article · Metabolomics
Pathogenic mitochondrial DNA mutations cause a wide range of metabolic diseases, but variable clinical presentations make their relationship with mutation load difficult to define. Using a controlled mouse model with an established mitochondrial DNA deletion, untargeted urinary metabolomics demonstrated progressive metabolic shifts that correspond to rising mutation burdens. Notably, specific metabolic changes emerged at a threshold of approximately sixty percent mutation load, which coincides with the onset of lactic acidemia and oxidative phosphorylation defects. When evaluating these alterations in human patients carrying the common m.3243A>G mutation, several urinary metabolites demonstrated matching trends across species. Among these, 2-hydroxyisovalerate showed the strongest disturbance in both mice and human subjects. Statistical analysis confirmed that urinary 2-hydroxyisovalerate possesses strong discriminatory power, establishing it as a promising candidate biomarker for tracking and identifying mitochondrial DNA-based disorders.
Mitochondrial genetic diseases are complex and difficult to track because patient symptoms vary widely even at similar mutation levels. Finding a reliable molecule in urine that mirrors disease severity in both animal models and humans provides a clearer view of underlying metabolic failure, helping scientists understand how mitochondrial dysfunction develops over time.
The discovery could enable non-invasive clinical diagnostic or monitoring tests for patients with mitochondrial DNA-based disorders. Diagnostics developers and clinical laboratories are the primary end users. The research is at an early translational stage, having confirmed strong discriminatory performance in human urine samples, but it requires further formal clinical validation studies before real-world diagnostic deployment.
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Pathogenic mitochondrial DNA (mtDNA) mutations contribute to a broad spectrum of both common and rare metabolic diseases. However, clinical presentation is highly variable and only partially explained by the proportion of mutant mtDNA or heteroplasmy. With the relationship between mutation burden and clinical manifestation poorly defined, controlled models are required to uncover underlying mechanisms. Here, we explore the metabolic consequences of increasing heteroplasmy in a well-characterised mouse model harbouring a pathogenic mtDNA deletion. Untargeted urinary metabolomics reveals distinct mutation load-dependent metabolic shifts with some metabolites declining early on, while others exhibit threshold-like increases beyond ~ 60% mutation load — the level at which lactic acidemia and OXPHOS defects become apparent in this model. To assess translational relevance, we examined these heteroplasmy-associated metabolites in urine from patients carrying the most common mtDNA mutation, m.3243 A > G. Several of these metabolites were differentially expressed in patients relative to controls, with conserved directionality across species. Among these, 2-hydroxyisovalerate (2-HIVA), which was most strongly affected in the mouse model, also emerged as the top discriminator in patients. Receiver operating characteristic analysis indicated that urinary 2-HIVA has strong discriminatory power, supporting its potential utility as a biomarker for mtDNA-based disorders. These findings enhance our understanding of mtDNA-related disease pathophysiology and establish a foundation for further validation studies. mtDNA mutation load in mice correlates with progressive metabolite shifts. ~60% heteroplasmy triggers OXPHOS-deficiency linked metabolic alterations in mice. Distinct mtDNA mutations in mice and humans cause shared urinary metabolite changes. 2-Hydroxyisovalerate is strongly perturbed in both Mito-mice and m.3243A>G patients. Urinary 2-HIVA is a promising biomarker candidate for mtDNA-based disorders.
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DOI: 10.1007/s11306-026-02518-1
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