bims-cemest 2025-02-09 papers

bims-cemest

Biomed News

on Cell metabolism and stress

Issue of 2025–02–09
twelve papers selected by
Jessica Rosarda, Uniformed Services University

Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.
Arginine: at the crossroads of nitrogen metabolism.
Activating AMPK improves pathological phenotypes due to mtDNA depletion.
P.1 and P.2 SARS-CoV-2 Brazilian variants activate the unfolded protein response with a time and pathway specificity.
A new player in the mammalian electron transport chain.
Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and α-synuclein pathology.
The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
Glycogen synthase is required for heat shock-mediated autophagy induction in neuronal cells.
Pericytes Are Odontoblast Progenitor Cells Depending on ER Stress.
Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid.
Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation.
Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.

bioRxiv. 2025 Jan 23. pii: 2025.01.22.634344. [Epub ahead of print]

Inhibition of cytosolic translation mitigates mitochondrial dysfunction in C. elegans.

Avijit Mallick, Yunguang Du, Theresa Ramalho, Rui Li, Levi Ali, Sookyung Kim, Lihua Julie Zhu, Cole M Haynes.

The mitochondrial unfolded protein response (UPR mt ) is regulated by the bZIP protein ATFS-1 which promotes mitochondrial protein homeostasis (proteostasis) and mitochondrial biogenesis in Caenorhabditis elegans . Upon mitochondrial perturbation, the ATFS-1-dependent transcriptional program promotes gene expression, leading to mitochondrial recovery. Conversely, atfs-1 -deletion worms harbor dysfunctional mitochondria, are developmentally impaired, and short-lived. However, atfs-1 -deletion worms develop to adults suggesting the presence of other signaling pathways that promote mitochondrial function and biogenesis in the absence of atfs-1 . We hypothesized that additional transcription factors regulate, or promote, mitochondrial function in the absence of atfs-1 . Here, we screened for transcription factors that could reduce the decline in mitochondrial function in the atfs-1 mutants when inhibited. Here, we demonstrate that inhibition of the nuclear hormone receptor NHR-180 re-establishes a functional mitochondrial network in atfs-1(null) worms, increases mtDNA content, and improves the developmental rate of wildtype worms. NHR-180 increases transcription of genes required for cytosolic protein synthesis in response to mitochondrial perturbation. Inhibition of the S6 kinase homolog, rsks-1 , in atfs-1(null) worms leads to a recovery of the mitochondrial network and mtDNA content consistent with nhr-180 regulating expression of protein synthesis components. Consistent with the observations in C. elegans , S6 kinase inhibition also increased mitochondrial biogenesis in mammalian atf5 -knockout cells that harbor severely impaired mitochondria. Intriguingly, nhr-180 or S6 kinase inhibition also rescues mitochondrial dysfunction caused by mutations in multiple genes required for oxidative phosphorylation. Combined, these studies suggest that increased protein synthesis contributes to the mitochondrial dysfunction caused by perturbations in OXPHOS gene expression and suggest a relatively straightforward approach to reducing the impact of mitochondrial dysfunction.

DOI: https://doi.org/10.1101/2025.01.22.634344
EMBO J. 2025 Feb 07.

Arginine: at the crossroads of nitrogen metabolism.

Tak Shun Fung, Keun Woo Ryu, Craig B Thompson.

  L-arginine is the most nitrogen-rich amino acid, acting as a key precursor for the synthesis of nitrogen-containing metabolites and an essential intermediate in the clearance of excess nitrogen. Arginine's side chain possesses a guanidino group which has unique biochemical properties, and plays a primary role in nitrogen excretion (urea), cellular signaling (nitric oxide) and energy buffering (phosphocreatine). The post-translational modification of protein-incorporated arginine by guanidino-group methylation also contributes to epigenetic gene control. Most human cells do not synthesize sufficient arginine to meet demand and are dependent on exogenous arginine. Thus, dietary arginine plays an important role in maintaining health, particularly upon physiologic stress. How cells adapt to changes in extracellular arginine availability is unclear, mostly because nearly all tissue culture media are supplemented with supraphysiologic levels of arginine. Evidence is emerging that arginine-deficiency can influence disease progression. Here, we review new insights into the importance of arginine as a metabolite, emphasizing the central role of mitochondria in arginine synthesis/catabolism and the recent discovery that arginine can act as a signaling molecule regulating gene expression and organelle dynamics.

