We conclude that mitochondrial localization of Dnmt3a and cytosine methylation of mtDNA are tissue-preferential, mostly confined to excitable tissues, and that regulatory mechanisms for epigenetic modification mtDNA, or non-catalytic functions of mitochondrial Dnmt3a, in skeletal muscle and spinal cord are aberrant in mouse ALS. The gene discussed is DNMT3A; the disease is amyotrophic lateral sclerosis.