bims-hisfre 2025-05-18 papers

bims-hisfre

Biomed News

on HSF1 and Creatine

Issue of 2025–05–18
nine papers selected by
James Heilman, Oregon Health & Science University

Activation mechanism of small heat shock protein HSPB5 revealed by disease-associated mutants.
Heat shock protein B1-mediated ferroptosis regulates mitochondrial dysfunction in adipose tissue of ketotic dairy cows.
Genome-Wide Identification and Evolution-Profiling Analysis of Heat Shock Protein Gene Family in Poaceae Barnhart.
Heterozygous females from a rat model for creatine transporter deficiency reveal altered behavioral response to stressors, normal body weight and slight metabolic changes.
NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.
Regulation of synaptic mitochondria by extracellular vesicles and its implications for neuronal metabolism and synaptic plasticity.
Calpains orchestrate secretion of annexin-containing microvesicles during membrane repair.
QRICH1 regulates ATF6 transcription to affect pathological cardiac hypertrophy progression.
Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.

Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2425061122

Activation mechanism of small heat shock protein HSPB5 revealed by disease-associated mutants.

Christopher N Woods, Maria K Janowska, Lindsey D Ulmer, Jasleen Kaur Sidhu, Natalie L Stone, Ellie I James, Miklos Guttman, Matthew F Bush, Rachel E Klevit.

  Found from bacteria to humans, small heat shock proteins (sHSPs) are the least understood protein chaperones. HSPB5 (or αB-crystallin) is among the most widely expressed of the 10 human sHSPs, including in muscle, brain, and eye lens where it is constitutively present at high levels. A high content of disorder in HSPB5 has stymied efforts to uncover how its structure gives rise to function. To uncover its mechanisms of action, we compared human HSPB5 and two disease-associated mutants, R120G and D109H. Expecting to learn how the mutations lead to loss of function, we found instead that the mutants are constitutively activated chaperones while wild-type HSPB5 can transition reversibly between nonactivated (low activity) and activated (high activity) states in response to changing conditions. Techniques that provide information regarding interactions and accessibility of disordered regions revealed that the disordered N-terminal regions (NTR) that are required for chaperone activity exist in a complicated interaction network within HSPB5 oligomers and are sequestered from solvent in nonactivated states. Either mutation or an activating pH change causes rearrangements in the network that expose parts of the NTR, making them more available to bind an aggregating client. Although beneficial in the short-term, failure of the mutants to adopt a state with lower activity and lower NTR accessibility leads to increased coaggregation propensity and, presumably, early cataract. The results support a model where chaperone activity and solubility are modulated through the quasi-ordered NTR and its multiple competing interactions.

Keywords:  protein aggregation; protein chaperones; small heat shock proteins

DOI:  https://doi.org/10.1073/pnas.2425061122
J Dairy Sci. 2025 May 08. pii: S0022-0302(25)00300-5. [Epub ahead of print]

Heat shock protein B1-mediated ferroptosis regulates mitochondrial dysfunction in adipose tissue of ketotic dairy cows.

Yunhui Fan, Li Ma, Xinyi Xu, Xinxin Fang, John Mauck, Juan J Loor, Xudong Sun, Hongdou Jia, Chuang Xu, Qiushi Xu.

  In the peripartal period, dairy cow adipose tissue undergo significant metabolic challenges, including oxidative stress and endoplasmic reticulum stress, which could be alleviated by inhibition of ferroptosis. Oxidative stress is often accompanied by mitochondrial damage. However, whether mitochondrial dysfunction occurs in the adipose tissue of ketotic cows are still unclear. Heat shock protein B1 (HSPB1), a key regulator of cellular redox homeostasis, is critical in managing oxidative stress and iron metabolism. Thus, this study aimed to investigate the role of HSPB1-mediated ferroptosis on mitochondrial dysfunction of adipocytes of ketotic dairy cows. We collected adipose tissue samples of clinical ketosis cows (n = 15) with a serum BHB concentration of 3.14 mM (interquartile range = 0.11) and healthy cows (n = 15) with a serum BHB concentration of 0.55 mM (interquartile range = 0.12). Compared with the healthy control group, the protein abundance of HSPB1, transferrin (TF), transferrin receptor 1 (TFR1), 6-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), divalent metal transporter 1 (DMT1), and acyl-CoA synthetase 4 (ACSL4), as well as levels of reactive oxygen species, Fe2+, and total iron were greater in adipose tissue of ketotic cows. Ketotic cows exhibited lower ferroportin (FPN), solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), mitochondrial oxidative phosphorylation complexes I-V (CO I-V), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), mitofusin-2 (MFN2), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam) protein expression levels, along with lower ATP content compared with control cows. Epinephrine (EPI) treatment upregulated protein abundance of HSPB1 and induced ferroptosis and mitochondrial dysfunction in adipocytes. Inhibition of ferroptosis by pretreatment with ferrostatin-1 (Fer-1) attenuated the EPI-induced decrease in ATP content. Knockdown of HSPB1 by small interfering RNA (si-RNA) exacerbated the EPI-induced upregulation of TF, TFR1, STEAP3, and DMT1 expression and the downregulation of FPN protein expression levels. Furthermore, in the presence of EPI and HSPB1 si-RNA, Fer-1 abolished the regulatory role of HSPB1 on mitochondrial dysfunction, confirming that HSPB1 regulates bovine adipocyte mitochondrial dysfunction in a ferroptosis-dependent manner. Collectively, these data suggest that HSPB1-mediated ferroptosis is an important regulatory mechanism for mitochondrial dysfunction in adipocytes of peripartal dairy cows under negative energy balance.

