Biology subjects

Slade, L.

Publications and source records attributed to Slade, L..

4 recordsLinked to original sources

bioRxiv2026

Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing

Identifying strategies to mitigate age-related physiological decline remains a central challenge. During ageing, the transcriptome undergoes extensive remodelling, but how this affects organismal health and lifespan is not well understood. The Integrator complex plays a central role in RNA polymerase II transcription and RNA 3' end processing. Surprisingly, we find that depletion of most Integrator subunits specifically in adults extends lifespan and healthspan in the nematode C. elegans. We show that loss of the catalytic subunit INTS-11 disrupts 3' end formation of small nuclear and spliced leader RNAs, impairing trans-splicing and promoting outron retention in a subset of transcripts enriched for spliceosomal and nucleocytoplasmic transport genes. These RNA-processing defects lead to altered levels of endogenous siRNAs, which are required for the longevity and healthspan benefits of INTS-11 depletion. In parallel, outron retention disrupts nuclear-encoded mitochondrial gene expression and protein production, inducing mitochondrial dysfunction and promoting lifespan extension. We also demonstrate that loss of INTS-11 perturbs transcription elongation at genes where Integrator is present at promoters, and that upregulation of enhancer elements within intragenic regions can affect the expression and isoform usage of nearby genes. Together, our findings identify Integrator as a key upstream regulator of non-coding RNA transcription, which in turn impacts protein-coding gene expression and mitochondrial function to shape the ageing process.

cell biology↗

bioRxiv2025

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca{superscript 2}-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

cancer biology↗

bioRxiv2021

Inhibiting BCKDK in triple-negative breast cancer suppress protein translation, impair mitochondrial function, and potentiate doxorubicin cytotoxicity

Triple-negative breast cancers (TNBCs) are characterized by poor survival, prognosis and gradual resistance to cytotoxic chemotherapeutics, like doxorubicin (DOX), which is limited by its cardiotoxic and chemoresistant effects that manifest over time. TNBC growth and survival are fuelled by reprogramming branched-chain amino acids (BCAAs) metabolism, which rewires oncogenic gene expression and cell signaling pathways. A regulatory kinase of the rate-limiting enzyme of the BCAA catabolic pathway, branched-chain ketoacid dehydrogenase kinase (BCKDK), have recently been implicated in driving tumor cell proliferation and conferring drug resistance by activating RAS/RAF/MEK/ERK signaling. However it remains unexplored if BCKDK remodels TNBC proliferation, survival and susceptibility to DOX-induced genotoxic stress. TNBC cell lines exhibited reduced BCKDK expression in response to DOX. Genetic and pharmacological inhibition of BCKDK in TNBC cell lines displayed reduced intracellular and secreted BCKAs. Moreover, BCKDK inhibition with concurrent DOX treatment exacerbated apoptosis, caspase activity and loss of TNBC proliferation. Transcriptome analysis of BCKDK silenced cells confirmed a marked upregulation of the apoptotic signaling pathway with increased protein ubiquitylation and compromised mitochondrial metabolism. BCKDK silencing in TNBC downregulated mitochondrial metabolism genes, reduced electron complex protein expression, oxygen consumption and ATP production. Silencing BCKDK in TNBC upregulated sestrin 2 and concurrently decreased protein synthesis and mTORC1 signaling. Inhibiting BCKDK in TNBC remodel BCAA flux, reduces protein translation triggering cell death, ATP insufficiency and susceptibility to genotoxic stress. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/444634v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@19d375eorg.highwire.dtl.DTLVardef@9dfe2corg.highwire.dtl.DTLVardef@9a1eecorg.highwire.dtl.DTLVardef@642fdb_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Studies of human twins reveal genetic variation that affects dietary fat perception

To learn more about the mechanisms of human dietary fat perception, 398 human twins rated fattiness and liking for six types of potato chips that differed in triglyceride content (2.5, 5, 10, and 15% corn oil); reliability estimates were obtained from a subset (n = 50) who did the task twice. Some chips also had a saturated long-chain fatty acid (hexadecanoic acid, 16:0) added (0.2%) to evaluate its effect on fattiness and liking. We computed the heritability of these measures and conducted a genome-wide association study (GWAS) to identify regions of the genome that co-segregate with fattiness and liking. Perceived fattiness and liking for the potato chips were reliable (r = 0.31-0.62, p < 0.05) and heritable (up to h2 = 0.29, p < 0.001, for liking). Adding hexadecanoic acid to the potato chips significantly increased ratings of fattiness but decreased liking. Twins with the G allele of rs263429 near GATA3-AS1 or the G allele of rs8103990 within ZNF729 reported more liking for potato chips than did twins with the other allele (multivariate GWAS, p < 1x10-5), with results reaching genome-wide suggestive but not significance criteria. Person-to-person variation in the perception and liking of dietary fat was (a) negatively affected by the addition of a saturated fatty acid and (b) related to inborn genetic variants. These data suggest liking for dietary fat is not due solely to fatty acid content and highlight new candidate genes and proteins within this sensory pathway.

genetics↗