The mitochondrial genome (mtDNA) is a 16.5 kb circular, double-stranded DNA molecule present in hundreds to thousands of copies per cell. It encodes 37 genes: 13 protein subunits of the oxidative phosphorylation complexes, 22 transfer RNAs, and 2 ribosomal RNAs. Everything else a mitochondrion needs, over 1,000 proteins including the machinery that replicates and repairs mtDNA itself, is encoded in the nucleus and imported. That division of labor is the single most tested idea about this genome: most "mitochondrial disease" genes are nuclear, and those disorders follow Mendelian inheritance even though the organelle is the one failing.
- Compact organization. mtDNA has no introns and almost no intergenic space; the only sizable non-coding stretch is the D-loop (control region), which contains the origins of replication and the promoters. Both strands are transcribed as long polycistronic transcripts that are cut apart at the tRNAs punctuating the genome.
- High mutation rate. mtDNA mutates roughly 10 times faster than nuclear DNA: it sits next to the respiratory chain's reactive oxygen species, lacks protective histones, and has limited repair capacity. The D-loop's hypervariability is also why mtDNA serves forensic and lineage studies.
- Polyplasmy and heteroplasmy. Each cell carries many mtDNA copies. When mutant and wild-type molecules coexist (heteroplasmy), the biochemical phenotype appears only above a tissue-specific threshold mutant fraction, and high-energy tissues (brain, heart, skeletal muscle, retina, cochlea) fail first.
- Replicative segregation. mtDNA molecules are distributed randomly as cells divide, so the mutant fraction drifts between daughter cells and between tissues over a lifetime. The same variant can produce different severity in different tissues of one person.
- The germline bottleneck. Only a small subset of a primary oocyte's mtDNA molecules repopulates each mature egg, so a mother's heteroplasmy level can shift dramatically in a single generation. This is why recurrence risks for heteroplasmic variants are so hard to counsel and why siblings can differ so widely.
- Nuclear-mitochondrial crosstalk. Nuclear genes such as POLG and TWNK maintain mtDNA; their failure causes mtDNA depletion or multiple secondary deletions, inherited as autosomal traits. A "mitochondrial" biochemical picture therefore requires both genomes on the differential.
- Point variants in tRNA genes disable translation of all 13 mtDNA-encoded proteins at once, which is why single-nucleotide changes like m.3243A>G in MT-TL1 (MELAS) and m.8344A>G in MT-TK (MERRF) produce multisystem disease.
- Structural rearrangements. Single large-scale deletions cause Kearns-Sayre syndrome and Pearson syndrome; these are usually sporadic rather than maternally inherited, a distinction worth holding onto.
- Homoplasmic disease exists. LHON variants (m.11778G>A in MT-ND4 and relatives) are typically homoplasmic, with incomplete penetrance and a male bias, showing that heteroplasmy is not required for mtDNA disease.
- Testing implications. Heteroplasmy levels differ by tissue and can be missed in blood; muscle, urine sediment, or buccal cells may reveal what blood hides. Quantifying the mutant fraction matters for interpretation, and mtDNA copy-number assays detect the depletion syndromes caused by nuclear maintenance genes.
For the transmission pattern itself, maternal inheritance and what heteroplasmy does to recurrence risk and pedigrees, see Mitochondrial Inheritance.