With the exception of SSBP1, a key component of the mitochondrial replication fork (19), to date, all nuclear genes directly involved in mtDNA replication (POLG, POLG2, TWINKLE, RNASEH1, DNA2, MGME1) have been associated with mitochondrial disease, mtDNA depletion, and/or mtDNA deletion (2). Here, POLG is linked to inborn mitochondrial metabolism disorder.