Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis DOI
Easun Arunachalam, Felix C. Keber, Richard C. Law

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 5, 2024

Abstract A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth and compensated by an increase fermentation, despite being more efficient than fermentation. This apparent preference for fermentation even the presence of oxygen known as aerobic glycolysis, occurs bacteria, yeast, cancer cells. Considerable work has focused on understanding potential benefits might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show glycolysis results from saturation mitochondrial decoupling biogenesis production other cellular components. Respiration insensitive to acute perturbations energetic demands or nutrient supplies, explained simply amount mitochondria per cell. Mitochondria accumulate at a nearly constant across different conditions, resulting largely determined cell division time. In contrast, glucose uptake not saturated, accurately predicted abundances affinities transporters. Combining these models provides quantitative, explanation glycolysis. The robustness specific biogenesis, paired flexibility bioenergetic biosynthetic fluxes, may play broad role shaping eukaryotic metabolism.

Language: Английский

Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research DOI Creative Commons
Eun Sun Jung, Hayoung Choi, Inhee Mook‐Jung

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

Citations

5
Translocation renal cell carcinoma says no to the Warburg effect DOI

Xingxiu Pan,

Valentin Cracan

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Language: Английский

Citations

1
Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production DOI Open Access
Kimberly S. Huggler,

Carlos A. Mellado Fritz,

Kyle M. Flickinger

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

ABSTRACT Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking first committed step glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to outer mitochondrial membrane (OMM). CRISPR screens across hundreds cell lines indicate both are dispensable for growth in traditional culture media. By contrast, HK2 deletion impairs Human Plasma-Like Medium (HPLM). Here, we find is required maintain sufficient cytosolic (OMM-detached) HK activity under conditions enhance HK1 binding OMM. Notably, OMM-detached rather than OMM-docked promotes “aerobic glycolysis” (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show several proposed theories this cannot explain dependence instead severely glycolytic ATP production with little impact on total yield HPLM. Our results reveal a basis conditional essentiality suggest demand compartmentalized underlies Warburg effect.

Language: Английский

Citations

1
Beyond nutritional immunity: immune-stressing challenges basic paradigms of immunometabolism and immunology DOI Creative Commons
E. Legrand

Frontiers in Nutrition, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 12, 2025

Pathogens have the well-known advantage of rapid evolution due to short generation times and large populations. However, pathogens rarely noted disadvantage vulnerability stress involved in proliferation as well being localized. Presented here are numerous new paradigms immunology, especially immunometabolism, which derived from examining how hosts capitalize on pathogen vulnerabilities stress. Universally, requires both resources synthesis, vulnerable resource-limiting damaging/noxious stress, respectively. particularly at time when they most threatening-when proliferating. Since immune cells actively controlling (effector cells) typically do not proliferate infected sites, there is a "stress gap" wherein proliferating more any type than attacking effector cells. Hosts by restricting (resource-limiting stress) generating noxious waste products (damaging/disruptive fundamental defense here-in termed "immune-stressing." While nutritional immunity emphasizes denying micronutrients, immune-stressing extends concept all resources, glucose oxygen, coupled with metabolic such lactic acid, reactive oxygen species (ROS), heat further harm or pathogens. At present much field immunometabolism centers nutrition metabolism regulate function, central feature inefficient use via aerobic glycolysis (with lactate/lactic acid production) In contrast, system uses control infections. Immune-stressing addresses cell site noting that high uptake linked output an ideal double-pronged stressor targeting Once basic recognized, other immunology whole, challenged.

Language: Английский

Citations

1
The Warburg effect: the hacked mitochondrial-nuclear communication in cancer DOI
Haowen Jiang, Jiangbin Ye

Seminars in Cancer Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Protocol to quantitatively assess glycolysis and related carbon metabolic fluxes using stable isotope tracing in Crabtree-positive yeasts DOI
Shreyas Niphadkar, Sreesa Sreedharan, Vineeth Vengayil

et al.

STAR Protocols, Journal Year: 2025, Volume and Issue: 6(2), P. 103786 - 103786

Published: April 22, 2025

Language: Английский

Citations

0
MOB rules: Antibiotic Exposure Reprograms Metabolism to MobilizeBacillus subtilisin Competitive Interactions DOI Creative Commons
Y.C. Liu, Sandra LaBonte,

Courtney Brake

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 20, 2024

Abstract Antibiotics have dose-dependent effects on exposed bacteria. The medicinal use of antibiotics relies their growth-inhibitory activities at sufficient concentrations. At subinhibitory concentrations, exposure vary widely among different and Bacillus subtilis responds to bacteriostatic translation inhibitors by mobilizing a population cells (MOB-Mobilized ) spread across surface. How B. regulates the antibiotic-induced mobilization is not known. In this study, we used chloramphenicol identify regulatory functions that requires coordinate cell following exposure. We measured changes in gene expression metabolism mapped results network proteins direct mobile response. Our data reveal several transcriptional regulators coordinately control reprogramming support mobilization. glycolysis, nucleotide metabolism, amino acid are signature features mobilized population. Among hundreds genes with changing expression, identified two, pdhA pucA , where magnitudes abundance associated metabolites, hallmark metabolic Using reporters visualized separation major branches regions regulated response enables bacteria states mount coordinated

Language: Английский

Citations

0
Robustness of mitochondrial biogenesis and respiration explain aerobic glycolysis DOI
Easun Arunachalam, Felix C. Keber, Richard C. Law

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 5, 2024

Abstract A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth and compensated by an increase fermentation, despite being more efficient than fermentation. This apparent preference for fermentation even the presence of oxygen known as aerobic glycolysis, occurs bacteria, yeast, cancer cells. Considerable work has focused on understanding potential benefits might justify this seemingly wasteful metabolic strategy, but its mechanistic basis remains unclear. Here we show glycolysis results from saturation mitochondrial decoupling biogenesis production other cellular components. Respiration insensitive to acute perturbations energetic demands or nutrient supplies, explained simply amount mitochondria per cell. Mitochondria accumulate at a nearly constant across different conditions, resulting largely determined cell division time. In contrast, glucose uptake not saturated, accurately predicted abundances affinities transporters. Combining these models provides quantitative, explanation glycolysis. The robustness specific biogenesis, paired flexibility bioenergetic biosynthetic fluxes, may play broad role shaping eukaryotic metabolism.

Language: Английский

Citations

0