses to cellular proteostasis. (shrink)

Neurodegenerative syndromes present as proteinopathies – does ribosomal infidelity contribute to the protein toxicity that is the driving force for neuronal cell loss? Intracellular and extracellular protein aggregates overwhelm the clearance capacity of cells and tissues. Proteins aggregate when hydrophobic residues are exposed. Hydrophobic residues become exposed when proteins are misfolded. Protein misfolding can originate from translational errors at the ribosome. Indeed, the most error‐prone process in gene expression is translation at the ribosome. Recent evidence indicates that manipulating the ribosomal (...) accuracy impacts on the lifespan of model organisms and a reduced translational accuracy is accompanied by neurodegeneration. The first hit in aging‐associated neurodegenerative disease may be the well‐documented decline of cellular buffering capacity by aging. A second hit that impacts on the quality of protein synthesis could be the driving force for the observed loss of proteostasis in neurodegeneration. This hypothesis provides an explanation for the late onset of most neurodegenerative diseases. (shrink)

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long‐lived C. elegans vhl‐1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans (...) by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy‐intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals. (shrink)

Recently, several studies have demonstrated that tetracyclines, the antibiotics most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals ranging from round worms, fruit flies, and mice to human cell lines. Importantly, plant chloroplasts, like their mitochondria, are also under certain conditions vulnerable to these and other antibiotics that are leached into our environment. Together these endosymbiotic organelles are not only essential for cellular and organismal homeostasis stricto sensu, (...) but also have an important role to play in the sustainability of our ecosystem as they maintain the delicate balance between autotrophs and heterotrophs, which fix and utilize energy, respectively. Therefore, stricter policies on antibiotic usage are absolutely required as their use in research confounds experimental outcomes, and their uncontrolled applications in medicine and agriculture pose a significant threat to a balanced ecosystem and the well‐being of these endosymbionts that are essential to sustain health.Also watch the Video Abstract. (shrink)

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifications. The ubiquitin/proteasome‐system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF‐1 receptor, the stability of downstream insulin/IGF‐1 signaling targets, and activity of nuclear receptors for control of gene expression. An age‐related (...) decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. (shrink)

Auxin is a key regulator of plant developmental processes. Its effects on transcription are mediated by the AUXIN RESPONSE FACTOR (ARF) family of transcription factors. ARFs tightly control specific auxin responses necessary for proper plant growth and development. Recent research has revealed that regulated ARF protein accumulation and ARF nucleo‐cytoplasmic partitioning can determine auxin transcriptional outputs. In this review, we explore these recent findings and consider the potential for regulated ARF accumulation in driving auxin responses in plants.

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive (...) responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. (shrink)