Aging in Heart Failure: Embracing Biology Over Chronology: JACC Family Series.

Age is among the most potent risk factors for developing heart failure and is strongly associated with adverse outcomes. As the global population continues to age and the prevalence of heart failure rises, understanding the role of aging in the development and progression of this chronic disease is essential. Although chronologic age is on a fixed course, biological aging is more variable and potentially modifiable in patients with heart failure. This review describes the current knowledge on mechanisms of biological aging that contribute to the pathogenesis of heart failure. The discussion focuses on 3 hallmarks of aging-impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing-that are currently being targeted in therapeutic development for older adults with heart failure. In assessing existing and emerging therapeutic strategies, the review also enumerates the importance of incorporating geriatric conditions into the management of older adults with heart failure and in ongoing clinical trials.

Identification of molecular signatures defines the differential proteostasis response in induced spinal and cranial motor neurons.

Amyotrophic lateral sclerosis damages proteostasis, affecting spinal and upper motor neurons earlier than a subset of cranial motor neurons. To aid disease understanding, we exposed induced cranial and spinal motor neurons (iCrMNs and iSpMNs) to proteotoxic stress, under which iCrMNs showed superior survival, quantifying the transcriptome and proteome for >8,200 genes at 0, 12, and 36 h. Two-thirds of the proteome showed cell-type differences. iSpMN-enriched proteins related to DNA/RNA metabolism, and iCrMN-enriched proteins acted in the endoplasmic reticulum (ER)/ER chaperone complex, tRNA aminoacylation, mitochondria, and the plasma/synaptic membrane, suggesting that iCrMNs expressed higher levels of proteins supporting proteostasis and neuronal function. When investigating the increased proteasome levels in iCrMNs, we showed that the activity of the 26S proteasome, but not of the 20S proteasome, was higher in iCrMNs than in iSpMNs, even after a stress-induced decrease. We identified Ublcp1 as an iCrMN-specific regulator of the nuclear 26S activity.

Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations.

Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronic disruption of mitochondrial proteostasis.

[Advances of proteostasis network and its stability maintenance mechanism].

Protein is fundamental to life, as it generates protein variants. The maintenance of a dynamic equilibrium in these protein variants, known as protein homeostasis, is crucial for cellular function. Various factors, both endogenous and exogenous, can disrupt protein homeostasis during protein synthesis. These factors include translational error, and biological functions mediated by regulatory factors, and more. When cell accumulate proteins with folding errors, it impairs protein homeostasis, leading to the development of related diseases. In response to protein folding errors, multiple monitoring mechanisms are activated to mediate pathways that sustain the dynamic equilibrium. This review highlights the complex relationships within the proteostasis network, which are influenced by a variety of factors. These insights potentially provide new directions for studying diseases caused by protein synthesis errors.

Relationships between protein degradation, cellular senescence, and organismal aging.

Aging is a major risk factor for many diseases. Recent studies have shown that age-related disruption of proteostasis leads to the accumulation of abnormal proteins and that dysfunction of the two major intracellular proteolytic pathways, the ubiquitin-proteasome pathway, and the autophagy-lysosome pathway, is largely responsible for this process. Conversely, it has been shown that activation of these proteolytic pathways may contribute to lifespan extension and suppression of pathological conditions, making it a promising intervention for anti-aging. This review provides an overview of the important role of intracellular protein degradation in aging and summarizes how the disruption of proteostasis is involved in age-related diseases.

Preface: Special issue "Brain Proteostasis in Health and Disease".

This preface introduces the Journal of Neurochemistry Special Issue on Brain Proteostasis. Adequate control of protein homeostasis, or proteostasis, has been at the center stage of brain physiology, and its deregulation may contribute to brain diseases, including several neuropsychiatric and neurodegenerative conditions. Therefore, delineating the processes underlying protein synthesis, folding, stability, function, and degradation in brain cells is key to promoting brain function and identifying effective therapeutic options for neurological disorders. This special issue comprises four review articles and four original articles covering the roles of protein homeostasis in several mechanisms that are of relevance to sleep, depression, stroke, dementia, and COVID-19. Thus, these articles highlight different aspects of proteostasis regulation in the brain and present important evidence on this growing and exciting field.