Keywords:  Arginine Deficiency; Arginine Metabolism; Metabolite Signaling; Mitochondria; Protein Synthesis

DOI:  https://doi.org/10.1038/s44318-025-00379-3
FEBS J. 2025 Feb 07.

Activating AMPK improves pathological phenotypes due to mtDNA depletion.

Gustavo Carvalho, Tran V H Nguyen, Bruno Repolês, Josefin M E Forslund, W M Ruchitha Rukmal Wijethunga, Farahnaz Ranjbarian, Isabela C Mendes, Choco Michael Gorospe, Namrata Chaudhari, Micol Falabella, Mara Doimo, Sjoerd Wanrooij, Robert D S Pitceathly, Anders Hofer, Paulina H Wanrooij.

  AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis that also plays a role in preserving mitochondrial function and integrity. Upon a disturbance in the cellular energy state that increases AMP levels, AMPK activity promotes a switch from anabolic to catabolic metabolism to restore energy homeostasis. However, the level of severity of mitochondrial dysfunction required to trigger AMPK activation is currently unclear, as is whether stimulation of AMPK using specific agonists can improve the cellular phenotype following mitochondrial dysfunction. Using a cellular model of mitochondrial disease characterized by progressive mitochondrial DNA (mtDNA) depletion and deteriorating mitochondrial metabolism, we show that mitochondria-associated AMPK becomes activated early in the course of the advancing mitochondrial dysfunction, before any quantifiable decrease in the ATP/(AMP + ADP) ratio or respiratory chain activity. Moreover, stimulation of AMPK activity using the specific small-molecule agonist A-769662 alleviated the mitochondrial phenotypes caused by the mtDNA depletion and restored normal mitochondrial membrane potential. Notably, the agonist treatment was able to partially restore mtDNA levels in cells with severe mtDNA depletion, while it had no impact on mtDNA levels of control cells. The beneficial impact of the agonist on mitochondrial membrane potential was also observed in cells from patients suffering from mtDNA depletion. These findings improve our understanding of the effects of specific small-molecule activators of AMPK on mitochondrial and cellular function and suggest a potential application for these compounds in disease states involving mtDNA depletion.

Keywords:  AMPK; AMP‐activated protein kinase; mitochondrial DNA depletion; polymerase ɣ

DOI:  https://doi.org/10.1111/febs.70006
J Proteomics. 2025 Feb 03. pii: S1874-3919(25)00024-7. [Epub ahead of print] 105397

P.1 and P.2 SARS-CoV-2 Brazilian variants activate the unfolded protein response with a time and pathway specificity.

Vinicius de Morais Gomes, Deivid Martins Santos, Janaina Macedo da Silva, Lucas C Lazari, Rafael Rahal Guaragna Machado, Ancely Ferreira Dos Santos, Danielle Bastos Araujo, João Vitor Paccini Coutinho, Gabriel Santos Arini, Claudia B Angeli, Edmarcia E de Souza, Rodolfo F Marques, Silvia Beatriz Boscardin, Carsten Wrenger, Claudio R F Marinho, Danielle B L Oliveira, Edison L Durigon, Leticia Labriola, Lívia Rosa-Fernandes, Giuseppe Palmisano.

