Editors' ChoiceAging

A One-Two Punch for Aging and Brain Malformations

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Science Translational Medicine  09 Oct 2013:
Vol. 5, Issue 206, pp. 206ec166
DOI: 10.1126/scitranslmed.3007713

Mitochondria—sometimes called the powerhouses of the cell because of their contribution to cellular metabolism and energy generation—have many features that are quite distinct from other subcellular compartments. Mitochondria are exclusively inherited from our mothers, contain their own (nonnuclear) DNA that is remarkably similar to the bacterial genome, and use oxygen to efficiently convert fuels (glucose, fat, amino acids) to the energy-rich compound adenosine triphosphate (ATP). Because of the catalytic role of ATP in critical biological reactions such as protein synthesis, muscle contraction, and nerve signaling, it is not surprising that mitochondrial dysfunction has been linked to a variety of disorders, particularly those involving skeletal muscle, heart and brain.

Now, Ross et al. provide evidence that mutations of mitochondrial DNA (mtDNA) lead to premature aging, reduced fertility, and brain malformations. The authors bred mice with different combinations of maternally inherited and subsequently acquired (somatic) mtDNA mutations. They found that maternally inherited mtDNA mutations caused premature aging and reduced litter sizes. Furthermore, one-third of animals with both maternally inherited and somatic mutations exhibited microscopic and occasionally macroscopic brain malformations. These malformations were often focal (69%) and involved a variety of brain regions, such as the hippocampus, cerebral cortex, and cerebellum. The authors propose that two hits—both maternally inherited and somatic mtDNA mutations—are required for such malformations to occur.

These findings suggest that a combination of inherited and somatic mtDNA mutations have an additive effect in creating pathological phenotypes relevant to human dysfunction and disease. If similar mechanisms also operate in humans, then it may be feasible to develop diagnostic tests aimed at assessing the risk for future disease based on the type and load of mtDNA mutations or even to devise therapies aimed at preventing such mutations from occurring and causing disease.

J. M. Ross et al., Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412–415 (2013). [Abstract]

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