Keywords:  bovine adipocytes; ferroptosis; ketosis; mitochondrial dysfunction

DOI:  https://doi.org/10.3168/jds.2025-26265
Int J Mol Sci. 2025 Apr 30. pii: 4269. [Epub ahead of print]26(9):

Genome-Wide Identification and Evolution-Profiling Analysis of Heat Shock Protein Gene Family in Poaceae Barnhart.

Xiaoyi Huang, Yue Liu, Xiao Yu, Yajun Cai, Lingyu Hou, Jingyuan Zhang, Hongchun Yang.

  Heat shock proteins (HSPs) function as molecular chaperones to maintain protein homeostasis and repair denatured proteins, counteracting abiotic stresses. Despite their functional importance, a systematic bioinformatics analysis of the HSP gene family was lacking in Poaceae. In this study, we revealed that HSPs are widely distributed from algae to eudicots, with varying numbers in Poaceae including Oryza, Triticum, and Panicum. Gene duplication events, particularly dispersed duplication (DSD), tandem duplication (TD), and genome polyploidization, have probably driven the increased number of HSP genes and the expansion of HSP family proteins. Gene Ontology (GO) annotation analyses suggested their conserved functions. Promoter cis-acting element analyses indicated that their expression levels were tightly regulated by abiotic stresses. We validated that many collinear HSP genes are indeed regulated by the cold stress by analyzing the published RNA-seq data in rice, maize, and wheat, and performing RT-qPCR in rice. Our findings shed light on the role of HSPs in the abiotic stress response, laying the groundwork for further exploration of HSP functions in Poaceae.

Keywords:  HSP; Poaceae; cold stress; gene duplication events

DOI:  https://doi.org/10.3390/ijms26094269
Front Neurosci. 2025 ;19 1520550

Heterozygous females from a rat model for creatine transporter deficiency reveal altered behavioral response to stressors, normal body weight and slight metabolic changes.

Lara Duran-Trio, Marc Lanzillo, Dunja Simicic, Clothilde Roux-Petronelli, Stephen J Bruce, Carmen Sandi, Cristina Cudalbu, Olivier Braissant.

  Creatine (Cr) is an organic acid essential for recycling ATP, important in tissues with high energy demand such as muscle or brain. Cr is synthesized in a 2-step pathway by the enzymes AGAT and GAMT, and transported by SLC6A8 (also called CrT). Cerebral Cr deficiency syndromes (CCDS), due to AGAT, GAMT or CrT deficiencies, are metabolic diseases characterized by brain Cr deficiency, causing a range of clinical features such as severe neurodevelopmental delays and intellectual disability, behavioral disturbances, motor dysfunction and epilepsy. Among CCDS, the X-linked CrT deficiency (CTD) is the most prevalent with no efficient treatment so far. Increasing number of human and animal studies contributes to the understanding of CTD pathology, its diagnosis and treatment, and the roles of Cr and CrT. However, most of them are focused in males and little is known about female carriers and how CrT deficiency affect them. In order to increase knowledge in female sex and roughly explore the relationship with SLC6A8 gene dosage, we present the first characterization of females' Slc6a8 Y389C rat model of CTD using both heterozygous and homozygous females. Brain Cr deficiency was found in all homozygous females, while heterozygous ones showed broad variability in brain Cr levels. Elevated and slightly elevated urinary Cr/Crn ratio were present in homozygous and heterozygous females, respectively. Reduced body weight, muscular mass and locomotor activity were hallmarks of homozygous, but not heterozygous, females. However, in contrast to Slc6a8 Y389C KI males, spontaneous alternation and grooming behaviors were not affected in any type of Slc6a8 Y389C mutant female rats. Interestingly, both Slc6a8 Y389C mutant female rats exhibited behavioral abnormalities such as increased prevalence of altered behavioral response to handling, being more frequent in homozygous female rats. Moreover, heterozygous females presented increased anxiety-like behavior to novelty in Open Field Novel Object test and altered behavioral response with increased locomotor activity in response to light as stressor in the Light Dark Box test. These results are coherent with the limited data from CTD human female carriers, validating the Slc6a8 Y389C rat females as a promising tool to better understand CTD in female sex. They also provide new insights about CTD pathology, revealing sex and zygotic phenotypic differences, highlighting the importance of including females in the study of CTD.

