Biology subjects

Procaccio, V.

Publications and source records attributed to Procaccio, V..

6 recordsLinked to original sources

bioRxiv2025

nAPOGEE: A machine-learning platform for clinically actionable pathogenicity assessment of all mitochondrial noncoding variants

Mitochondrial noncoding variants, particularly those in tRNA and rRNA genes, pose significant challenges for clinical interpretation due to heteroplasmy, broad phenotypic heterogeneity where symptoms can overlap with other conditions, and the limited availability of well-established genotype-phenotype correlations. Despite their central role in mitochondrial translation, these variants have remained largely unexplored by the existing variant-effect predictors. Here, we present nAPOGEE, a novel machine-learning framework specifically designed to assess the pathogenicity of all possible single-nucleotide variants in human mitochondrial noncoding RNAs. nAPOGEE integrates two specialized predictors: tAPOGEE, which outperforms existing tools for tRNAs, and rAPOGEE, the first dedicated classifier for mitochondrial rRNA variants. Using curated training datasets, phylogenetic conservation metrics, secondary structure modeling, RNA-specific embeddings, and thermodynamic features, nAPOGEE provides biologically interpretable predictions and posterior probabilities aligned with the ACMG/AMP guidelines. Applied to both curated variant sets and population-scale data, nAPOGEE revealed consistent spatial correlation of the predicted pathogenicity, reflecting underlying structural and evolutionary constraints. This study addresses a longstanding gap in mitochondrial genomics and offers a clinically applicable tool for variant prioritization, reclassification, and research into mitochondrial disease mechanisms.

bioinformatics↗

bioRxiv2023

APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants

APOGEE 2 is a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP), APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2s ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.

bioinformatics↗

bioRxiv2022

Chronic Glucocorticoid Stress Reveals Increased Energy Expenditure and Accelerated Aging as Cellular Features of Allostatic Load

Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by [~]60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.

cell biology↗

bioRxiv2021

OxPhos Dysfunction Causes Hypermetabolism and Reduces Lifespan in Cells and in Patients with Mitochondrial Diseases

Patients with primary mitochondrial diseases present with fatigue and multi-system disease, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. Integrating data from 17 cohorts of patients with mitochondrial diseases (n=690), we find that clinical mitochondrial disorders increase resting energy expenditure, a state termed hypermetabolism. In a longitudinal cellular model of primary patient-derived fibroblasts from multiple donors, we show that genetic and pharmacological disruptions of oxidative phosphorylation (OxPhos) similarly trigger increased energy consumption in a cell-autonomous manner, despite near-normal OxPhos coupling efficiency. Hypermetabolism is associated with mtDNA instability, activation of the integrated stress response, increased extracellular secretion of age-related cytokines and metabokines including GDF15, as well as an accelerated rate of telomere erosion and epigenetic aging, and a reduced Hayflick limit. Together with these dynamic measures, we have generated a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations in response to OxPhos dysfunction. The increased energetic cost of living, or hypermetabolism, in cells and organisms with OxPhos defects has important biological and clinical implications.

cell biology↗

bioRxiv2021

A Multi-Omics and Bioenergetics Longitudinal Aging Dataset in Primary Human Fibroblasts with Mitochondrial Perturbations

Aging is a process of progressive change. In order to develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omic longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n=6) and individuals with lifespan-shortening mitochondrial disease (n=3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the "hallmarks of aging", with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/

cell biology↗

bioRxiv2019

Nicotinamide Deficiency In Primary Open-Angle Glaucoma

PurposeTo investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG).\n\nMethodsPlasma of 34 POAG individuals were compared to that of 30 age-and sex-matched controls using a semi-quantitative method based on liquid chromatography coupled to high-resolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls.\n\nResultsUsing the semi-quantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 {micro}M (median: 0.12 {micro}M; range: 0.06-0.28 {micro}M) in the POAG group (-30 %; p = 0.022), and 0.19 {micro}M (median: 0.18 {micro}M; range: 0.08-0.47 {micro}M) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (-33 %; p = 0.011) in the replicative cohort with mean concentrations of 0.14 {micro}M (median: 0.14 {micro}M; range: 0.09-0.25 {micro}M) in the POAG group, and 0.19 {micro}M (median: 0.21 {micro}M; range: 0.09-0.26 {micro}M) in the control group.\n\nConclusionsGlaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.

biochemistry↗