Proteostasis networks in aging: novel insights from text-mining approaches.

Aging is a topic of paramount importance in an increasingly elderly society and has been the focus of extensive research. Protein homeostasis (proteostasis) decline is a hallmark in aging and several age-related diseases, but which specific proteins and mechanisms are involved in proteostasis (de)regulation during the aging process remain largely unknown. Here, we used different text-mining tools complemented with protein-protein interaction data to address this complex topic. Analysis of the integrated protein interaction networks identified novel proteins and pathways associated to proteostasis mechanisms and aging or age-related disorders, indicating that this approach is useful to identify previously unknown links and for retrieving information of potential novel biomarkers or therapeutic targets.

A Year at the Forefront of Proteostasis and Aging.

During aging, animals experience a decline in proteostasis activity, including loss of stress-response activation, culminating in the accumulation of misfolded proteins and toxic aggregates, which are causal in the onset of some chronic diseases. Finding genetic and pharmaceutical treatments that can increase organismal proteostasis and lengthen life is an ongoing goal of current research. The regulation of stress responses by cell non-autonomous mechanisms appears to be a potent way to impact organismal healthspan. In this Review, we cover recent findings in the intersection of proteostasis and aging, with a special focus on articles and preprints published between November 2021 and October 2022. A significant number of papers published during this time increased our understanding of how cells communicate with each other during proteotoxic stress. Finally, we also draw attention to emerging datasets that can be explored to generate new hypotheses that explain age-related proteostasis collapse.

Proteostasis in Parkinson's disease: Recent development and possible implication in diagnosis and therapeutics.

The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of α-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., α-synuclein protein in PD. The proper functioning the of intricately woven proteostasis network is quite resilient to sustain under the influence of stressors. The synuclein protein turnover is hugely influenced by the autosomal dominant, recessive, and X-linked mutational changes of a gene involved in UPR, UPS, and ALP. The methylation, acetylation-related epigenetic modifications of DNA and histone proteins along with microRNA-mediated transcriptional changes also lead to extensive proteostasis dysregulation. The result of defective proteostasis is the deposition of many proteins which start appearing in the biofluids and can be identified as potential biomarkers for early diagnosis of PD. The therapeutic intervention targeted at different strata of proteostasis machinery holds great possibilities for delaying the age-related accumulation of pathological hallmarks.

Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors.

The age-related loss of protein homeostasis (proteostasis) is at the heart of numerous neurodegenerative diseases. Therefore, finding ways to preserve proteome integrity in aged cells may be a powerful way to promote long-term health. Here, we show that reducing the activity of a highly conserved mitochondrial outer membrane protein, MTCH-1/MTCH2, suppresses age-related proteostasis collapse in Caenorhabditis elegans without disrupting development, growth, or reproduction. Loss of MTCH-1 does not influence proteostasis capacity in aged tissues through previously described pathways but instead operates by reducing CED-4 levels. This results in the sequestration of HSP-90 by inactive CED-3, which in turn leads to an increase in HSF-1 activity, transcriptional remodeling of the proteostasis network, and maintenance of proteostasis capacity with age. Together, our findings reveal a role for programmed cell death factors in determining proteome health and suggest that inhibiting MTCH-1 activity in adulthood may safeguard the aging proteome and suppress age-related diseases.

Age-associated proteostasis collapse.

