A human mitofusin 2 mutation can cause mitophagic cardiomyopathy.

Mitochondria are organelles with an essential role in providing energy to the cells of the body. If damaged, they are repaired by fusing and exchanging contents with sister mitochondria in a process that requires mitofusin proteins. While mutations in the gene for mitofusin 2 have been linked to nerve damage, they do not appear to affect the heart ­ despite high concentrations of mitochondria in heart muscle cells. However, previous research showed that experimentally disrupting the programmed removal of mitochondria, a process also regulated by mitofusin 2, can cause heart muscle disease known as cardiomyopathy. This suggests that mutations affecting different mitofusin 2 roles might harm individual cell types in different ways. To investigate, Franco et al. carried out a genetic screen of people with cardiomyopathy, identifying a rare mitofusin 2 mutation, called R400Q, that was more common in this group. Experiments showed that R400Q caused cardiomyopathy in mice and affected mitochondrial repair and replacement, but not movement. By contrast, a mutation linked to Charcot-Marie-Tooth disease type 2A ­ which causes nerve damage ­ affected mitochondrial movement but not clearance, leading to nerve cell damage but not cardiomyopathy. This led Franco et al. to suggest that mitochondrial movement is central to nerve cell health, whereas mitochondrial repair and replacement plays an important role in cardiac development. Genetic cardiomyopathies affect around 1 in 500 people, but only half of the gene mutations responsible are known. These results suggest that mutations affecting mitochondrial quality control factors could be involved, highlighting a direction for future studies into modifiers of cardiomyopathy.