Mitochondrial myopathies

Abstract

Mitochondrial diseases, defined restrictively as disorders due to defects of the mitochondrial respiratory chain, are notoriously heterogeneous, both clinically and genetically. Here, we review only disorders affecting exclusively or predominantly skeletal muscle (mitochondrial myopathies). As the respiratory chain is under dual genetic control, we consider first myopathies due to defects in mitochondrial DNA (mtDNA), distinguishing those due to defects of mitochondrial protein synthesis in toto from those due to mutations in proteinencoding genes. We then divide disorders due to nuclear gene defects into six groups and discuss mitochondrial myopathies due to genetic defects affecting: respiratory chain components; the protein importation machinery; the inner membrane lipid milieu; and intergenomic signaling. We conclude with some considerations on therapy.

Cytoplasmic transfer of the mtDNA nt 8993 T-->G (ATP6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates cosegregation with a decrease in state III respiration and ADP/O ratio.

“…The present findings further support the role of energy deficiency as an important pathoetiologic agent in Leigh syndrome, as evidenced from reports of the syndrome being caused by defects of the pyruvate dehydrogenase complex (39,40) or cytochrome oxidase (41,42). Moreover, both mtDNA mutations (discussed in this study) as well as nuclear mutations (43) have been demonstrated.…”

Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

“…Severe intolerance ofphysical exercise associated with elevated blood lactate levels at rest or with minimal exercise is a wellrecognized syndrome of skeletal muscle mitochondrial disease (1,2). In many cases the underlying biochemical abnormality is undefined, but in others a defect involving the respiratory chain in skeletal muscle at the level ofcomplex 1 (NADH-CoQ oxireductase) or complex III (CoQ-cytochrome c oxireductase) has been identified (1,2).…”

The Use of Skin Fibroblast Cultures in the Detection of Respiratory Chain Defects in Patients with Lacticacidemia

“…Patients with severe defects in either complex I or cytochrome oxidase had complexe s that were only partially The inb orn errors of metabolism kn own to be primary causes of lacticacidemia include defects in pyru vate carboxylase ( I), th e pyru vate dehydrogenase complex (2), and the respiratory chain (3). Altho ugh the first two produce devastating result s in early life in th ose affected, the majorit y of report ed cases with respiratory chain defects have thus far been older children or adults (4,5). Th ese cases have often been diagnosed after the present ation of " mitoc ho ndrial myopath y" with ab normal mitochondrial appearance in mu scle, either by light or electro n microscop y.…”