The inner mitochondrial membrane ATPase family AAA domain-containing protein 3 (ATAD3) has several cellular roles, as shown in numerous organisms. In their Research Article (Peralta et al., 2018), Carlos Moraes and colleagues use a mouse strain with a conditional knockout that is specific to skeletal muscles to address the in vivo role of ATAD3. They find that loss of ATAD3 in muscles leads to progressive myopathy after 2-3 months in these mice. Furthermore, the cristae structure of mitochondria is disrupted and the surface area of cristae decreased. In absence of ATAD3, protein levels of the cristae biogenesis complex mitochondrial contact site and cristae organising system (MICOS) are reduced. The authors show that this, in turn, leads to changes in cholesterol metabolism, depletion of mitochondrial DNA (mtDNA) and impaired mtDNA replication. Interestingly, ATAD3 is not crucial for mitochondrial translation, since the observed decrease of levels in oxidative phosphorylation (OXPHOS) complex members occurs after the defect in cristae appearance. This work establishes the in vivo function of ATAD3 as mediating the ultrastructure of mitochondria and the control of key regulators of cristae morphology, such as MICOS, and, subsequently, the mtDNA replication process and metabolism.