Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology DOI Creative Commons
Daniel Barnett, Till S. Zimmer, Caroline Booraem

et al.

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

Published: Aug. 20, 2024

Abstract Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors genetic manipulations together with imaging multiomic profiling, we found that CIII is dominant source astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS was dependent on nuclear factor-κB (NF-κB) sodium-calcium exchanger (NCLX) caused oxidation select cysteines within immune metabolism-associated proteins linked neurological disease. amplified metabolomic pathology-associated transcriptional changes astrocytes, STAT3 activity as a major mediator, facilitated neuronal toxicity non-cell- autonomous manner. As proof-of-concept, suppression mice decreased dementia-linked tauopathy neuroimmune cascades extended lifespan. Our findings establish an important immunometabolic signal transducer tractable therapeutic target neurodegenerative

Language: Английский

Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription DOI Creative Commons
Yu Zhang, Hang Song, Meili Li

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(3)

Published: March 1, 2024

Abstract Heightened lactate production in cancer cells has been linked to various cellular mechanisms such as angiogenesis, hypoxia, macrophage polarisation and T‐cell dysfunction. The lactate‐induced lactylation of histone lysine residues is noteworthy, it functions an epigenetic modification that directly augments gene transcription from chromatin. This originating effectively fosters a reliance on transcription, thereby expediting tumour progression development. Herein, this review explores the correlation between characteristics, revealing innovative process enhances vulnerability malignancy. Moreover, imperative acknowledge paramount importance acknowledging therapeutic methodologies for proficiently managing by precisely targeting signalling. comprehensive illuminates crucial yet inadequately investigated aspect lactylation, providing valuable insights into its clinical ramifications prospective interventions centred lactylation.

Language: Английский

Citations

17
The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging DOI Open Access
Eva Untersmayr, Annette Brandt, Larissa Koidl

et al.

Nutrients, Journal Year: 2022, Volume and Issue: 14(5), P. 949 - 949

Published: Feb. 23, 2022

The intestinal barrier, composed of the luminal microbiota, mucus layer, and physical barrier consisting epithelial cells immune cells, latter residing underneath within plays a special role in health disease. While there is growing knowledge on changes to different layers associated with disease development, function also an important during aging. Besides composition cellular junctions, entire gastrointestinal physiology contributes essential age-related changes. This reflected by substantial differences microbial throughout life span. Even though it remains difficult define physiological distinguish them from early signs pathologies, studies centenarians provide insights into features longevity. reviewed this narrative review article might contribute definition strategies prevent development diseases elderly. Thus, targeted interventions improve overall will be prevention for healthy aging future.

Language: Английский

Citations

55
Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling DOI Creative Commons
Jina Yun, Simon Hansen, Otto Morris

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 11, 2023

Abstract Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging age-related disease, SASP-related inflammation is thought to contribute tissue dysfunction diseased animals. However, whether how SASP factors influence regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model regeneration, we show that released by senescent fibroblasts deregulate stem cell activity differentiation ultimately impair crypt formation. We identify secreted N-terminal domain Ptk7 key component activates non-canonical Wnt / Ca 2+ signaling through FZD7 cells (ISCs). Changes cytosolic [Ca ] elicited promote nuclear translocation YAP induce expression YAP/TEAD target genes, impairing symmetry breaking differentiation. Our study discovers factor provides insight into mechanism which cellular contributes disease.

Language: Английский

Citations

31
EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation DOI Creative Commons

Chenge Zhang,

Yinhua Jin, Marco Marchetti

et al.