Keywords:  SLC6A8; X-linked disorder; behavior; creatine; creatine transporter deficiency; female; inherited metabolic disease

DOI:  https://doi.org/10.3389/fnins.2025.1520550
Front Mol Neurosci. 2025 ;18 1551571

NFE2L1 as a central regulator of proteostasis in neurodegenerative diseases: interplay with autophagy, ferroptosis, and the proteasome.

Hossein Khodadadi, Kamila Łuczyńska, Dawid Winiarczyk, Paweł Leszczyński, Hiroaki Taniguchi.

  Maintaining proteostasis is critical for neuronal health, with its disruption underpinning the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Nuclear Factor Erythroid 2-Related Factor 1 (NFE2L1) has emerged as a key regulator of proteostasis, integrating proteasome function, autophagy, and ferroptosis to counteract oxidative stress and protein misfolding. This review synthesizes current knowledge on the role of NFE2L1 in maintaining neuronal homeostasis, focusing on its mechanisms for mitigating proteotoxic stress and supporting cellular health, offering protection against neurodegeneration. Furthermore, we discuss the pathological implications of NFE2L1 dysfunction and explore its potential as a therapeutic target. By highlighting gaps in the current understanding and presenting future research directions, this review aims to elucidate NFE2L1's role in advancing treatment strategies for neurodegenerative diseases.

Keywords:  NFE2L1; autophagy; ferroptosis; mitochondrial health; neurodegenerative diseases; oxidative stress; proteasome; proteostasis

DOI:  https://doi.org/10.3389/fnmol.2025.1551571
J Cereb Blood Flow Metab. 2025 May 14. 271678X251337630

Regulation of synaptic mitochondria by extracellular vesicles and its implications for neuronal metabolism and synaptic plasticity.

Yuzhou Zeng, Anna Antoniou.

  Mitochondrial metabolism in neurons is necessary for energetically costly processes like synaptic transmission and plasticity. As post-mitotic cells, neurons are therefore faced with the challenge of maintaining healthy functioning mitochondria throughout lifetime. The precise mechanisms of mitochondrial maintenance in neurons, and particularly in morphologically complex dendrites and axons, are not fully understood. Evidence from several biological systems suggests the regulation of cellular metabolism by extracellular vesicles (EVs), secretory lipid-enclosed vesicles that have emerged as important mediators of cell communication. In the nervous system, neuronal and glial EVs were shown to regulate neuronal circuit development and function, at least in part via the transfer of protein and RNA cargo. Interestingly, EVs have been implicated in diseases characterized by altered metabolism, such as cancer and neurodegenerative diseases. Furthermore, nervous system EVs were shown to contain proteins related to metabolic processes, mitochondrial proteins and even intact mitochondria. Here, we present the current knowledge of the mechanisms underlying neuronal mitochondrial maintenance, and highlight recent evidence suggesting the regulation of synaptic mitochondria by neuronal and glial cell EVs. We further discuss the potential implications of EV-mediated regulation of mitochondrial maintenance and function in neuronal circuit development and synaptic plasticity.

Keywords:  Exosomes; extracellular vesicles; metabolism; mitochondria; synaptic plasticity

DOI:  https://doi.org/10.1177/0271678X251337630
J Cell Biol. 2025 Jul 07. pii: e202408159. [Epub ahead of print]224(7):

Calpains orchestrate secretion of annexin-containing microvesicles during membrane repair.

Justin Krish Williams, Jordan Matthew Ngo, Abinayaa Murugupandiyan, Dorothy E Croall, H Criss Hartzell, Randy Schekman.

