Impact of mtDNA Signature on Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Progression and Cardiometabolic Outcomes in Mice

Abstract

Cardiometabolic diseases (CMDs) are a major global health burden, with metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as both a prevalent comorbidity and an independent risk factor for adverse outcomes. While diet and lifestyle are established contributors, variation in mitochondrial DNA (mtDNA) has been linked to differences in bioenergetic function, oxidative stress, and disease susceptibility. Given mitochondria’s central role in metabolism and their unique maternal genomes, mtDNA haplotypes, shaped by evolutionary adaptation, may influence CMDs onset and progression, yet this relationship remained poorly defined. This thesis first reviews MASLD pathophysiology, diagnostic challenges, and epidemiological trends, highlighting the interplay of lipid accumulation, oxidative injury, and inflammatory signalling in progression towards steatohepatitis, fibrosis, and hepatocellular carcinoma. A review of preclinical models identified the Mitochondrial-Nuclear eXchange (MNX) mouse as a robust tool for isolating mtDNA effects from nuclear genetic background. The experimental study uses wildtype and MNX mice carrying distinct mtDNA signatures, exposed to control or Western-style diets over three, six, twelve, and eighteen weeks. Morphometric, biochemical, histological, and glucose homeostasis assessments revealed that mtDNA background influenced hepatic lipid deposition and glucose regulation. These findings indicate that mtDNA variation modulates disease onset and trajectory under dietary stress in mice. Collectively, this work integrates clinical context, preclinical model evaluation, and novel experimental evidence to link mitochondrial genetics with CMDs pathophysiology. Results highlight mtDNA as a potential determinant of MASLD susceptibility, supporting future mechanistic studies and the development of precision medicine approaches for metabolic disease prevention and management.