Mitochondria are the major source of energy in cells. They contain their own DNA (mtDNA) whose genes encode components of the respiratory chain. They are maternally inherited and are absolutely critical for the function of those tissues that are highly dependent on aerobic metabolism, such as brain and muscle. In the last syndrome (KSS), myoclonus epilepsy with ragged-red fibers (MERRF), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Mutations in nuclear DNA (nDNA) also cause a variety of mitochondrial encephalopathies, including Leigh syndrome (LS), which is commonly associated with cytochrome c oxidase (COX) deficiency and which is inherited as an autosomal recessive trait. Based on our recent observations indicating a disruption of the blood- brain barrier (BBB) in MELAS and a faulty blood-CFS barrier in KSS, we now propose to follow up on these observations with studies of the BB, the choroid plexus, and the mitochondrial respiratory chain in brain regions of patients with mitochondrial encephalopathies. First, we will study components of the BB to determine if a faculty barrier is a common denominator in the mitochondrial encephalopathies. To sort this out, we will apply a combination of morphologic and immunohistochemical techniques design to demonstrate alterations in permeability of the BBB. Second, we will study the choroid plexus from patients with mitochondrial encephalopathies in order to determine if there is a consistent defect of the respiratory chain in the epithelial cells of the plexus. To investigate this question, we will carry out immunohistochemical of the respiratory chain of the choroid plexus and we will correlate these observations with the alterations in the composition of the patients' CSF. Third, we will conduct immunohistochemical studies of COX assembly factors and of the subunits of COX in muscle and brain from patients with LS associated with COX deficiency. Because the clinical manifestations of mitochondrial encephalomyopathies are dominated by signs and symptoms of brain involvement, including developmental delay, mental retardation, ataxia, seizures, and dementia, molecular and immunohistochemical studies on affected brains may provide further understanding of CNS dysfunction in specialized regions. This may clarify pathogenetic mechanisms and help us devise rational therapeutic approaches.
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