Introduction to Mitochondrial Genome

Mitochondrial DNA (mtDNA) comprises a small, circular, double-stranded genome spanning 16,569 base pairs.
Exists independently of nuclear DNA (nDNA) and lacks histones.
Encodes 37 genes essential for cellular energy production.
Gene distribution includes 13 protein-coding genes, 22 transfer RNAs (tRNAs), and 2 ribosomal RNAs (rRNAs).
Protein-coding genes provide subunits for the oxidative phosphorylation (OXPHOS) electron transport chain:
- Complex I (NADH dehydrogenase): 7 subunits.
- Complex III (Cytochrome bc1): 1 subunit.
- Complex IV (Cytochrome c oxidase): 3 subunits.
- Complex V (ATP synthase): 2 subunits.

Principles of Mitochondrial Inheritance

Follows a non-classical, matrilineal transmission pattern distinct from Mendelian genetics.

Inheritance Principle	Description
Maternal Transmission	Transmitted exclusively through the oocyte. Sperm mitochondria are degraded post-fertilization.
Offspring Risk	Affected mothers transmit the mutation to all offspring (males and females).
Paternal Transmission	Affected fathers do not transmit the disease to any offspring.
Polyploidy	Each cell contains hundreds to thousands of mtDNA copies.

Heteroplasmy: Presence of a mixture of mutant and wild-type mtDNA within a single cell or tissue.
Homoplasmy: State in which all copies of the mitochondrial genome carry the identical sequence variant.
Threshold Effect: Clinical disease manifests only when the mutant mtDNA load exceeds a specific, tissue-dependent threshold, typically >60-90%.
High-energy demand tissues (brain, muscle, heart, liver, kidney) are highly susceptible to OXPHOS defects.

High Mutation Rate: Rate is 10-20 times higher than nDNA due to proximity to reactive oxygen species (ROS) and limited repair mechanisms.
Replicative Segregation: Random distribution of mtDNA during cell division causes variable heteroplasmy across tissues, explaining variable penetrance and disease progression.
Bottleneck Phenomenon: A small number of mitochondria are sampled during oogenesis, causing rapid and unpredictable shifts in heteroplasmy levels between generations.

Clinical Syndrome	Gene/Mutation	Key Clinical Features
MELAS	MT-TL1 (m.3243A>G)	Stroke-like episodes, lactic acidosis, seizures, short stature, diabetes.
MERRF	MT-TK (m.8344A>G)	Myoclonus, epilepsy, ataxia, ragged-red fibers, lipomas.
LHON	MT-ND1, MT-ND4, MT-ND6	Bilateral, painless, subacute visual loss in young adults.
Kearns-Sayre Syndrome	Large mtDNA deletion	Progressive external ophthalmoplegia, pigmentary retinopathy, heart block.
Pearson Syndrome	Large mtDNA deletion	Sideroblastic anemia, exocrine pancreatic dysfunction, lactic acidosis.
NARP	MT-ATP6 (m.8993T>G)	Neuropathy, ataxia, retinitis pigmentosa.
Leigh Syndrome	MT-ATP6 or nDNA	Subacute necrotizing encephalomyelopathy, basal ganglia lesions, respiratory failure.

Histopathology: Muscle biopsy reveals ragged-red fibers (Gomori trichrome stain), COX-negative fibers, and structurally abnormal mitochondria on electron microscopy.
Molecular Testing: Targeted mtDNA sequencing via next-generation sequencing (NGS) to detect heteroplasmy levels.
Specimen Selection: Blood testing may be inadequate due to variable tissue distribution; muscle, liver, or buccal swab sampling is often required.
Biochemical Screening: Elevated blood lactate and Growth and Differentiation Factor 15 (GDF-15) can indicate mitochondrial dysfunction.

Therapeutics: Management is largely supportive. Riboflavin supplementation may benefit patients with mitochondrial Complex I and Complex II deficiencies.
Surveillance: Annual electrocardiogram, echocardiogram, ophthalmology, audiology, and endocrine assessments are mandated.
Genetic Counselling: Highly complex due to variable heteroplasmy; prenatal diagnosis has limited predictive value regarding disease severity. Preimplantation genetic diagnosis (PGD) is utilized for selected cases. Mitochondrial replacement therapy (three-parent IVF) is an emerging preventive option.