Mitochondrial Disease - Causes

Causes and Genetics — Navigating Dual-Genome Inheritance

Introduction

Mitochondrial diseases are genetically complex because they can be caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Understanding inheritance patterns and mitochondrial biology is crucial for accurate diagnosis and counseling.

mtDNA Mutations: Maternal Inheritance

• Maternally inherited: mtDNA is passed from mothers to all their children; only daughters pass it onward.

• Heteroplasmy: Cells can carry both normal and mutated mtDNA. The mutation load—the percentage of mutated mtDNA—and its uneven distribution across tissues determine if, when, and how symptoms appear.

• Threshold effect: Disease manifests when the proportion of defective mitochondria in a tissue exceeds a critical threshold needed for normal function.

Examples of mtDNA-related disorders:

• MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes

• LHON: Leber’s Hereditary Optic Neuropathy

• MERRF: Myoclonus Epilepsy with Ragged-Red Fibers

nDNA Mutations: Mendelian Patterns

Mutations in nuclear genes that:

• Build respiratory chain components

• Assemble and maintain mitochondrial complexes

• Preserve mtDNA integrity (e.g., POLG variants causing Alpers-Huttenlocher syndrome)

• Regulate fusion and fission (mitochondrial dynamics)

These follow classic inheritance:

• Autosomal recessive

• Autosomal dominant

• X-linked

Examples:

• POLG-related disorders (mtDNA replication defects)

• Friedreich’s ataxia (mitochondrial protein frataxin involved in iron-sulfur cluster biogenesis)

• Complex I deficiency and other respiratory chain defects

Acquired Mitochondrial Dysfunction

Secondary mitochondrial dysfunction emerges in:

• Aging

• Common diseases such as Parkinson’s, Alzheimer’s, type 2 diabetes, and heart failure

These are not primary mitochondrial diseases but share mitochondrial involvement.

Genetic Counseling Considerations

• Family planning: The maternal inheritance of mtDNA has unique generational implications.

• Variable expressivity: Even within families, severity varies due to heteroplasmy and tissue distribution.

• Testing strategies: Guided by phenotype, family history, and suspected inheritance pattern.

Conclusion

Mitochondrial diseases reflect a complex interplay between two genomes. Recognizing maternal inheritance (mtDNA), Mendelian nuclear genetics (nDNA), and acquired dysfunction is key to diagnosis, risk assessment, and counseling.