Microvesicles (MVs) are membrane-enclosed, plasma membrane-derived particles released by cells from all branches of life. MVs have utility as disease biomarkers and may participate in intercellular communication; however, physiological processes that induce their secretion are not known. Here, we isolate and characterize annexin-containing MVs and show that these vesicles are secreted in response to the calcium influx caused by membrane damage. The annexins in these vesicles are cleaved by calpains. After plasma membrane injury, cytoplasmic calcium-bound annexins are rapidly recruited to the plasma membrane and form a scab-like structure at the lesion. In a second phase, recruited annexins are cleaved by calpains-1/2, disabling membrane scabbing. Cleavage promotes annexin secretion within MVs. Our data support a new model of plasma membrane repair, where calpains relax annexin-membrane aggregates in the lesion repair scab, allowing secretion of damaged membrane and annexins as MVs. We anticipate that cells experiencing plasma membrane damage, including muscle and metastatic cancer cells, secrete these MVs at elevated levels.

DOI: https://doi.org/10.1083/jcb.202408159
Mol Med. 2025 May 13. 31(1): 183

QRICH1 regulates ATF6 transcription to affect pathological cardiac hypertrophy progression.

Lihui Zhang, Hongping Chen, Guangmei Zou, Wenjuan Jia, Haibin Dong, Chunxiao Wang, Hua Wang, Yugang Liu, Da Teng, Bowen Xu, Lin Zhong, Lei Gong, Jun Yang.

   BACKGROUND: Many studies have shown that pathological cardiac hypertrophy is associated with active endoplasmic reticulum (ER) stress. Glutamine-rich protein 1 (QRICH1), as a transcriptional regulator, belongs to the caspase recruitment domain (CARD)-containing gene family. QRICH1 has been shown to influence the outcomes of endoplasmic reticulum stress by regulating the transcription of proteostasis-related genes. In this study, we explored the role of QRICH1 in pathological cardiac hypertrophy.
METHODS: We observed an increased expression of QRICH1 in the hearts of humans and mice with left ventricular hypertrophy (LVH). To assess the functional impact in this context, we employed gain- and loss-of-function approaches, using AAV9 injections to establish cardiac-specific QRICH1 knockdown or overexpression models in transverse aortic constriction (TAC) or isoproterenol (ISO)-induced cardiac hypertrophy.
RESULTS: Our data indicated that cardiomyocyte-specific knockdown of QRICH1 alleviated the hypertrophic phenotype in response to TAC or ISO injection. However, overexpression of QRICH1 exacerbated cardiac hypertrophy, remodeling, dysfunction, cell apoptosis, and inflammatory responses. Mechanistically, we demonstrated that ATF6 was significantly enriched by QRICH1 in cardiomyocytes treated with ISO using RNA-seq combined with CUT&TAG analysis. ChIP-qPCR and luciferase assays further confirmed that ATF6 is a target gene of QRICH1 in cardiomyocytes under growth stimulation. Knockdown of QRICH1 in cardiomyocytes blocked ISO-mediated induction of ATF6, activation of mTORC1, and cellular growth. And all of the above was restored by the overexpression of ATF6.
CONCLUSIONS: QRICH1 plays a pivotal role in cardiac hypertrophy by regulating ATF6, and QRICH1 may be a potential new therapeutic target for pathological cardiac hypertrophy.

Keywords:  Cardiac remodeling; Endoplasmic reticulum stress; Heart failure; Pressure overload

DOI:  https://doi.org/10.1186/s10020-025-01241-2
Aging Dis. 2025 Apr 22.

Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.

Yu Sun, Jin Wei, Shiyin Ma, Chang He, Liutao Sui, Xudong Pan, Xiaoyan Zhu.

Lysosomes are degradation centers and signaling hubs that in cells and play important roles in cellular homeostasis, development, and aging. Growing evidence has also implicated the role of lysosome-related mechanisms in the aging process. Meanwhile, the potential impact of lysosomal dysfunction on the production of inflammatory molecules, cellular metabolic status, and mitochondrial function is becoming increasingly significant. In this review, we provide a comprehensive overview of the physiological roles of lysosomes and their association with aging. At the cellular level, lysosomal dysfunction and cellular senescence show strong correlations. Herein, we elucidated the precise mechanisms by which lysosomal dysfunction contributes to various cellular physiological processes, as well as its potential implications in age-related hallmarks. More importantly, we discuss how lysosomal homeostasis is disrupted in several age-related diseases, including atherosclerosis, heart diseases, cancer, neurodegenerative diseases, metabolic disorders, and motor system diseases. Thus, a deeper understanding of lysosomal function may provide fundamental insights into human physiology and age-related diseases. Furthermore, these discoveries emphasize the role of the lysosome in the development of novel therapeutic strategies.

DOI: https://doi.org/10.14336/AD.2025.0275