bims-celmim 2024-11-24 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2024–11–24
29 papers selected by
Marc Segarra Mondejar

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.
AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.
Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
Sensitivities in protein allocation models reveal distribution of metabolic capacity and flux control.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.
A mitochondrial redox switch licenses the onset of morphogenesis in animals.
ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice.
H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission.
Carboxylation in de novo purine biosynthesis.
Glucose-independent human cytomegalovirus replication is supported by metabolites that feed upper glycolytic branches.
Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance.
Metabolic complementation between cells drives the evolution of tissues and organs.
TET3 regulates terminal cell differentiation at the metabolic level.
NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.
Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.
A hybrid in silico/in-cell controller that handles process-model mismatches using intracellular biosensing.
Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency.
Sticky enzymes: increased metabolic efficiency via substrate-dependent enzyme clustering.
Development of fluorescence lifetime biosensors for ATP, cAMP, citrate, and glucose using the mTurquoise2-based platform.
F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
The role of pyroptosis in cancer: key components and therapeutic potential.
Calcium nanoparticles target and activate T cells to enhance anti-tumor function.

bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

DOI: https://doi.org/10.1101/2024.10.31.621317
Sci Rep. 2024 11 16. 14(1): 28296

Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.

Kaade Edgar, Mausbach Simone, Erps Nina, Sylvester Marc, Shakeri Farhad, Ron D Jachimowicz, Gieselmann Volkmar, Thelen Melanie.

Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation.

DOI: https://doi.org/10.1038/s41598-024-78873-7
Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263

AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.

Hui Jiang.

In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.

DOI: https://doi.org/10.1016/j.molcel.2024.10.040
PLoS Pathog. 2024 Nov 18. 20(11): e1012711

Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.

Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce.

Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.

DOI: https://doi.org/10.1371/journal.ppat.1012711
bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]

Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.

Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.

The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.

DOI: https://doi.org/10.1101/2024.10.30.621159
JCI Insight. 2024 Nov 22. pii: e184279. [Epub ahead of print]9(22):

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

Andrew S Perry, Paolo Piaggi, Shi Huang, Matthew Nayor, Jane Freedman, Kari E North, Jennifer E Below, Clary B Clish, Venkatesh L Murthy, Jonathan Krakoff, Ravi V Shah.

  Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.

Keywords:  Amino acid metabolism; Carbohydrate metabolism; Intermediary metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.184279
Bioinformatics. 2024 Nov 18. pii: btae691. [Epub ahead of print]

Sensitivities in protein allocation models reveal distribution of metabolic capacity and flux control.

Samira van den Bogaard, Pedro A Saa, Tobias B Alter.

MOTIVATION: Expanding on constraint-based metabolic models, protein allocation models (PAMs) enhance flux predictions by accounting for protein resource allocation in cellular metabolism. Yet, to this date, there are no dedicated methods for analyzing and understanding the growth-limiting factors in simulated phenotypes in PAMs.
RESULTS: Here, we introduce a systematic framework for identifying the most sensitive enzyme concentrations (sEnz) in PAMs. The framework exploits the primal and dual formulations of these models to derive sensitivity coefficients based on relations between variables, constraints, and the objective function. This approach enhances our understanding of the growth-limiting factors of metabolic phenotypes under specific environmental or genetic conditions. Compared to other traditional methods for calculating sensitivities, sEnz requires substantially less computation time and facilitates more intuitive comparison and analysis of sensitivities. The sensitivities calculated by sEnz cover enzymes, reactions and protein sectors, enabling a holistic overview of the factors influencing metabolism. When applied to an Escherichia coli PAM, sEnz revealed major pathways and enzymes driving overflow metabolism. Overall, sEnz offers a computational efficient framework for understanding PAM predictions and unravelling the factors governing a particular metabolic phenotype.
AVAILABILITY AND IMPLEMENTATION: sEnz is implemented in the modular toolbox for the generation and analysis of PAMs in Python (PAModelpy; v.0.0.3.3), available on Pypi (https://pypi.org/project/PAModelpy/). The source code together with all other python scripts and notebooks are available on GitHub (https://github.com/iAMB-RWTH-Aachen/PAModelpy).
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DOI: https://doi.org/10.1093/bioinformatics/btae691
bioRxiv. 2024 Nov 07. pii: 2024.11.06.622291. [Epub ahead of print]

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2- null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2- null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2- null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.

