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Stochastic mutations in the mitochondrial genome (mtDNA) have been linked to many diseases, and their accumulation has been proposed to act as a driving force in the ageing process itself. For the past 15 years the main animal model used to study this phenomenon has been the ‘mutator’ mouse, harbouring a proofreading defective mtDNA polymerase (POLG). These models accumulate high levels of mtDNA point mutations, but also large and small deletions and mtDNA depletion, causing progeroid (accelerated ageing) phenotypes.

Mitochondria generate the cellular fuel, adenosine triphosphate, or ATP, to sustain complex life. Production of ATP depends on the oxidation of energy rich compounds to produce a chemical potential difference for hydrogen ions (or proton motive force, pmf), across the inner mitochondrial membrane (IMM).

Disruption of the IMM, dissipation of the pmf and cell death occur if the total concentration of calcium inside mitochondria is elevated sufficiently to open a pore in the IMM. It has been proposed that the pore is in the membrane sector of the ATP synthase.