BRAIN DYSFUNCTION AND NEUROPATHOLOGY IN MITOCHONDRIAL DISORDERS

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 critically important for the function of tissues that are highly dependent on aerobic metabolism, such as brain and muscle. In the last two decades, mtDNA mutations have been associated with a number of neuromuscular disorders, including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with ragged-red fibers (MERRF), and Kearns-Sayre syndrome (KSS). 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. From 1999 to 2004 with NICHD support, we identified a disruption of the blood-brain barrier (BBB) in MELAS, a faulty blood-CFS barrier in KSS, MELAS and COX-deficient LS, and - in collaboration with Dr. E.A. Schon's group - we characterized the neuropathology caused by pathogenic mutations in the human SCO2 gene in four patients with fatal cardioencephalomyopathy and COX deficiency. In addition, (1) we discovered a reduction of the monocarboxylate transporter 1 (MCT1) and an upregulation of the water channel (AQP4) in the BBB of MELAS patients;(2) we identified a defective respiratory chain in the ependymal lining of KSS patients;and (3) we uncovered a depletion of calbindin D (CalD) in the dentate gyrus of the hippocampal formation (HF) of patients with MELAS. In this competitive renewal, we propose to follow up on this progress with further studies of the BBB, the ependymal lining, and the HF in brain samples from patients with mitochondrial encephalopathies. Because the clinical manifestations of mitochondrial include developmental delay, mental retardation, seizures, and cognitive deficits, molecular, immunohistochemical, and immunological 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.