DOI: https://doi.org/10.1101/2024.11.06.622291
J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004

Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.

  Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.

Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux

DOI:  https://doi.org/10.1016/j.jbc.2024.108004
J Cell Biol. 2024 Dec 02. pii: e202407193. [Epub ahead of print]223(12):

PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.

Ravi Chidambaram, Kamal Kumar, Smriti Parashar, Gowsalya Ramachandran, Shuliang Chen, Susan Ferro-Novick.

Here, we report that the RTN3L-SEC24C endoplasmic reticulum autophagy (ER-phagy) receptor complex, the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L, and the FIP200 autophagy initiating protein, target mutant proinsulin (Akita) condensates for lysosomal delivery at ER tubule junctions. When delivery was blocked, Akita condensates accumulated in the ER. In exploring the role of tubulation in these events, we unexpectedly found that loss of the Parkinson's disease protein, PINK1, reduced peripheral tubule junctions and blocked ER-phagy. Overexpression of the PINK1 kinase substrate, DRP1, increased junctions, reduced Akita condensate accumulation, and restored lysosomal delivery in PINK1-depleted cells. DRP1 is a dual-functioning protein that promotes ER tubulation and severs mitochondria at ER-mitochondria contact sites. DRP1-dependent ER tubulating activity was sufficient for suppression. Supporting these findings, we observed PINK1 associating with ER tubules. Our findings show that PINK1 shapes the ER to target misfolded proinsulin for RTN3L-SEC24C-mediated macro-ER-phagy at defined ER sites called peripheral junctions. These observations may have important implications for understanding Parkinson's disease.

DOI: https://doi.org/10.1083/jcb.202407193
bioRxiv. 2024 Oct 29. pii: 2024.10.28.620733. [Epub ahead of print]

A mitochondrial redox switch licenses the onset of morphogenesis in animals.

Updip Kahlon, Francesco Dalla Ricca, Saraswathi J Pillai, Marine Olivetta, Kevin M Tharp, Li-En Jao, Omaya Dudin, Kent McDonald, Mustafa G Aydogan.

Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3-6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2 -) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2 - production. Importantly, depleting mitochondrial O2 - fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2 - similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.

DOI: https://doi.org/10.1101/2024.10.28.620733
Nat Commun. 2024 Nov 22. 15(1): 9977

ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice.

Masahiro Takahashi, Shinya Yamamoto, Shigenori Yamamoto, Akihiro Okubo, Yasuaki Nakagawa, Koichiro Kuwahara, Taiji Matsusaka, Shingo Fukuma, Masamichi Yamamoto, Michiyuki Matsuda, Motoko Yanagita.

Acute kidney injury (AKI), typically caused by ischemia, is a common clinical complication with a poor prognosis. Although proteinuria is an important prognostic indicator of AKI, the underlying causal mechanism remains unclear. In vitro studies suggest that podocytes have high ATP demands to maintain their structure and function, however, analyzing their ATP dynamics in living kidneys has been technically challenging. Here, using intravital imaging to visualize a FRET-based ATP biosensor expressed systemically in female mice due to their suitability for glomerular imaging, we monitor the in vivo ATP dynamics in podocytes during ischemia reperfusion injury. ATP levels decrease during ischemia, but recover after reperfusion in podocytes, exhibiting better recovery than in glomerular endothelial cells. However, prolonged ischemia results in insufficient ATP recovery in podocytes, which is inversely correlated with mitochondrial fragmentation and foot process effacement during the chronic phase. Furthermore, preventing mitochondrial fission via pharmacological inhibition ameliorates podocyte injury in vitro, ex vivo, and in vivo. Thus, these findings provide several insights into how ATP depletion and mitochondrial fragmentation contribute to podocyte injury after ischemic AKI and could potentially be therapeutic targets.

DOI: https://doi.org/10.1038/s41467-024-54222-0
bioRxiv. 2024 Nov 03. pii: 2024.10.30.621162. [Epub ahead of print]

H 2 S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.

David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.

Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.
Significance Statement: Hydrogen sulfide is a product of host as well as gut microbial metabolism and has the dual capacity for activating respiration as a substrate, and inhibiting it at the level of complex IV. In this study, we report that chronic albeit low-level sulfide exposure elicits profound changes in mitochondrial architecture in cultured human cells. Disruption of mitochondrial networks is reversed upon removal of sulfide from the growth chamber atmosphere. Sulfide-dependent depolarization of the inner mitochondrial membrane is associated with loss of cristae and respiratory supercomplexes. Our study reveals the potential for sulfide to be an endogenous regulator of mitochondrial ultrastructure and function via modulation of electron flux and for this process to be corrupted in sulfide dysregulated diseases.

DOI: https://doi.org/10.1101/2024.10.30.621162
PLoS Comput Biol. 2024 Nov 18. 20(11): e1012596

A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission.

Anna K Leinheiser, Colleen C Mitchell, Ethan Rooke, Stefan Strack, Chad E Grueter.

Mitochondrial hyperfission in response to cellular insult is associated with reduced energy production and programmed cell death. Thus, there is a critical need to understand the molecular mechanisms coordinating and regulating the complex process of mitochondrial fission. We develop a nonlinear dynamical systems model of dynamin related protein one (Drp1)-dependent mitochondrial fission and use it to identify parameters which can regulate the total fission rate (TFR) as a function of time. The TFR defined from a nondimensionalization of the model undergoes a Hopf bifurcation with bifurcation parameter [Formula: see text] where [Formula: see text] is the total concentration of mitochondrial fission factor (Mff) and k+ and k- are the association and dissociation rate constants between oligomers on the outer mitochondrial membrane. The variable μ can be thought of as the maximum build rate over the disassembling rate of oligomers. Though the nondimensionalization of the system results in four dimensionless parameters, we found the TFR and the cumulative total fission (TF) depend strongly on only one, μ. Interestingly, the cumulative TF does not monotonically increase as μ increases. Instead it increases with μ to a certain point and then begins to decrease as μ continues to increase. This non-monotone dependence on μ suggests interventions targeting k+, k-, or [Formula: see text] may have a non-intuitive impact on the fission mechanism. Thus understanding the impact of regulatory parameters, such as μ, may assist future therapeutic target selection.

DOI: https://doi.org/10.1371/journal.pcbi.1012596
Methods Enzymol. 2024 ;pii: S0076-6879(24)00548-2. [Epub ahead of print]708 389-424

Carboxylation in de novo purine biosynthesis.

Marcella F Sharma, Steven M Firestine.

  De novo purine biosynthesis is one of two pathways for the synthesis of purine nucleotides that are critical for numerous biological processes, most notably nucleic acid replication. Within the pathway, there is only one carbon-carbon bond formation which is the carboxylation of 5-aminoimidazole ribonucleotide (AIR) to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR). Interestingly, there are two unique pathways within purine biosynthesis to accomplish this transformation and this divergence is species specific. In humans and higher eukaryotes, CAIR is synthesized directly from AIR and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast, fungi and plants, CAIR synthesis requires two steps. In the first, AIR is converted into the unstable carbamate, N5-CAIR by the enzyme N5-CAIR synthetase. N5-CAIR is then converted into CAIR by transfer of the CO2 group from N5 to C4. This is catalyzed by the enzyme N5-CAIR mutase. This divergence has provided a biochemical rationale for targeting CAIR synthesis in the development of antimicrobial agents, but recent studies have provided strong evidence that AIR carboxylase plays a critical role in several cancers. Given the significance of these enzymes as drug targets, methods to prepare and evaluate these enzymes is of interest. In this chapter, we have accumulated the most relevant assays and provided methods to synthesize the substrates and purify the enzymes.

Keywords:  4-Carboxy-5-aminoimidazole ribonucleotide; 5-Aminoimdazole ribonucleotide; Carboxylase; Enzyme assays; Purine biosynthesis

DOI:  https://doi.org/10.1016/bs.mie.2024.10.021
Proc Natl Acad Sci U S A. 2024 Nov 26. 121(48): e2412966121

Glucose-independent human cytomegalovirus replication is supported by metabolites that feed upper glycolytic branches.

Rebekah L Mokry, John G Purdy.

