Molecular mechanism of the recovery in infantile reversible cytochrome c oxidase (COX) deficiency myopathy

Childhood-onset mitochondrial diseases are usually severe, progressive conditions with fatal outcome. However, ?benign? (better, ?reversible?) cytochrome c oxidase deficiency myopathy is an exception because it shows spontaneous complete recovery if infants survive a critical postnatal period of severe weakness and respiratory failure. Although potentially benign, this myopathy is life-threatening in the first months of life and patients require vigorous life-sustaining measures. We have recently found that reversible COX deficiency myopathy is caused by a homoplasmic mt-tRNAGlu mutation m.14674T C. Neither the exact mechanism nor the molecular basis of the recovery is currently understood. Interestingly, some homoplasmic mutation carriers (siblings of patients) do not develop any signs of myopathy, strongly suggesting the existence of protective disease modifiers. Understanding the spontaneous improvement in this mitochondrial condition may reveal a more general insight in the disease pathomechanism, and similar compensatory factors may offer clues towards molecular therapies of at least some mitochondrial diseases. The long-term goal of this approach would be to upregulate or boost compensatory factors in patients with mitochondrial disease and exploit them for therapy.

We have recently identified the molecular genetic cause of a puzzling clinical syndrome, initially termed ?benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase (COX) deficiency?. While childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions with fatal outcome, this syndrome stands out by showing complete (or almost complete) spontaneous recovery. We have detected the homoplasmic m.14674T C mutation in the mitochondrial mt-tRNAGlu gene in 17 affected individuals from 12 independent families of different ethnic origins. The m.14674T C mutation affects the discriminator base of mt-tRNAGlu, the last base at the 3‘-end of the molecule, where the amino acid via the terminal CCA is attached, therefore thought to impair mitochondrial translation, as reflected by the COX-negative fibres and the multiple respiratory chain defects in skeletal muscle. The identification of a homoplasmic mt-tRNA mutation in reversible COX deficiency myopathy raised a number of important issues.
We will investigate, i) why patients with homoplasmic m.14674T C show an isolated muscle involvement, ii) why symptoms start uniformly in the first days or weeks of life, and iii) what is behind the molecular basis of the age-dependent, spontaneous recovery. The spontaneous recovery of the patients suggests the existence of so far unknown cellular compensatory mechanisms. We will study mt-tRNA processing and function in human primary cells and muscle of patients with reversible COX deficiency myopathy, and based on the results we will extend the investigations on different types of mitochondrial disease.
The identification of the pathomechanism of reversible COX deficiency myopathy may have implications in other mitochondrial conditions. The long-term goal of this approach would be to upregulate or boost compensatory factors in patients with different types of mitochondrial disease with the aim to open new avenues for therapy.