Healthy cells utilize a series of protein quality regulatory networks to maintain the integrity and functionality of their proteome, named as protein homeostasis (proteostasis). However, the phenomenon of proteostasis collapse, including the destruction of the balance between protein synthesis, folding and degradation, are common with aging. The main causes of age-associated proteostasis collapse are as follows: (1) the decline in transcriptional activation of stress response related pathways, (2) the reduction of proteasome and autophagy activity, and (3) ribosome pausing during translation. In addition, proteostasis is regulated mainly through chaperones, proteasomes, and autophagy systems of proteostasis network in aging. This paper mainly reviews the causes of age-associated proteostasis collapse and the pathways of proteostasis regulation, which may open the way to explore aging studies and solve aging problems.

The disturbance of protein synthesis/degradation homeostasis is a common trait of age-related neurodegenerative disorders.

Protein homeostasis or "proteostasis" represent the process that regulates the balance of the intracellular functional and "healthy" proteins. Proteostasis is fundamental to preserve physiological metabolic processes in the cell and it allow to respond to any given stimulus as the expression of components of the proteostasis network is customized according to the proteomic demands of different cellular environments. In conditions that promote unfolding/misfolding of proteins chaperones act as signaling molecules inducing extreme measures to either fix the problem or destroy unfolded proteins. When the chaperone machinery fails under pathological insults unfolded proteins induce the endoplasmic reticulum (ER) stress activating the unfolded protein response (UPR) machinery. The activation of the UPR restores ER proteostasis primarily through the transcriptional remodeling of ER protein folding, trafficking, and degradation pathways, such as the ubiquitin proteasome system (UPS). If these mechanisms do not manage to clear the aberrant proteins, proteasome overload and become defective, and misfolded proteins may form aggregates thus extending the UPR mechanism. These aggregates are then attempted to be cleared by macroautophagy. Impaired proteostasis promote the accumulation of misfolded proteins that exacerbate the damage to chaperones, surveillance systems and/or degradative activities. Remarkably, the removal of toxic misfolded proteins is critical for all cells, but it is especially significant in neurons since these cannot be readily replaced. In neurons, the maintenance of efficient proteostasis is essential to healthy aging since the dysregulation of the proteostasis network can lead to neurodegenerative disease. Each of these brain pathologies is characterized by the repeated misfolding of one of more peculiar proteins, which evade both the protein folding machinery and cellular degradation mechanisms and begins to form aggregates that nucleate out into large fibrillar aggregates. In this chapter we describe the mechanisms, associated with faulty proteostasis, that promote the formation of protein aggregates, amyloid fibrils, intracellular, and extracellular inclusions in the most common nondegenerative disorders also referred to as protein misfolding disorders.

The emerging roles of deubiquitinases in plant proteostasis.

Proper regulation of protein homeostasis (proteostasis) is essential for all organisms to survive. A diverse range of post-translational modifications (PTMs) allow precise control of protein abundance, function and cellular localisation. In eukaryotic cells, ubiquitination is a widespread, essential PTM that regulates most, if not all cellular processes. Ubiquitin is added to target proteins via a well-defined enzymatic cascade involving a range of conjugating enzymes and ligases, while its removal is catalysed by a class of enzymes known as deubiquitinases (DUBs). Many human diseases have now been linked to DUB dysfunction, demonstrating the importance of these enzymes in maintaining cellular function. These findings have led to a recent explosion in studying the structure, molecular mechanisms and physiology of DUBs in mammalian systems. Plant DUBs have however remained relatively understudied, with many DUBs identified but their substrates, binding partners and the cellular pathways they regulate only now beginning to emerge. This review focuses on the most recent findings in plant DUB biology, particularly on newly identified DUB substrates and how these offer clues to the wide-ranging roles that DUBs play in the cell. Furthermore, the future outlook on how new technologies in mammalian systems can accelerate the plant DUB field forward is discussed.

A proteostasis network safeguards the chloroplast proteome.