  Viruses with broad tissue distribution and cell tropism successfully replicate in various nutrient environments in the body. Several viruses reprogram metabolism for viral replication. However, many studies focus on metabolic reprogramming in nutrient-rich conditions that do not recapitulate physiological environments in the body. Here, we investigated how viruses may replicate when a metabolite thought to be essential for replication is limited. We use human cytomegalovirus infection in glucose-free conditions as a model to determine how glucose supports virus replication and how physiologically relevant nutrients contribute to glucose-independent virus production. We find that glucose supports viral genome synthesis, viral protein production and glycosylation, and infectious virus production. Notably, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc-metabolites that feed upper glycolytic branches like the pentose phosphate pathway-results in partially restored virus replication, including low levels of infectious virus production. Supplementing lower glycolysis in glucose-free cultures using pyruvate fails to restore virus replication. These results indicate that nutrients can compensate for glucose via feeding upper glycolytic branches to sustain low levels of virus production. More broadly, our findings suggest that viruses may successfully replicate in diverse metabolic niches, including those in the body with low glucose levels, through alternative nutrient usage.

Keywords:  glycolysis; herpesviruses; human cytomegalovirus; metabolism

DOI:  https://doi.org/10.1073/pnas.2412966121
Nat Commun. 2024 Nov 22. 15(1): 10111

Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance.

Zhuo Chen, Baocheng Wan, Hong Zhang, Lina Zhang, Rong Zhang, Lianxi Li, Yi Zhang, Cheng Hu.

Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyzes, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity and our results mainly concern male mice.

DOI: https://doi.org/10.1038/s41467-024-54488-4
Biol Lett. 2024 Nov;20(11): 20240490

Metabolic complementation between cells drives the evolution of tissues and organs.

Mihaela Pavlicev, J DiFrisco, Alan C Love, Günter P Wagner.

  Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already present in constituent cell types? We propose a hypothesis for this kind of evolutionary transition based on two features of cellular metabolism: metabolic constraints on functional performance and the capacity for metabolic complementation between parenchymal and supporting cells. These features suggest a scenario whereby pre-existing specialized cell types are integrated into tissues when changes to the internal or external environment favour offloading metabolic burdens from a primary specialized cell type onto supporting cells. We illustrate this process of 'supra-functionalization' using the nervous system and pancreas.

Keywords:  levels of organization; metabolic complementation; metabolic constraint; self-maintenance; tissue origin

DOI:  https://doi.org/10.1098/rsbl.2024.0490
Nat Commun. 2024 Nov 18. 15(1): 9749

TET3 regulates terminal cell differentiation at the metabolic level.

Isabel Mulet, Carmen Grueso-Cortina, Mireia Cortés-Cano, Daniela Gerovska, Guangming Wu, Stefania Alexandra Iakab, Daniel Jimenez-Blasco, Andrea Curtabbi, Pablo Hernansanz-Agustín, Harmony Ketchum, Israel Manjarrés-Raza, F Thomas Wunderlich, Juan Pedro Bolaños, Meelad M Dawlaty, Carsten Hopf, José Antonio Enríquez, Marcos J Araúzo-Bravo, Natalia Tapia.

TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.

DOI: https://doi.org/10.1038/s41467-024-54044-0
Nat Commun. 2024 Nov 16. 15(1): 9945

NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.

Jie Wang, Rui Zhao, Sha Xu, Xiang-Yu Zhou, Ke Cai, Yu-Ling Chen, Ze-Yu Zhou, Xin Sun, Yan Shi, Feng Wang, Yong-Hao Gui, Hui Tao, Jian-Yuan Zhao.

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.

DOI: https://doi.org/10.1038/s41467-024-54407-7
Commun Biol. 2024 Nov 21. 7(1): 1551

Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.

Christopher S Morrow, Pallas Yao, Carlos A Vergani-Junior, Praju Vikas Anekal, Paula Montero Llopis, Jeffrey W Miller, Bérénice A Benayoun, William B Mair.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as "mito-NAD(P)H age clocks." Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.

DOI: https://doi.org/10.1038/s42003-024-07243-w
Sci Rep. 2024 11 18. 14(1): 27252

A hybrid in silico/in-cell controller that handles process-model mismatches using intracellular biosensing.

Tomoki Ohkubo, Yuichi Sakumura, Fuzhong Zhang, Katsuyuki Kunida.

