Here the authors show that loss of TANGO2, a gene linked to an autosomal recessive disorder characterised by developmental delay, rhabdomyolysis, cardiac arrhythmias and metabolic disturbances, disrupts mitochondrial and cytoskeletal structure by impairing its interaction with CRYAB, leading to desmin aggregation and desminopathy, causing cardiomyopathy, muscle weakness, and metabolic dysfunction in mice and human cells. This evidence concerns the gene DES and Desminopathy.