Several protein homeostasis (proteostasis) pathways safeguard the integrity of thousands of proteins that localize in plant chloroplasts, the indispensable organelles that perform photosynthesis, produce metabolites, and sense environmental stimuli. In this review, we discuss the latest efforts directed to define the molecular process by which proteins are imported and sorted into the chloroplast. Moreover, we describe the recently elucidated protein folding and degradation pathways that modulate the levels and activities of chloroplast proteins. We also discuss the links between the accumulation of misfolded proteins and the activation of signalling pathways that cope with folding stress within the organelle. Finally, we propose new research directions that would help to elucidate novel molecular mechanisms to maintain chloroplast proteostasis.

Proteostasis Response to Protein Misfolding in Controlled Hypertension.

Hypertension is the most determinant risk factor for cardiovascular diseases. Early intervention and future therapies targeting hypertension mechanisms may improve the quality of life and clinical outcomes. Hypertension has a complex multifactorial aetiology and was recently associated with protein homeostasis (proteostasis). This work aimed to characterize proteostasis in easy-to-access plasma samples from 40 individuals, 20 with controlled hypertension and 20 age- and gender-matched normotensive individuals. Proteostasis was evaluated by quantifying the levels of protein aggregates through different techniques, including fluorescent probes, slot blot immunoassays and Fourier-transform infrared spectroscopy (FTIR). No significant between-group differences were observed in the absolute levels of various protein aggregates (Proteostat or Thioflavin T-stained aggregates; prefibrillar oligomers and fibrils) or total levels of proteostasis-related proteins (Ubiquitin and Clusterin). However, significant positive associations between Endothelin 1 and protein aggregation or proteostasis biomarkers (such as fibrils and ubiquitin) were only observed in the hypertension group. The same is true for the association between the proteins involved in quality control and protein aggregates. These results suggest that proteostasis mechanisms are actively engaged in hypertension as a coping mechanism to counteract its pathological effects in proteome stability, even when individuals are chronically medicated and presenting controlled blood pressure levels.

Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.

Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and ß-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.

Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives.

In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure-activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well.

The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging.

Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets.

Proteostasis and resilience: on the interphase between individual's and intracellular stress.

A long proportion of the population is resilient to the negative consequences of stress. Glucocorticoids resulting from endocrine responses to stress are essential adaptive mediators, but also drive alterations to brain function, negatively impacting neuronal connectivity, synaptic plasticity, and memory-related processes. Recent evidence has indicated that organelle function and cellular stress responses are relevant determinant of vulnerability and resistance to environmental stress. At the molecular level, a fundamental mechanism of cellular stress adaptation is the maintenance of proteostasis, which also have key roles in sustaining basal neuronal function. Here, we discuss recent evidence suggesting that proteostasis unbalance at the level of the endoplasmic reticulum, the main site for protein folding in the cell, represents a possible mechanistic link between individuals and cellular stress.

Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca2+-induced proteostasis disease stress.

The cellular defense mechanisms against cumulative endo-lysosomal stress remain incompletely understood. Here, we identify Ubr1 as a protein quality control (QC) E3 ubiquitin-ligase that counteracts proteostasis stresses by facilitating endosomal cargo-selective autophagy for lysosomal degradation. Astrocyte regulatory cluster membrane protein MLC1 mutations cause endosomal compartment stress by fusion and enlargement. Partial lysosomal clearance of mutant endosomal MLC1 is accomplished by the endosomal QC ubiquitin ligases, CHIP and Ubr1 via ESCRT-dependent route. As a consequence of the endosomal stress, a supportive QC mechanism, dependent on both Ubr1 and SQSTM1/p62 activities, targets ubiquitinated and arginylated MLC1 mutants for selective endosomal autophagy (endophagy). This QC pathway is also activated for arginylated Ubr1-SQSTM1/p62 autophagy cargoes during cytosolic Ca2+-assault. Conversely, the loss of Ubr1 and/or arginylation elicited endosomal compartment stress. These findings underscore the critical housekeeping role of Ubr1 and arginylation-dependent endophagy/autophagy during endo-lysosomal proteostasis perturbations and suggest a link of Ubr1 to Ca2+ homeostasis and proteins implicated in various diseases including cancers and brain disorders.