  The discrepancy between model predictions and actual processes, known as process-model mismatch (PMM), remains a substantial challenge in bioprocess optimization. We previously introduced a hybrid in silico/in-cell controller (HISICC) that combines model-based optimization with cell-based feedback to address this problem. Here, we extended this approach to regulate a key enzyme level using intracellular biosensing. The extended HISICC was implemented using an Escherichia coli strain engineered for fatty acid production (FA3). This strain contains a genetically encoded feedback controller that decelerates the expression of acetyl-CoA carboxylase (ACC) in response to malonyl-CoA synthesized through the enzymatic reaction. We modeled FA3 to allow the HISICC to optimize an inducer input that accelerates the enzyme expression. Simulations showed that the HISICC slowed the unexpectedly rapid accumulation of ACC resulting from PMMs before it reached cytotoxic levels, thereby improving fatty acid yields. These results highlight the potential of our approach, particularly in cases where monitoring intracellular biomolecules is required to handle PMMs.

Keywords:  Bioprocess control; Genetic circuit engineering; Model-based optimization; Negative feedback; Synthetic biology

DOI:  https://doi.org/10.1038/s41598-024-76029-1
Cancer Metab. 2024 Nov 19. 12(1): 35

Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.

   BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.

Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria

DOI:  https://doi.org/10.1186/s40170-024-00364-0
Sci Rep. 2024 Nov 21. 14(1): 28815

Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency.

Mehmet Cihan Balci, Asuman Gedikbasi, Sukru Anil Dogan, Sevde Kahraman, Suzin Tatoryan, Sebnem Tekin Neijmann, Meryem Karaca, Fatmahan Atalar, Gulden Gokcay.

  Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD+ and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD+/NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD++NADH and NADH levels. The alterations in NAD+, FGF-21, GDF-15 levels, and NAD+/NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients.

Keywords:  Cystathionine beta synthase deficiency; Fibroblast growth factor 21; Growth differentiation factor 15; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1038/s41598-024-80273-w
bioRxiv. 2024 Nov 08. pii: 2024.11.05.622105. [Epub ahead of print]

Sticky enzymes: increased metabolic efficiency via substrate-dependent enzyme clustering.

Alejandro Martínez-Calvo, Jello Zhou, Yaojun Zhang, Ned S Wingreen.

Coclustering of subsequent enzymes in a pathway can accelerate the processing of metabolic intermediates, with benefits including increased pathway fluxes, reduced toxicity, and sensitive branch-point regulation. While the optimal organization of such clusters has been explored theoretically, little is known about how to achieve such organization inside cells. Here we propose that phase-separating enzymes can self-organize into nearly-optimally sized and spaced clusters, provided that their "stickiness" is regulated by local substrate availability. In a nutshell, enzyme clusters only form when and where they are needed to process substrate. We study a mathematical model that implements this scheme for simple metabolic pathways, including all thermodynamic constraints. We find that pathway fluxes can be increased by 50 to 1000-fold and toxic metabolites can be decreased by 10 to 100-fold, at realistic enzyme densities. Finally, we discuss how enzyme "stickiness" could be allosterically regulated. This study presents a self-organization strategy that goes beyond current paradigms for natural and engineered enzyme clusters, and thus represents a motivating challenge to the fields of synthetic biology and metabolic engineering.

DOI: https://doi.org/10.1101/2024.11.05.622105
Cell Rep Methods. 2024 Nov 18. pii: S2667-2375(24)00292-3. [Epub ahead of print]4(11): 100902

Development of fluorescence lifetime biosensors for ATP, cAMP, citrate, and glucose using the mTurquoise2-based platform.

Chongxia Zhong, Satoshi Arai, Yasushi Okada.

  Single-fluorescent protein (FP)-based FLIM (fluorescence lifetime imaging microscopy) biosensors can visualize intracellular processes quantitatively. They require a single wavelength for detection, which facilitates multi-color imaging. However, their development has been limited by the absence of a general design framework and complex screening processes. In this study, we engineered FLIM biosensors for ATP (adenosine triphosphate), cAMP (cyclic adenosine monophosphate), citrate, and glucose by inserting each sensing domain into mTurquoise2 (mTQ2) between Tyr-145 and Phe-146 using peptide linkers. Fluorescence intensity-based screening yielded FLIM biosensors with a 0.5 to 1.0 ns dynamic range upon analyte binding, demonstrating that the mTQ2(1-145)-GT-X-EF-mTQ2(146-238) backbone is a versatile platform for FLIM biosensors, allowing for simple intensity-based screening while providing dual-functional biosensors for both FLIM and intensity-based imaging. As a proof of concept, we monitored cAMP and Ca2+ dynamics simultaneously in living cells by dual-color imaging. Our results complement recent studies, establishing mTQ2 as a valuable framework for developing FLIM biosensors.

