Molecular Biology
Mitochondrial DNA
A 16.5 kb circular genome inherited from your mother, your grandmother, your great-grandmother — every generation, only matrilineal
Mitochondrial DNA is a small circular genome — 16,569 base pairs in humans — that lives inside mitochondria and encodes 37 genes: 13 proteins of the respiratory chain, 22 tRNAs, and 2 rRNAs. It descends, with rare exception, only from the mother. It mutates about ten times faster than nuclear DNA, exists in many copies per cell (heteroplasmy), and underlies a distinct class of human disease whose inheritance pattern looks like nothing else in genetics. Its rapid clock made it the molecular tool for tracing matrilineal ancestry — and for naming Mitochondrial Eve, the woman from whom every human alive today inherits their mtDNA.
- Size16,569 bp circular (human)
- Genes13 proteins, 22 tRNAs, 2 rRNAs (37 total)
- InheritanceStrictly maternal (rare paternal leakage)
- Copies per cell100s to 1000s — heteroplasmic
- Mutation rate~10-20× nuclear DNA
- Mitochondrial Eve~150-200 kya, Africa
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A circular relic of a free-living bacterium
Mitochondria descend from a free-living α-proteobacterium engulfed by an ancestral eukaryote about 1.5 billion years ago (the endosymbiotic theory, championed by Lynn Margulis). The original endosymbiont had thousands of genes; most were lost or transferred to the host nucleus. What remains encodes only the most hydrophobic, hardest-to-import respiratory-chain subunits and the translation machinery to make them in place.
Human mtDNA is 16,569 bp of double-stranded circular DNA. The two strands differ in base composition enough to separate by CsCl buoyant density — the heavy (H) strand is G-rich, the light (L) strand C-rich. Most genes live on H. There are essentially no introns, no spacer regions, and some genes overlap by a single base.
╭──── D-loop ────╮ (control region, ~1 kb,
/ origin of H-rep \ promoters + ori-H)
│ 12S, 16S rRNAs │
│ ND1-6, ND4L │ ← complex I (7 subunits)
│ CYTB │ ← complex III (1)
│ COX1, COX2, COX3 │ ← complex IV (3)
│ ATP6, ATP8 │ ← complex V (2)
│ 22 tRNAs as │
│ "punctuation" │
│ between genes │
\ /
╰─────────────────╯The 13 protein genes encode 7 of complex I (ND1-6, ND4L), 1 of complex III (CYTB), 3 of complex IV (COX1-3), and 2 of complex V (ATP6, ATP8). Complex II (succinate dehydrogenase) is entirely nuclear-encoded — convenient in clinical genetics, because complex-II disorders never show maternal inheritance.
The D-loop and replication
The single non-coding region is the D-loop (displacement loop), ~1.1 kb, containing both H- and L-strand promoters and the origin of H-strand replication (ori-H). In the classic strand-displacement model (Vinograd, 1972), DNA polymerase γ starts at ori-H and synthesizes a new H strand around the whole circle, displacing the parental H into a triple-strand D-loop intermediate. Only when synthesis reaches ori-L (about two-thirds around) does L-strand synthesis begin in the opposite direction. The replication machine is entirely nuclear-encoded: POLG (polymerase γ), TWINKLE (helicase), mtSSB.
The D-loop is also the most variable region of the genome — hypervariable HV1/HV2 mutate fast enough to differentiate close relatives, the basis of forensic mtDNA ID and consumer matrilineal-ancestry tests.
A slightly different genetic code
Mitochondrial translation uses a modified table: UGA = Trp (standard: stop); AUA = Met (standard: Ile); AGA/AGG = stop (standard: Arg). The 22 mtDNA-encoded tRNAs are the smallest set known (vs ~31 cytosolic) thanks to permissive third-position wobble. Different lineages have different reassignments — the mitochondrial code evolved repeatedly and independently from a bacterial ancestor.
