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

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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.