Mitochondrial DNA

Mitochondrial DNA (mtDNA) is the genetic material located within the mitochondria, the energy-producing organelles found in virtually all eukaryotic cells. These organelles convert chemical energy from nutrients into adenosine triphosphate (ATP), and their genomes encode essential components of the oxidative phosphorylation system. In contrast to the much larger nuclear genome, mtDNA represents only a small fraction of a cell’s total DNA content. In plants and algae, additional genetic material is also located in plastids such as chloroplasts.
Human mtDNA was the first substantial portion of the human genome to be fully sequenced, revealing a circular molecule of 16,569 base pairs that encodes 13 protein subunits of oxidative phosphorylation, along with 22 transfer RNAs and 2 ribosomal RNAs. The mitochondrial genome plays a central role in evolutionary biology because it evolves more rapidly than nuclear DNA in most animals and is inherited maternally, allowing detailed tracing of population histories and phylogenetic relationships.

Origin and evolutionary context

Nuclear and mitochondrial genomes have distinct evolutionary origins. According to the endosymbiotic theory, mitochondria arose when ancestral eukaryotic cells engulfed free-living bacteria. Over evolutionary time, most genes originally carried in the bacterial genome were transferred to the nuclear genome, leaving the mitochondria with a greatly reduced but still essential set of genes. Modern mammalian mitochondria contain approximately 1,500 proteins, nearly all of which are encoded by nuclear DNA and imported into the organelle.
Why mitochondria retain a small number of genes remains a subject of research. Some hypotheses include:

• Hydrophobicity constraints: highly hydrophobic proteins encoded by mtDNA may be difficult to import if synthesised in the cytosol.
• Local control (CoRR hypothesis): retaining certain genes allows direct coupling of gene expression to mitochondrial redox state.
• Lineage-specific patterns: analyses across eukaryotes indicate that both protein hydrophobicity and redox regulation influence gene retention.

Intriguingly, some mitochondrion-related organelles in anaerobic species have completely lost their genomes, demonstrating that full gene loss is possible under specific selective conditions.

Genome structure and diversity

Across eukaryotes, mitochondrial genomes display remarkable structural diversity. They can be circular or linear, with variations in size, organisation, intron content, and the number of DNA molecules present. Six major genome types are recognised based on these structural features.
AnimalsMost bilaterian animals possess small, circular mitochondrial genomes of around 16,000 base pairs. Typically, animal mtDNA contains 37 genes: 13 for proteins, 22 for tRNAs, and 2 for rRNAs. Some lineages, such as Medusozoa and certain calcareous sponges, possess linear mtDNA. Extremes of genome size include:

• Isarachnanthus nocturnus (anemone): ~80,923 bp, the largest known animal mtDNA
• Vallicula multiformis (comb jelly): ~9,961 bp, among the smallest
• Henneguya salminicola: a parasite lacking a mitochondrial genome entirely, demonstrating a complete loss of aerobic respiration

Plants and fungiPlant and fungal mtDNAs are highly variable, with circular or linear genomes ranging from about 19 kbp to more than 1 Mbp. Some species possess multiple autonomous molecules; for example, the cucumber (Cucumis sativus) mitochondrial genome comprises three circular chromosomes. Enormous plant mtDNAs, such as the ~11.3 Mbp genome in Silene conica, may contain expanded non-coding regions yet encode similar gene complements to relatives with far smaller genomes.
ProtistsProtists show the greatest diversity. Their mtDNAs may consist of heterogeneous collections of circular or linear molecules, spanning from a few kilobases to over a megabase. The smallest known mitochondrial genome, at 5,967 bp, belongs to the parasite Plasmodium falciparum. This diversity reflects widely differing metabolic strategies and evolutionary histories.
Endosymbiotic gene transfer—movement of genes from the mitochondrial genome to the nucleus—helps explain why complex organisms often have smaller mtDNAs than unicellular protists.

Replication and inheritance

MtDNA is typically inherited maternally, as mitochondria present in the egg cytoplasm pass to the embryo. In humans, the two strands of mtDNA are designated the heavy (H) and light (L) strands due to their differing nucleotide composition. A major non-coding region (NCR) of around 1,100 base pairs contains key promoters:

• Two L-strand promoters (LSP, LSP2)
• One H-strand promoter (HSP)

Replication begins at strand-specific origins: O_H for the heavy strand located within the NCR, and O_L for the light strand located within a tRNA gene cluster. DNA polymerase γ, composed of one catalytic subunit and two accessory subunits, carries out replication. Additional nuclear-encoded proteins, including the helicase TWINKLE, mitochondrial single-stranded binding proteins, and polymerase PEO1, form a replisome suited to the organelle’s unique environment.
During early embryonic development, mtDNA replication is downregulated from fertilisation through pre-implantation stages. This produces a mitochondrial bottleneck, where random segregation of mtDNA copies can reduce the transmission of harmful mutations. Replication resumes specifically in trophectoderm cells at the blastocyst stage, whereas inner cell mass cells restrict replication until receiving differentiation signals.

DNA repair

Mitochondria contain several DNA repair pathways, though base excision repair is the best characterised. Nuclear-encoded repair enzymes are imported into mitochondria, where they address oxidative damage and base mispairing. Some mismatch repair capacity exists within mitochondria, but it is mechanistically distinct from the nuclear mismatch repair system. The interplay of mitochondrial repair and turnover contributes to cellular homeostasis and influences ageing and metabolic health.

Functional significance

The mitochondrial genome is essential for cellular energy production, encoding key subunits of the oxidative phosphorylation complexes embedded in the inner mitochondrial membrane. Mutations in mtDNA can impair ATP synthesis, leading to a wide range of mitochondrial diseases characterised by neuromuscular and systemic dysfunction.