Mitochondrial DNA (mtDNA)

Mitochondrial DNA (mtDNA) is the small genome contained within mitochondria, the cell’s energy-producing organelles. In most animals, including humans, mtDNA is a compact, circular molecule inherited almost exclusively from the mother.

Key Features

• Genome size: ~16.5 kilobases in humans
• Structure: Typically circular; packaged into nucleoprotein structures called nucleoids
• Copy number: Hundreds to thousands of copies per cell, varying by tissue and metabolic demand
• Gene content (human):
  • 13 protein-coding genes for oxidative phosphorylation (OXPHOS) complexes I, III, IV, V
  • 22 tRNAs and 2 rRNAs for mitochondrial translation
  • Non-coding control region (D-loop) housing replication and transcription control elements

Genetic Code Differences

Mitochondria use a variant of the standard genetic code. In humans:

• UGA encodes tryptophan (not stop)
• AUA encodes methionine (not isoleucine)
• AGA and AGG are stop codons (not arginine)

Transcription and Translation

• Transcription: Initiated at heavy-strand (HSP) and light-strand (LSP) promoters; carried out by mitochondrial RNA polymerase (POLRMT) with transcription factors (TFAM, TFB2M).
• RNA processing: Polycistronic transcripts are cleaved at tRNA “punctuation” sites.
• Translation: Occurs on dedicated mitochondrial ribosomes with mitochondrial tRNAs and factors distinct from cytosolic systems.

Replication and Maintenance

• Replication origins: OH (heavy strand) in the D-loop; OL (light strand) in a tRNA cluster.
• Models: Strand-displacement and RITOLS are debated; replication relies on DNA polymerase gamma (POLG), helicase TWINKLE, and single-strand binding protein (mtSSB).
• Packaging: TFAM compacts mtDNA into nucleoids, influencing copy number and transcription.
• Repair: Robust base excision repair; limited capacity for double-strand break repair. mtDNA is susceptible to oxidative damage due to proximity to the respiratory chain.

Inheritance, Heteroplasmy, and the Bottleneck

• Maternal inheritance is the rule; “paternal leakage” is rare and usually eliminated.
• Heteroplasmy: Coexistence of mutant and wild-type mtDNA within a cell or organism.
• Threshold effect: Clinical expression often occurs once mutant load exceeds a tissue-specific threshold.
• Mitochondrial bottleneck: During oogenesis, only a subset of mtDNA molecules transmits to the next generation, causing rapid shifts in heteroplasmy between generations.

Variation, Haplogroups, and Evolution

• High mutation rate relative to nuclear DNA (though not uniformly high across taxa).
• Haplogroups: Lineages defined by shared mtDNA variants; used to study human migrations and ancestry.
• “Mitochondrial Eve”: The most recent common matrilineal ancestor; a population genetic concept, not a single founding mother.
• Forensics: mtDNA is useful when nuclear DNA is degraded due to high copy number; hypervariable regions in the control region (HV1, HV2, HV3) are commonly analyzed.

Clinical Relevance

• Disorders caused by mtDNA mutations typically affect high-energy tissues (nervous system, muscle, heart).
• Examples:
  • Leber Hereditary Optic Neuropathy (LHON)
  • MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)
  • MERRF (myoclonic epilepsy with ragged-red fibers)
  • NARP and Leigh syndrome (often from ATP6/ND gene variants)
  • Large-scale deletions: Kearns–Sayre syndrome, Pearson syndrome
• Diagnostic tools:
  • Heteroplasmy quantification (NGS, digital PCR)
  • Muscle biopsy with histology/enzymology
  • mtDNA deletion/duplication analysis and copy-number assessment
• Therapeutics and management:
  • Supportive metabolic therapy, exercise, symptom-specific care
  • Mitochondrial replacement therapy (MRT, “three-parent IVF”) prevents transmission of pathogenic mtDNA
  • Emerging editing tools (e.g., DdCBE, TALE-linked base editors) target point mutations; CRISPR is limited due to gRNA import barriers

Mito-Nuclear Interactions

• Most mitochondrial proteins are nuclear-encoded and imported into mitochondria.
• Functional OXPHOS depends on coordinated expression of mtDNA and nuclear genes.
• Mitonuclear incompatibilities can influence fitness, disease risk, and speciation.
• Quality control: Mitophagy removes damaged mitochondria; fusion/fission dynamics (MFN1/2, OPA1, DRP1) help maintain mtDNA integrity and distribution.

Beyond Animals

• Plants: mtDNA is often large, structurally complex, and recombinogenic with low mutation rates; multipartite and frequently rearranged.
• Fungi/yeast: mtDNA may contain introns and mobile elements; inheritance can be biparental or uniparental depending on species.
• Some protists have linear mtDNA or highly reduced/fragmented genomes.

Current Frontiers and Open Questions

• Mechanisms and prevalence of mtDNA recombination in animals
• Determinants of heteroplasmy dynamics across tissues and lifespan
• Safe and efficient mtDNA editing and delivery methods
• Links between mtDNA mutations, aging, and neurodegeneration
• How mtDNA copy number and nucleoid organization respond to metabolic states

Quick Facts

• Location: Mitochondria
• Shape: Usually circular (animals)
• Copies per cell: Hundreds to thousands
• Genes (human): 13 proteins, 22 tRNAs, 2 rRNAs
• Inheritance: Predominantly maternal
• Medical importance: Energy metabolism disorders; ancestry and forensic applications

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