Biology subjects

Pierga, A.

Publications and source records attributed to Pierga, A..

4 recordsLinked to original sources

bioRxiv2026

Loss of MTPAP disrupts mitochondrial RNA processing causing upregulation of type I interferon signalling

Mitochondrial poly-A polymerase (MTPAP) is essential for mitochondrial mRNA (mt-mRNA) polyadenylation, a critical step in mt-mRNA maturation. Mutations in MTPAP have been reported to cause a mitochondrial cytopathy. Here, we provide evidence of enhanced type I interferon (IFN) signalling in the blood of patients carrying mutations in MTPAP. Further, deletion of MTPAP in a fibroblast cell model led to abnormalities in mitochondrial respiration and mtRNA processing, and an upregulation of type I IFN signalling. Notably, both in patients fibroblast and in MTPAP-deleted cells, we observed the accumulation of non-coding mtRNA and mitochondrial double-stranded RNA (mt-dsRNA) within enlarged mitochondrial RNA granules. Cytosolic release of mt-dsRNA led to type I IFN induction mediated primarily by the RNA sensor MDA5 and its adaptor MAVS. Our findings reveal a novel consequence of MTPAP dysfunction, highlighting how impaired mtRNA maturation can drive innate immune system activation.

cell biology↗

bioRxiv2025

Epigenetic profile drives accurate survival prediction in breast cancer via a multi-omics machine learning model

Accurate overall survival (OS) prediction is key for personalized treatment in breast cancer, but mutation burden alone is insufficient. To improve prognostic accuracy, we integrated genomic, transcriptomic, proteomic, epigenetic, and clinical features from 802 breast cancer patients to develop BANDOL (Breast cancer Analysis with Neoplastic Data and Omics Learning), a Random Survival Forest model. BANDOL correctly predicted survival ranking in 73% of patient pairs and outperformed mutation-based models (time-dependent AUC: 0.9-1 vs. 0.4-0.9). Immune activation signatures correlated with a longer OS after therapy, while a shorter OS was linked to TREM2 myeloid cells, B cells, and leptin signaling. The transferability of the model was further explored in three independent TCGA cohorts from distinct cancer types (uterine, ovarian and lower-grade glioma), where moderate predictive performance was maintained despite biological differences between tumors. Epigenetic features were the strongest OS predictors for BANDOL. Current therapies may be combined with strategies to target the methylations of ME3, PPARG, OLIG3 and SLC25A22 genes. This study demonstrates that multi-omics integration via machine learning enhances survival prediction and reveals actionable biomarkers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/667894v6_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1f3efc6org.highwire.dtl.DTLVardef@2cff0org.highwire.dtl.DTLVardef@a1c3baorg.highwire.dtl.DTLVardef@392114_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Spatacsin regulates directionality of lysosome trafficking

The endoplasmic reticulum (ER) forms contacts with the lysosomal compartment, regulating lysosome positioning and motility. The movement of lysosomes are controlled by the attachment of molecular motors to their surface. However, the molecular mechanisms by which ER controls lysosome dynamics are still elusive. Here, we demonstrate that spatacsin is an ER-resident protein that regulates ER-lysosomes contacts to promote lysosome motility, shown by the presence of tubular lysosomes. Tubular lysosomes, which are highly dynamic, are entangled in a network of tubular ER. Screening for spatacsin partners required for tubular lysosome formation showed spatacsin to act by regulating protein degradation. We demonstrate that spatacsin promotes the degradation of its partner AP5Z1, which regulates the relative amount of spastizin and AP5Z1 at lysosomes. Spastizin and AP5Z1 contribute to lysosome trafficking by interacting with anterograde and retrograde motor proteins, kinesin KIF13A and dynein/dynactin subunit p150Glued, respectively. Ultimately, investigations in polarized neurons demonstrated that spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking. Collectively, our results identify spatacsin as a protein regulating the directionality of lysosome trafficking.

cell biology↗

bioRxiv2019

Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis

Mutations in SPG11, leading to loss of spatacsin function, impair the formation of membrane tubules in lysosomes and cause the accumulation of lipids in lysosome compartment. However, the full nature of lipids accumulating in lysosomes and the physiological consequences of such accumulation are not known. Here we show that loss of spatacsin, but also downregulation of clathrin, inhibited the formation of tubules on late endosomes/lysosomes and prevented the clearance of cholesterol from this subcellular compartment. Using spatacsin-deficient cells, we evaluated the consequences of impaired cholesterol clearance from late endosomes/lysosomes. The accumulation of cholesterol in late endosomes/lysosomes led to lower cholesterol levels in the plasma membrane, enhancing the entry of extracellular calcium by store-operated calcium entry and increasing resting cytosolic calcium levels. Higher cytosolic calcium levels promoted the nuclear translocation of the master regulator of lysosomes TFEB. Downregulation of TFEB or decrease in resting calcium levels in absence of spatacsin partially corrected the formation of tubules and the accumulation of cholesterol in lysosomes, suggesting that spatacsin could be indirectly implicated in the formation of tubules. Our work reveals a homeostatic balance between cholesterol trafficking and cytosolic calcium levels and shows that loss of spatacsin impairs this homeostatic equilibrium.

cell biology↗