Glial-derived mitochondrial signals affect neuronal proteostasis and aging.

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.

Glial-derived mitochondrial signals impact neuronal proteostasis and aging.

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored non-neuronal cells of the nervous system. Here, we found that UPRMT activation in four, astrocyte-like glial cells in the nematode, C. elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Surprisingly, we find that glial cells utilize small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then impact neuron-mediated effects in organismal homeostasis and longevity.

The economic value of personal protective equipment for healthcare workers.

In this paper, we examine the cost effectiveness of investment in personal protective equipment (PPE) for protecting health care workers (HCWs) against two infectious diseases: Ebola virus and methicillin-resistant Staphylococcus aureus (MRSA). This builds on similar work published for COVID-19 in 2020. We developed two separate decision-analytic models using a payer perspective to compare the costs and effects of multiple PPE use scenarios for protection of HCW against Ebola and MRSA. Bayesian multivariate sensitivity analyses were used to consider the uncertainty surrounding all key parameters for both diseases. We estimate the cost to provide adequate PPE for a HCW encounter with an Ebola patient is $13.04, which is associated with a 97% risk reduction in infections. The mean incremental cost-effectiveness ratio (ICER) is $3.98 per disability-adjusted life year (DALY) averted. Because of lowered infection and disability rates, this investment is estimated to save $132.27 in averted health systems costs, a financial ROI of 1,014%. For MRSA, the cost of adequate PPE for one HCW encounter is $0.88, which is associated with a 53% risk reduction in infections. The mean ICER is $362.14 per DALY averted. This investment is estimated to save $20.18 in averted health systems costs, a financial ROI of 2,294%. In terms of total health savings per death averted, investing in adequate PPE is the dominant strategy for Ebola and MRSA, suggesting that it is both more costly and less clinically optimal to not fully invest in PPE for these diseases. There are many compelling reasons to invest in PPE to protect HCWs. This analysis examines the economic case, building on previous evidence that protecting HCWs with PPE is cost-effective for COVD-19. Ebola and MRSA scenarios were selected to allow assessment of both endemic and epidemic infectious diseases. While PPE is cost-effective for both conditions, compared to our analysis for COVID-19, PPE is relatively more cost-effective for Ebola and relatively less so for MRSA. Further research is needed to assess shortfalls in the PPE supply chain identified during the COVID-19 pandemic to ensure an efficient and resilient supply in the face of future pandemics.

SKN-1 regulates stress resistance downstream of amino catabolism pathways.

The deleterious potential to generate oxidative stress is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and consequences of this remain unknown. Here, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that knockdown of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires ELT-3, NHR-49 and MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate. Activating SKN-1 results in increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 acts downstream of key catabolic pathways to influence physiology and stress resistance.

Measurements of Physiological Stress Responses in C. Elegans.

Organisms are often exposed to fluctuating environments and changes in intracellular homeostasis, which can have detrimental effects on their proteome and physiology. Thus, organisms have evolved targeted and specific stress responses dedicated to repair damage and maintain homeostasis. These mechanisms include the unfolded protein response of the endoplasmic reticulum (UPRER), the unfolded protein response of the mitochondria (UPRMT), the heat shock response (HSR), and the oxidative stress response (OxSR). The protocols presented here describe methods to detect and characterize the activation of these pathways and their physiological consequences in the nematode, C. elegans. First, the use of pathway-specific fluorescent transcriptional reporters is described for rapid cellular characterization, drug screening, or large-scale genetic screening (e.g., RNAi or mutant libraries). In addition, complementary, robust physiological assays are described, which can be used to directly assess sensitivity of animals to specific stressors, serving as functional validation of the transcriptional reporters. Together, these methods allow for rapid characterization of the cellular and physiological effects of internal and external proteotoxic perturbations.

Systemic effects of mitochondrial stress.

Multicellular organisms are complex biological systems, composed of specialized tissues that require coordination of the metabolic and fitness state of each component. In the cells composing the tissues, one central organelle is the mitochondrion, a compartment essential for many energetic and fundamental biological processes. Beyond serving these functions, mitochondria have emerged as signaling hubs in biological systems, capable of inducing changes to the cell they are in, to cells in distal tissues through secreted factors, and to overall animal physiology. Here, we describe our current understanding of these communication mechanisms in the context of mitochondrial stress. We focus on cellular mechanisms that deal with perturbations to the mitochondrial proteome and outline recent advances in understanding how local perturbations can affect distal tissues and animal physiology in model organisms. Finally, we discuss recent findings of these responses associated with metabolic and age-associated diseases in mammalian systems, and how they may be employed as diagnostic and therapeutic tools.