MASLD-Mitochondrial Digital Twin: Mapping mitonuclear epistasis to predict disease trajectory and systemic bioenergetic homeostasis

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ID: 332637
2026
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Abstract
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic disorder with marked clinical heterogeneity and divergent outcomes. Current pathophysiological models fail to fully account for inter-individual variation in progression toward steatohepatitis and systemic multimorbidity. This Perspective posits the mitochondrion as an integrative functional hub where genomic predisposition, epigenomic plasticity, and bioenergetic signaling converge to shape the disease's longitudinal trajectory. We synthesize evidence from the mitonuclear interactome—the co-evolutionary and functional coordination between nuclear and mitochondrial genomes, hepatic epigenomic remodeling, and circulating mitochondrial metabotypes to propose a unified systems biology framework: the MASLD-Mitochondrial Digital Twin (MASLD-MDT). This multiscale platform integrates high-resolution biological data—including single-cell mitochondrial DNA (mtDNA) heteroplasmy, NAD+ redox dynamics, and the systemic efflux of mitochondrial-derived peptides (MDPs)—to simulate individualized disease kinetics. By reframing MASLD as a systemic mitochondriopathy, the MASLD-MDT could quantify critical bioenergetic thresholds, providing a novel metric for risk stratification and the in silico optimization of therapeutic deployment. This hypothesis-oriented instrument aims to advance the field toward a mitochondrial precision medicine strategy, enabling the discovery of targeted interventions to intercept multi-organ compromise.
Reference Key
openalex_W7222838224 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Carlos Jose Pirola, Silvia C. Sookoian
Journal PNAS nexus
Year 2026
DOI
10.1093/pnasnexus/pgag357
URL
https://doi.org/10.1093/pnasnexus/pgag357
Keywords Keywords not found

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