The mitochondrial genome — 16,569 base pairs that power every cell. When these genes fail, the consequences are devastating and complex.
Every human cell contains hundreds to thousands of mitochondria, each carrying 2-10 copies of a small, circular genome (mtDNA). At just 16,569 base pairs, the mitochondrial genome encodes 37 genes: 13 proteins of the electron transport chain, 22 tRNAs, and 2 rRNAs. It is maternally inherited, has no introns, minimal non-coding sequence, and a mutation rate 10-17 times higher than nuclear DNA.
What makes mitochondrial genetics unique is heteroplasmy — the coexistence of mutant and wild-type mtDNA within a single cell. The proportion of mutant molecules determines disease severity, creating a threshold effect: symptoms typically appear when mutant load exceeds 60-90% depending on the tissue and mutation.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Usually m.3243A>G in MT-TL1. Heteroplasmy determines severity.
Leber hereditary optic neuropathy. Painless bilateral vision loss, typically in young men. Three primary mutations account for ~95% of cases.
Progressive neurodegenerative disorder of infancy. Can be caused by mutations in mtDNA or nuclear-encoded mitochondrial genes.
Myoclonic epilepsy with ragged red fibers. m.8344A>G in MT-TK. Progressive myoclonus, seizures, ataxia, and myopathy.
Mitochondrial sequencing requires specialized approaches beyond standard exome/genome. Dedicated mtDNA sequencing achieves deep coverage (>1000x) necessary to detect low-level heteroplasmy. Long-range PCR followed by next-generation sequencing can detect heteroplasmy as low as 1-3%. For nuclear-encoded mitochondrial genes (~1,500 genes), comprehensive nuclear + mitochondrial genome analysis is required.
Tissue selection matters profoundly: a mutation undetectable in blood may be present at high levels in muscle, urine sediment, or buccal cells. Muscle biopsy remains the gold standard tissue for mitochondrial disease evaluation.