  COVID-19 is a human respiratory syndrome caused by the infection of the SARS-CoV-2 virus that has a high rate of infection and mortality. Viruses modulate the host machinery by altering cellular mechanisms that favor their replication. One of the mechanisms that viruses exploit is the protein folding and processing of post-translational modifications that occur in the endoplasmic reticulum (ER). When ER function is impaired, there is an accumulation of misfolded proteins leading to endoplasmic reticulum stress (ER stress). To maintain homeostasis, cells trigger an adaptive signaling mechanism called the Unfolded Protein Response (UPR) which helps cells deal with stress, but under severe conditions, can activate the apoptotic cell death mechanism. This study elucidated an activation of a diversity of molecular mechanisms by Brazilian variants of SARS-CoV-2 by a time-resolved and large-scale characterization of SARS-CoV-2-infected cells proteomics and immunoblotting. Furthermore, it was shown that pharmacological UPR modulation could reduce viral release by counteracting the different viral activations of its cellular response. Analysis of human clinical specimens and disease outcomes focusing on ER stress reinforces the importance of UPR modulation as a host regulatory mechanism during viral infection and could point to novel therapeutic targets. SIGNIFICANCE: Since the emergence of SARS-CoV-2 and the consequent COVID-19 pandemic, the rapid emergence of variants of this new coronavirus has been a cause for concern since many of them have significantly higher rates of transmissibility and virulence, being called Variants of Concern (VOC). In this work, we studied the VOCs Gamma (P.1) and Zeta (P.2), also known as Brazilian variants. Constant evidence has reported that there are particularities related to each variant of SARS-CoV-2, with different rates of transmissibility, replication and modulation of host biological processes being observed, in addition to the mutations present in the variants. For this reason, this work focused on infections caused by the Brazilian variants of SARS-CoV-2 in different cell lines, in which we were able to observe that the infections caused by the variants induced endoplasmic reticulum stress in the infected cells and activated the UPR pathways, presenting specific modulations of each variant in this pathway. Furthermore, transcriptome analysis of patients revealed a correlation between ER-related genes and COVID-19 progression. Finally, we observed that the use of UPR modulators in host cells decreased viral release of all variants without affecting cell viability. The data presented in this work complement the observations of other studies that aim to understand the pathogenicity of SARS-CoV-2 VOCs and possible new therapeutic strategies, mainly targeting biological processes related to the endoplasmic reticulum.

Keywords:  ER stress; P.1; P.2; Proteomics; SARS-CoV-2; Unfolded protein response; Viral strains

DOI:  https://doi.org/10.1016/j.jprot.2025.105397
Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00494-7. [Epub ahead of print]37(2): 310-312

A new player in the mammalian electron transport chain.

Judy Hirst.

In an evolutionary twist to mammalian bioenergetics, Spinelli and coworkers reveal the presence of rhodoquinones in mammalian mitochondria, expanding the established premise that the mammalian respiratory chain relies uniquely on ubiquinones for catalysis.

DOI: https://doi.org/10.1016/j.cmet.2024.12.012
Front Mol Neurosci. 2024 ;17 1507033

Brain network and energy imbalance in Parkinson's disease: linking ATP reduction and α-synuclein pathology.

Hirohisa Watanabe, Sayuri Shima, Kazuya Kawabata, Yasuaki Mizutani, Akihiro Ueda, Mizuki Ito.

  Parkinson's disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in the pentose phosphate pathway and purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple brain functions, require significant energy due to their dense synaptic activity and long-range connections. Deficits in ATP production in PD can severely impair these hubs. The energy imbalance also affects subcortical regions, including the massive axonal arbors in the striatum of substantia nigra pars compacta neurons, due to their high metabolic demand. This ATP decline may result in α-synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown and accelerated neurodegeneration. We propose an "ATP Supply-Demand Mismatch Model" to help explain the pathogenesis of PD. This model emphasizes how ATP deficits drive pathological protein aggregation, impaired autophagy, and the degeneration of key brain networks, contributing to both motor and non-motor symptoms.

Keywords:  ATP metabolism; cortical hubs; energy imbalance; hypoxanthine; mitochondrial dysfunction; α-synuclein aggregation

DOI:  https://doi.org/10.3389/fnmol.2024.1507033
Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00005-1. [Epub ahead of print]37(2): 316-329

The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.

Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis.

  Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.

Keywords:  BCAA metabolism; BCAAs; MMA; aging; branched-chain amino acids; cancer metabolism; metabolic disorders; methylmalonic acid; methylmalonyl-CoA; propionate; propionyl-CoA

DOI:  https://doi.org/10.1016/j.cmet.2025.01.005
Biol Open. 2025 Feb 06. pii: bio.061605. [Epub ahead of print]

Glycogen synthase is required for heat shock-mediated autophagy induction in neuronal cells.

Pratibha Bhadauriya, Akanksha Onkar, Kamali Nagarajan, Kavikumar Angamuthu Karuppusamy, Subramaniam Ganesh, Saloni Agarwal.

  Autophagy is an essential cellular process that facilitates the degradation of aggregated proteins and damaged organelles to maintain cellular homeostasis and promote cell survival. Recent studies have indicated a direct role for glycogen synthase (GS) in activating neuronal autophagy and in conferring protection against cytotoxic misfolded proteins. Since heat shock induces protein misfolding and autophagy is an essential component of the heat shock response that clears the misfolded proteins, we looked at the possible role of GS in heat shock response pathways in neuronal cells. We demonstrate an increase in the activity and level of GS and a concomitant increase in the glycogen level during the heat shock and post-heat shock recovery period. These changes had a direct correlation with autophagy induction. We further demonstrate that heat shock transcription factor 1 regulates the level and activation of GS during heat shock and that GS is essential for the induction of autophagy during heat stress in neuronal cells. Intriguingly, the partial knock-down of GS led to increased death due to heat shock in neuronal cells and Drosophila. Our study offers a novel insight into the role of GS and glycogen metabolic pathways in heat shock response in neuronal cells.

Keywords:  Metabolism; Misfolded proteins; Neuronal cells; Proteolysis; Stress response

DOI:  https://doi.org/10.1242/bio.061605
J Dent Res. 2025 Feb 04. 220345241307944

Pericytes Are Odontoblast Progenitor Cells Depending on ER Stress.

T Ouchi, M Ando, R Kurashima, M Kimura, N Saito, A Iwasaki, H Sekiya, K Nakajima, T Hasegawa, T Mizoguchi, Y Shibukawa.

  Odontoblasts are terminally differentiated cells that exhibit mechanosensitivity and mineralization capacity. Mechanosensitive ion channels such as Piezo1 are present in odontoblasts and are associated with their physiological functions via Ca2+ signaling. Both Ca2+ signals via Ca2+ influx from mechanosensitive ion channels and Ca2+ release from Ca2+ stores function as secondary messenger systems for various biological phenomena. The endoplasmic reticulum (ER) serves as an intracellular Ca2+ store that mobilizes intracellular Ca2+. Changes in Ca2+ concentration inside the ER are among the factors that cause ER stress. Perivascular cells are located around odontoblasts in the dental pulp. Although such formation indicates that perivascular cells interact with odontoblasts, their detailed profiles under developmental and pathological conditions remain unclear. In this study, we revealed that pericyte marker, neural/glial antigen 2 (NG2)-positive cells, in cell-rich zones (CZs) can differentiate into Piezo1-positive odontoblasts following genetic odontoblast depletion in mice, and modeled as odontoblast death after severe dentin injury and as reparative dentin formation. NG2-positive pericytes differentiated into odontoblasts faster than glial cells. To determine how NG2-positive cells differentiate into Piezo1-positive odontoblasts, we focused on the ER-stress sensor protein, activating transcription factor 6a (ATF6a). After genetic odontoblast depletion, NG2-positive cells regenerated in the odontoblast layer and were capable of acting as functional odontoblasts. In the presence of extracellular Ca2+, the application of a sarco/ER Ca2+-ATPase (SERCA) inhibitor, thapsigargin, known as an ER-stress inducer, increased the intracellular Ca2+ concentration in the odontoblast lineage cells (OLCs). The increase was significantly inhibited by the application of a pharmacologic Piezo1 inhibitor, indicating that ER stress by SERCA inhibition augmented Piezo1-induced responses in odontoblast progenitor cells. However, the physiological activation of Gq-coupled receptors by adenosine diphosphate did not induce Piezo1 activation. Gene silencing of ATF6a and/or NG2 impaired the mineralization of OLCs. Overall, ATF6a orchestrates the differentiation of NG2-positive pericytes into functional odontoblasts that act as sensory receptor cells and dentin-forming cells.

