Primary mitochondrial diseases are relatively rare, probably because major defects in the Krebs cycle or the respiratory chain are incompatible with life and many affected embryos die at an early stage. Nevertheless, about 150 different types of hereditary mitochondrial defect have been reported, and mitochondria play an important part in several common conditions. Mitochondrial DNA is maternally inherited through the egg cell cytoplasm, but many of the inherited defects map to the nuclear genome since the majority of mitochondrial proteins are imported from the cytosol. Heteroplasmy is a complicating factor: affected cells may contain a mixed mitochondrial population, and the defect may only involve a proportion of the mitochondria. (In healthy people all the copies of the mitochondrial DNA are identical.) Mitochondrial defects may be confined to a limited range of tissues, and, unexpectedly, they may change substantially as the patient ages. There has recently been great interest in mitochondrial diseases with an autoimmune component, and in those involving apoptosis (programmed cell death).
Respiratory defects: A huge variety of individual defects have been described, affecting one or more of the respiratory chain redox carriers. (A defect in mitochondrial protein import, for example, might affect dozens of enzymes to a greater or lesser extent.) The tissues which rely most extensively on aerobic metabolism are most severely affected, so patients commonly present with a myopathy or encephalopathy, or both. Lactic acidosis, muscular weakness, deafness, blindness, ataxia and dementia are common findings. These mitopathies are often fresh mutations, so there is no family history. In many cases the diseases are obvious from birth, but may develop in later life if the number of defective mitochondria increases with age.
Light microscopy of muscle biopsies frequently reveals a proportion of "ragged red" fibres or the absence of key respiratory enzymes from particular cell types after histochemical staining. Abnormal mitochondria may be visible in the electron microscope: for example "parking lot" mitochondria where the normal cristae are replaced by a rectangular grid. Even where the nature of the mutation has been identified by DNA sequencing, there is only limited correlation between the genetic defect and the time course of the disease or the severity of the symptoms.
The classification of this heterogeneous group of diseases leaves much to be desired, but the following are typical examples: myoclonic epilepsy with ragged red fibres (MERRF), mitochondrial encephalopathy with lactic acidosis and stroke (MELAS), neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP).
Auto-immune diseases: There are some relatively common diseases where patients have been reported to produce auto-antibodies against mitochondrial proteins. These include primary biliary cirrhosis (pyruvate dehydrogenase complex), dilated cardiomyopathy (adenine nucleotide porter) and Leber's heriditary optic neuropathy (LHON).
LHON is the most curious, because the antigen displayed on the plasmalemma is derived from a mitochondrially-encoded subunit of NADH dehydrogenase (complex 1). LHON is closely related to multiple sclerosis, and is the most common cause of blindness in otherwise healthy young men. It mainly affects young adult males, but it is maternally transmitted and female relatives are often carriers. It can be distinguished from an X-linked recessive condition, because male patients are normally unable to transmit the mutation to their children.
The permeability transition: Under conditions of extreme stress (e.g. pathological calcium ion concentrations, free radical mediated oxygen damage) mitochondria undergo an autocatalytic collapse, associated with the loss of the normal membrane potential and a complete failure of ATP production. The transition is irreversible and is normally a prelude to cell death. It is routinely prevented during the laboratory isolation of mitochondria by including a calcium ion chelator (EDTA or EGTA) in the isotonic preparation medium.
The transition involves the incorporation of subunits from the adenine nucleotide porter, and other proteins derived from the outer membrane, into a large pore which allows unrestricted access of small ions to the mitochondrial interior. Pore formation is favoured by atractyloside and inhibited by bongkrekic acid, and can also be blocked by the fungal toxin cyclosporin A which binds to a protein called cyclophillin in the mitochondrial matrix. [Cyclosporin A is a cyclic peptide which is widely used as an immuno - suppressant after transplant surgery, but this may be unconnected with its effects on mitochondria.]
Apoptosis: The mitochondrial permeability transition is believed to be involved in the suicidal process of apoptosis, or programmed cell death. This elaborate self-destruction cascade is responsible for the programmed loss of cells during tissue differentiation, the self-destruction of tumours and virally - infected cells, and the unwanted cell damage which follows loss of tissue perfusion in cardiovascular disease. It is proposed that mitochondria which undergo the permeability transition release a protease from the inter-membrane space which then activates the subsequent nuclear stages of the apoptotic cascade.
Apoptosis is closely regulated at numerous points along the cascade. Key effectors include (1) the tumour suppressor protein p53, which induces cells to undergo apoptosis when irreparable DNA damage is detected, and (2) the proto-oncogene bcl-2 which prevents the permeability transition, suppresses apoptosis and potentially allows the survival of damaged or cancerous cells. Bcl-2 is concentrated in the mitochondrial outer membrane, where it is closely involved in regulating the permeability transition.