MASLD-Mitochondrial Digital Twin: Mapping mitonuclear epistasis to predict disease trajectory and systemic bioenergetic homeostasis
- 1National Scientific and Technical Research Council , Ciudad Autonoma de Buenos Aires, C1425FQB ,
- 2Department of Systems Biology of Complex Diseases, Translational Research in Health Center-Maimonides University , Ciudad Autonoma de Buenos Aires, C1405BCK ,
- 3Department of Clinical and Molecular Hepatology, Translational Research in Health Center-Maimonides University , Ciudad Autonoma de Buenos Aires, C1405BCK ,
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.
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BibTeX
@article{pirola2026masldmitochondrial,
title = {{MASLD-Mitochondrial Digital Twin: Mapping mitonuclear epistasis to predict disease trajectory and systemic bioenergetic homeostasis}},
author = {Carlos José Pirola and Silvia Sookoian},
journal = {PNAS Nexus},
year = {2026},
month = oct,
doi = {10.1093/pnasnexus/pgag357},
url = {https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag357/8935257},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - MASLD-Mitochondrial Digital Twin: Mapping mitonuclear epistasis to predict disease trajectory and systemic bioenergetic homeostasis
AU - Carlos José Pirola
AU - Silvia Sookoian
PY - 2026
DA - 2026/10/17
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag357
UR - https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag357/8935257
AB - 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.
SN - 2752-6542
ER -