Evaluation of endpoints for the study and diagnosis of mitochondrial toxicity and disease: a narrative review
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Published on: September 16, 2020
Prashamsa Gharti1, Jessica F Fletcher1, Katherine E Chapman1
1Swansea University Medical School, Swansea University, Swansea, SA2 8PP, UK.
Abstract:
Mitochondrial DNA mutation and toxicity have been linked to several inherited and acquired diseases; however, these are challenging to diagnose and characterize due to clinical and genetic heterogeneity. This review investigates current techniques for the analysis of mitochondrial perturbations, and novel, emerging endpoints for routine application within the clinical setting. Particular focus is given to the biochemistry of the mitochondria influencing each endpoint and the relation of these to toxicity. Current approaches such as the use of metabolic markers (e.g. lactate production), and muscle biopsies to measure mitochondrial proteins were found to lack specificity. Newly emerging identified endpoints were: fibroblast growth factor-21, glucose uptake, mitochondrial membrane potential, mitochondrial morphology, mtDNA heteroplasmy, and mutation of mtDNA and nuclear DNA. Owed to the advancement in genetic analysis techniques, it is suggested by this review that genotypic endpoints of mtDNA mutation and heteroplasmy show particular promise as indicators of mitochondrial disease. It is, however, acknowledged that any single endpoint in isolation offers limited information; therefore, it is recommended that analysis of several endpoints simultaneously will offer the greatest benefit in terms of disease diagnosis and study. It is hoped that this review further highlights the need for advancement in understanding mitochondrial disease.
Insights
Mitochondrial DNA mutations cause diseases that are hard to diagnose. New genetic tests for mitochondrial DNA mutations and heteroplasmy show promise for better diagnosis.
Area of Science:
- Biochemistry
- Genetics
- Toxicology
Background:
- Mitochondrial DNA (mtDNA) mutations and toxicity are implicated in various inherited and acquired diseases.
- Clinical and genetic heterogeneity complicates the diagnosis and characterization of these conditions.
- Current diagnostic methods often lack specificity.
Approach:
- This review examines existing techniques for analyzing mitochondrial dysfunction.
- It investigates novel, emerging endpoints for clinical application.
- The review focuses on mitochondrial biochemistry, its influence on endpoints, and toxicity relationships.
Key Points:
- Established methods like lactate production and muscle biopsy lack specificity.
- Emerging endpoints include fibroblast growth factor-21, glucose uptake, membrane potential, morphology, and mtDNA/nuclear DNA mutations.
- Genotypic endpoints, specifically mtDNA mutation and heteroplasmy, show significant diagnostic potential due to advanced genetic analysis.
Conclusions:
- A combination of multiple endpoints is recommended for comprehensive diagnosis and study.
- Further research is needed to advance the understanding and diagnosis of mitochondrial diseases.
- Emerging genotypic markers offer a promising avenue for improved clinical assessment.