Mitochondrial DNA vs nuclear DNA
| Mitochondrial DNA | Nuclear DNA | |
|---|---|---|
| Topology | Circular, double-stranded | Linear chromosomes (46 in humans), telomere-capped |
| Size | 16,569 bp (one circle) | ~3.2 × 10⁹ bp (across 22 + X + Y) |
| Genes | 37 (13 proteins, 22 tRNAs, 2 rRNAs) | ~20,000 protein-coding + many ncRNAs |
| Copies per cell | 100s to 1000s — heteroplasmic | 2 (one maternal, one paternal — except gametes) |
| Inheritance | Strictly maternal (with rare exception) | Mendelian — both parents |
| Packaging | TFAM (no histones); nucleoid-organized | Histones, nucleosomes, chromatin levels |
| Mutation rate | ~10⁻⁷ per bp per generation | ~10⁻⁸ per bp per generation |
| Genetic code | Modified (UGA = Trp, AGA/AGG = stop) | Standard universal code |
| Introns | None in mammals | Most genes contain them |
| Recombination | Effectively none in animals | Yes — in meiosis |
Mitochondrial diseases
Inheritance is strictly maternal; affected fathers never transmit. Tissues most dependent on oxidative metabolism (muscle, brain, heart, retina, cochlea) are most affected. Severity scales with heteroplasmy — most mutations have a clinical threshold around 60-90%.
- LHON. Leber hereditary optic neuropathy. Sudden bilateral central vision loss in young men. Three classic complex I mutations: m.3460G>A (ND1), m.11778G>A (ND4), m.14484T>C (ND6). Retinal ganglion cells are uniquely vulnerable to complex I impairment.
- MELAS. Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes. Most often m.3243A>G in MT-TL1 (leucine tRNA). Stroke-like lesions cross vascular territories — regions of high metabolic demand failing.
- MERRF. Myoclonic epilepsy with ragged-red fibers. Most often m.8344A>G in MT-TK (lysine tRNA). Ragged-red fibers visible by Gomori trichrome.
- NARP / Leigh syndrome. Neuropathy/ataxia/retinitis at lower load; subacute necrotizing encephalomyelopathy at higher load. Typically m.8993T>G in ATP6. Same mutation, threshold-determined phenotype.
- Kearns-Sayre / CPEO. Large mtDNA deletions; progressive ptosis, ophthalmoplegia, heart block (KSS), retinitis pigmentosa.
- Aminoglycoside ototoxicity. Carriers of m.1555A>G in MT-RNR1 (12S rRNA) deafen on aminoglycosides — the mutation makes the mitoribosome bacterial-like enough that the antibiotic binds.
Many "mitochondrial" diseases are caused by nuclear genes affecting mtDNA maintenance (POLG, TWINKLE) or imported proteins.
Mitochondrial Eve and the molecular clock
Because mtDNA is maternal and non-recombining, every living human's mtDNA traces back through an unbroken female line to a single woman — Mitochondrial Eve, the most recent matrilineal common ancestor. Her existence is guaranteed by the coalescent: any sample of mtDNAs has a most recent common ancestor.
The 1987 paper (Cann, Stoneking, Wilson, Nature) sequenced mtDNA from 147 women and inferred coalescence ~200,000 years ago in Africa. The estimate is robust: 150-200 kya. Eve is not "the first woman" — many contemporary women lived; we descend from many of them through nuclear DNA. She is simply the matrilineal coalescent point. The Y-chromosome analog ("Y-chromosomal Adam") need not have lived contemporaneously.
Why mitochondrial DNA matters
- Inherited disease. A class of disease — maternal, threshold-dependent — that only makes sense once you know mtDNA exists.
- Forensic ID. High copy number lets mtDNA be recovered from old or hair-shaft samples. Tsar Nicholas II's remains were identified by mtDNA match to Prince Philip.
- Phylogenetics. Fast clock dates Neanderthal-modern divergence at ~500 kya by mtDNA.
- Population genetics. Mitochondrial Eve, haplogroup migrations, the peopling of the Americas — all from mtDNA.
- Aging research. Mutator mice (POLG with disabled proofreading) accumulate mtDNA mutations and show premature aging.
- Mitochondrial replacement therapy. Three-parent IVF for severe mutations — legal in the UK since 2015.
Common misconceptions
- mtDNA encodes all mitochondrial proteins. Only 13. The other ~1,200 are nuclear-encoded and imported.