Current Biology, Journal Year: 2022, Volume and Issue: 32(17), P. 3704 - 3719.e7

Published: July 26, 2022

Language: Английский

Citations

36
The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore DOI Open Access
Hagai Rottenberg

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12295 - 12295

Published: Aug. 1, 2023

It is widely reported that the mitochondrial membrane potential, ∆Ψm, reduced in aging animals. was recently suggested lower ∆Ψm aged animals modulates bioenergetics and this effect a major cause of since artificially increased C. elegans lifespan. Here, I critically review studies reduction animals, including worms, conclude many these observations are best interpreted as evidence fraction depolarized mitochondria cells because enhanced activation permeability transition pore, mPTP. Activation voltage-gated mPTP depolarizes mitochondria, inhibits oxidative phosphorylation, releases large amounts calcium mROS, depletes cellular NAD+, thus accelerating degenerative diseases aging. Since inhibition shown to restore retard aging, lifespan extension by generated explained Similarly, unfolded protein response preservation dietary restriction treatment resulting from or mPTP, respectively.

Language: Английский

Citations

17
The serum small non‐coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults DOI Creative Commons
Mark A. Burton, Elie Antoun, Emma Garratt

et al.

The FASEB Journal, Journal Year: 2024, Volume and Issue: 38(3)

Published: Jan. 31, 2024

Abstract Small noncoding RNAs (sncRNAs) are implicated in age‐associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider sncRNA transcriptome older individuals associations with IR. expression miRNAs, transfer (tRNAs), tRNA‐associated fragments (tRFs), piwi‐interacting (piRNAs) was measured serum from 21 healthy sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) HOMA2‐IR. Associations age, HOMA2‐IR were examined predicted gene targets biological pathways characterized. Of total among controls, piRNAs abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), tRFs (0.5%). Age associated (FDR < 0.05) 2 58 tRNAs, 14 tRFs, chromatin organization, WNT signaling, response to stress enriched targets. nominally ( p .05) 12 3 6 piRNAs, target genes linked cell proliferation differentiation such as Notch Receptor 1 NOTCH1 ), DISC1 scaffold protein GLI family zinc finger‐2 GLI2 ). (p<0.05) 9 tRF, 19 lysine degradation, circadian rhythm, fatty acid biosynthesis pathways. These findings identify changes human chronological sarcopenia, may clinical utility biomarkers ageing pathologies provide novel therapeutic intervention.

Language: Английский

Citations

6
Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury DOI Creative Commons

Daniel Jun-Kit Hu,

Jina Yun, Justin Elstrott

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Dec. 9, 2021

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate positioning localized integration new cells into the damaged epithelium achieved, however, remains unclear. Here, we show enteroendocrine coordinate migration towards a wound Drosophila intestinal epithelium. In response to injury, release N-terminal domain PTK7 orthologue, Otk, which activates non-canonical Wnt signaling cells, promoting actin-based protrusion formation wound. We find this migratory behavior is closely linked proliferation, it required for efficient tissue repair during injury. Our findings highlight role epithelium, identify cell-released ligands as critical coordinators migration.

Language: Английский

Citations

40
An energetics perspective on geroscience: mitochondrial protonmotive force and aging DOI
Brandon J. Berry, Matt Kaeberlein

GeroScience, Journal Year: 2021, Volume and Issue: 43(4), P. 1591 - 1604

Published: April 17, 2021

Language: Английский

Citations

39
Reactive Oxygen Species in intestinal stem cell metabolism, fate and function DOI
Otto Morris, Heinrich Jasper

Free Radical Biology and Medicine, Journal Year: 2021, Volume and Issue: 166, P. 140 - 146

Published: Feb. 16, 2021

Language: Английский

Citations

38
Insect Gut Regeneration DOI Open Access
Peng Zhang, Bruce A. Edgar

Cold Spring Harbor Perspectives in Biology, Journal Year: 2021, Volume and Issue: 14(2), P. a040915 - a040915

Published: July 26, 2021

Peng Zhang1,2 and Bruce A. Edgar1,2 1Huntsman Cancer Institute, University of Utah; 2Department Oncological Sciences, Utah, Salt Lake City, Utah 84112, USA Correspondence: bruce.edgar{at}hci.utah.edu

Language: Английский

Citations

38