Mitochondrial diseases may arise either due to mutations in mtDNA or nuclear DNA encoding a mitochondrial protein. Mitochondrial diseases are severely debilitating, often fatal and characteristically complex in nature. Current estimates place the incidence of mitochondrial disease at about 1 in 2000 to 1 in 5000 live births in Western countries. We do not yet know exact incidence of mitochondrial diseases in India.

Mitochondria play a crucial role in energy production, mediate cell death, and perform different functions in different tissues. Because of its vicinity to electron transport chain and lack of histones, mitochondrial DNA (mtDNA) is prone to mutations at about ten times the rate of nuclear DNA. These variations cause impairment of oxidative phosphorylation and normal physiology of mitochondria leading to hundreds of mitochondrial disorder. Each disorder produces a wide spectrum of dysfunction that can be extremely perplexing to the scientist and physician.

One of the diagnostic hallmarks of Mitochondrial myopathy on light microscopy are the presence of 'ragged blue' fibers on Succinic dehydrogenase (SDH) staining (irregular, increased subsarcolemmal accumulation of reaction product) and 'ragged red' fibers on Modified Gomoris trichrome (MGT) stain. These fibers may be negative on Cytochrome C oxidase (COX) staining. This may be reflected by increased accumulation of abnormal mitochondria (varying size, altered cristae and paracrystalline inclusions). However, these changes are not universally present in all the cases of mitochondrial encephalomyopathies due to variability and severity of muscle involvement. With the advent of molecular genetics and identification of mtDNA mutations, a larger number of mitochondrial disorders have been detected. Thus, the exact sensitivity and specificity of muscle biopsy needs to be ascertained by correlating molecular genetics and clinical evidence.

MtDNA mutations can lead to various syndromes such as CPEO (Chronic progressive external ophthalmoplegia), KSS (Kearns-Sayre Syndrome), MERRF (Myoclonic epilepsy with ragged red fibers), MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes), NARP (Neuropathy, Ataxia and Retinitis pigmentosa), MNGIE (Myoneurogastrointestinal disorder and encephalopathy), recurrent myoglobinuria due to Coenzyme Q 10 deficiency, etc., affecting major organs. These are associated with changes in the skeletal muscle thus enabling diagnosis by muscle biopsy. However conditions like Leigh's Syndrome and LHON (Leber's hereditary optic neuropathy) are not associated with myopathic features. Severe neurodegenerative diseases like Parkinson's and Alzheimer's diseases can also be caused by mtDNA mutations, and mutations are also seen in Type II Diabetes Mellitus.

MtDNA mutations are not always homogenous in all cells. The mutations are selectively eliminated from highly proliferating tissues, like blood, by a process of cytological negative selection. However, the mutant level will increase in post-mitotic tissues due to lack of such selection. The increased mutant load will lead to progression of the disease. The coexistence of both the normal and mutant mtDNA is referred to as heteroplasmy, and provides a reason why phenotypes are so variable, even within the families. The disease manifests when the level of the mutant mtDNA increases beyond a certain threshold, illustrated by NARP and MILS (Maternally Inherited Leigh Syndrome), caused by a single pathogenic point mutation T8993G in ATPase 6.

Mitochondrial diseases may also arise from processes other than germline mutations in mtDNA. Recent reports show somatic and homoplasmic mutations in mtDNA causing multiple neonatal deaths. Generally, mtDNA deletions involved in pathogenesis are not inherited from the mother. The disease onset may be either early or late depending on the load of mutant mtDNA. Some mtDNA mutations may cause disease only when the bearer is exposed to an environmental toxin: aminoglycoside-induced ototo.toxicity is one such case.