Less direct evidence comes from observations that mice with mutations of the POLG gene, which encodes a subunit of mtDNA polymerase, exhibit depression-like symptoms (Kasahara et al., 2006), and that polymorphisms of genes that code for mitochondrial enzymes, such as MTHFD1L, are associated with negative rumination, which is a precursor to depression (Eszlari et al., 2016). This evidence concerns the gene POLG and major depressive disorder.