- Every cell has 1-2 mtDNA copies. Hundreds to thousands; oocytes have 100,000+.
- mtDNA uses the standard code. Mammalian mtDNA differs in four codons.
- Mitochondrial Eve is the only female ancestor. Most recent matrilineal — many contemporaries contributed nuclear DNA.
- Sperm mtDNA contributes. Almost never — sperm mitochondria are actively destroyed after fertilization.
Frequently asked questions
How big is the human mitochondrial genome and what does it encode?
16,569 bp circular dsDNA (Cambridge Reference Sequence, Anderson 1981). Encodes 37 genes: 13 proteins (all OXPHOS subunits — 7 of complex I, 1 of complex III, 3 of complex IV, 2 of ATP synthase), 22 tRNAs, and 2 rRNAs (12S, 16S). The other ~1,200 mitochondrial proteins are nuclear-encoded, made on cytosolic ribosomes, and imported via TOM/TIM.
Why is mitochondrial DNA inherited only from the mother?
An egg cell contains hundreds of thousands of mitochondria; a sperm cell contributes only its nucleus, with the few sperm mitochondria packed in the midpiece getting actively destroyed after fertilization. In humans, sperm mitochondria are tagged with ubiquitin and degraded by the proteasome; in C. elegans, autophagy of paternal mitochondria has been visualized directly. The result is strict maternal inheritance — an mtDNA variant in your mother is in you and in all your siblings; your father's mtDNA is gone. Rare exceptions exist (a 2018 paper documented paternal transmission in a few human pedigrees) but maternal inheritance is the rule.
What is heteroplasmy?
Each cell has hundreds to thousands of mtDNA copies. If they are all identical the cell is homoplasmic; if some carry a mutation and others do not, the cell is heteroplasmic. Mitochondrial diseases typically have a threshold effect — symptoms only appear when mutant load exceeds 60-90% of mtDNA copies, depending on the mutation and tissue. Heteroplasmy levels vary across tissues (often higher in muscle and brain) and across generations because of the mitochondrial bottleneck during oogenesis, when only a small subset of mtDNA seeds the next generation.
Why does mtDNA mutate faster than nuclear DNA?
About 10-20× faster. Three reasons: ROS generated at the inner membrane bathe mtDNA in mutagens; mtDNA is not histone-packaged (only TFAM-coated); pol γ has weaker proofreading and the matrix lacks elaborate NER. The high mutation rate is what makes mtDNA useful for forensic ID, deep phylogenetics, and tracing maternal lineage to Mitochondrial Eve.
What is Mitochondrial Eve?
The most recent woman from whom every living human inherits their mtDNA in an unbroken female line. Lived in Africa ~150-200 kya. Not the only female ancestor — many contemporary women contributed nuclear DNA. She is the matrilineal coalescent point; everyone else's mtDNA lineage went extinct (daughters had only sons, or genetic drift). The Y-chromosome analog (Y-chromosomal Adam) need not have lived contemporaneously.
What is mitochondrial replacement therapy?
"Three-parent IVF." For women carrying severe mtDNA mutations, the egg's nucleus is transferred into a donor's enucleated egg with healthy mitochondria, then fertilized in vitro. The resulting embryo has the intended mother's nuclear DNA and the donor's mtDNA. The UK legalized maternal spindle transfer and pronuclear transfer in 2015; the first reported case was a child born in Mexico in 2016 to avoid Leigh syndrome. Long-term safety remains an active research question — small carryover of mutant mtDNA can sometimes amplify in subsequent generations.
How does mtDNA differ in plants and fungi?
Plants have larger mitochondrial genomes (200 kb to several megabases) with substantial repetitive sequence and many gene rearrangements; they often contain RNA editing systems that change C to U at specific transcript positions. Fungal mtDNA varies enormously — Saccharomyces cerevisiae mtDNA is ~85 kb but encodes a similar gene set to mammals because most of it is intergenic. Trypanosomes have an extraordinary "kinetoplast" of catenated mini- and maxi-circles with extensive RNA editing. The 16.5 kb tightly packed mammalian mtDNA is unusually compact, not representative.