Keywords:  ATP; CP: Imaging; FLIM; biosensors; cAMP; citrate; fluorescence lifetime imaging microscopy; fluorescent protein; glucose; quantitative imaging

DOI:  https://doi.org/10.1016/j.crmeth.2024.100902
bioRxiv. 2024 Nov 04. pii: 2024.11.04.621834. [Epub ahead of print]

F2,6BP restores mitochondrial genome integrity in Huntington's Disease.

Anirban Chakraborty, Santi M Mandal, Mikita Mankevich, Sravan Gopalkrishnashetty Sreenivasmurthy, Muralidhar L Hegde, Balaji Krishnan, Gourisankar Ghosh, Tapas Hazra.

Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3'-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients' brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.

DOI: https://doi.org/10.1101/2024.11.04.621834
Cell Commun Signal. 2024 Nov 15. 22(1): 548

The role of pyroptosis in cancer: key components and therapeutic potential.

Zixi Liu, Simiao Xu, Lin Chen, Jun Gong, Min Wang.

  Pyroptosis is a lytic and inflammatory form of gasdermin protein-mediated programmed cell death that is typically initiated by inflammasomes. The inflammasome response is an effective mechanism for eradicating germs and cancer cells in the event of cellular injury. The gasdermin family is responsible for initiating pyroptosis, a process in which holes are made in the cell membrane to allow inflammatory chemicals to escape. Mounting evidence indicates that pyroptosis is critical for controlling the development of cancer. In this review, we provide a general overview of pyroptosis, examine the relationship between the primary elements of pyroptosis and tumors, and stress the necessity of pyroptosis-targeted therapy in tumors. Furthermore, we explore its dual nature as a double-edged sword capable of both inhibiting and facilitating the growth of cancer, depending on the specific conditions. Ultimately, pyroptosis is a phenomenon that has both positive and negative effects on tumors. Using this dual impact in a reasonable manner may facilitate investigation into the initiation and progression of tumors and offer insights for the development of novel treatments centered on pyroptosis.

Keywords:  Gasdermin; Inflammasome; Pyroptosis; Targeted therapy

DOI:  https://doi.org/10.1186/s12964-024-01932-z
Nat Commun. 2024 Nov 21. 15(1): 10095

Calcium nanoparticles target and activate T cells to enhance anti-tumor function.

Wei Yang, Zhizi Feng, Xinning Lai, Jianwen Li, Zhengwei Cao, Fangchao Jiang, Fanghui Chen, Shuyue Zhan, Feng Kong, Li Yang, Yong Teng, Wendy T Watford, Gang Zhou, Jin Xie.

Calcium signaling plays a crucial role in the activation of T lymphocytes. However, modulating calcium levels to control T cell activation in vivo remains a challenge. In this study, we investigate T cell activation using 12-myristate 13-acetate (PMA)-encapsulated CaCO3 nanoparticles. We find that anti-PD-1 antibody-conjugated CaCO3 nanoparticles can be internalized by T cells via receptor-mediated endocytosis and then gradually release calcium. This results in an increase in cytosolic calcium, which triggers the activation of NFAT and NF-κB pathways, especially when the surface of the CaCO3 nanoparticles is loaded with PMA. Animal studies demonstrate that the PMA-loaded calcium nanoparticles enhance the activation and proliferation of cytotoxic T cells, leading to improved tumor suppression without additional toxicity. When tested in metastatic tumor models, T cells loaded with the calcium nanoparticles prior to adoptive cell transfer control tumor growth better, resulting in prolonged animal survival. Our approach offers an alternative T cell activation strategy to potentiate immunotherapy by targeting a fundamental signaling pathway.

DOI: https://doi.org/10.1038/s41467-024-54402-y