Keywords:  ATF6a; NG2; dental pulp; dentin; dentinogenesis; ion channels

DOI:  https://doi.org/10.1177/00220345241307944
Diabetes. 2025 Feb 03. pii: db240360. [Epub ahead of print]

Atf4 protects islet β-cell identity and function under acute glucose-induced stress but promotes β-cell failure in the presence of free fatty acid.

Mahircan Yagan, Sadia Najam, Ruiying Hu, Yu Wang, Mathew Dickerson, Prasanna Dadi, Yanwen Xu, Alan J Simmons, Roland Stein, Christopher M Adams, David A Jacobson, Ken S Lau, Qi Liu, Guoqiang Gu.

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells down-regulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.

DOI: https://doi.org/10.2337/db24-0360
Proc Natl Acad Sci U S A. 2025 Feb 11. 122(6): e2411916122

Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation.

Ebimobowei O Preh, Manuel A Ramirez, Sidharth Mohan, Chanté R Guy, Deborah Bell-Pedersen.

  Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased uncharged tRNA levels trigger GCN1 and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of the Neurospora crassa homolog of GCN2, CPC-3, is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant (un-3ts) that has high levels of uncharged tRNAVal at all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation.

Keywords:  circadian clock; eIF2α; ribosome; tRNA synthetase; translation initiation

DOI:  https://doi.org/10.1073/pnas.2411916122
Aging (Albany NY). 2025 Feb 06. 17

Mitochondrial dysfunction, iron accumulation, lipid peroxidation, and inflammasome activation in cellular models derived from patients with multiple sclerosis.

Raquel García-Salas, Paula Cilleros-Holgado, Anna Di Spirito, David Gómez-Fernández, Rocío Piñero-Pérez, José Manuel Romero-Domínguez, Mónica Álvarez-Córdoba, Diana Reche-López, Ana Romero-González, Alejandra López-Cabrera, José Antonio Sánchez-Alcázar.

  Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Despite advancements in managing relapsing active illness, effective treatments for the irreversible progressive decline in MS remain limited. Research employing skin fibroblasts obtained from patients with neurological disorders revealed modifications in cellular stress pathways and bioenergetics. However, research using MS patient-derived cellular models is scarce. In this study, we collected fibroblasts from two MS patients to investigate cellular pathological alterations. We observed that MS fibroblasts showed a senescent morphology associated with iron/lipofuscin accumulation and altered expression of iron metabolism proteins. In addition, we found increased lipid peroxidation and downregulation of antioxidant enzymes expression levels in MS fibroblasts. When challenged against erastin, a ferroptosis inducer, MS fibroblasts showed decreased viability, suggesting increased sensitivity to ferroptosis. Furthermore, MS fibroblasts presented alterations in the expression levels of autophagy-related proteins. Interestingly, these alterations were associated with mitochondrial dysfunction and inflammasome activation. These findings were validated in 7 additional patient-derived cell lines. Our findings suggest that the underlying stress phenotype of MS fibroblasts may be disease-specific and recapitulate the main cellular pathological alterations found in the disease such as mitochondrial dysfunction, iron accumulation, lipid peroxidation, inflammasome activation, and pro-inflammatory cytokine production.

Keywords:  inflammasome; iron accumulation; lipid peroxidation; mitochondrial dysfunction; multiple sclerosis

DOI:  https://doi.org/10.18632/aging.206198