The majority of the core proteins of the mtDNA replication and expression machinery are dedicated mitochondrial proteins, with pathological variants resulting solely in mitochondrial disease phenotypes, including POLG (Van Goethem et al, 2001), POLG2 (Longley et al, 2006), TWINKLE (Spelbrink et al, 2001), MGME1 (Kornblum et al, 2013) and POLRMT (Olahova et al, 2021). Here, MGME1 is linked to inborn mitochondrial metabolism disorder.