Gimap3: A foot-in-the-door to tissue-specific regulation of mitochondrial DNA genetics.

Mitochondrial DNA (mtDNA) is a multi-copy genome encoding for proteins essential for aerobic energy metabolism. Mutations in mtDNA can lead to a variety of human diseases, from mild metabolic syndromes to severe fatal encephalomyopathies. Most mtDNA mutations co-exist with wild type genomes in a state known as heteroplasmy. The segregation of these pathogenic mutants is tissue and mutation specific, and a key determinant in the onset and severity of human mitochondrial disorders. We used a forward genetic approach in mice to identify and demonstrate that Gimap3 (GTP ase of immunity associated protein) is a key regulator of mtDNA segregation in leukocytes. The Gimap gene cluster is found only in vertebrates and appear to be a class of nucleotide-dependent dimerization GTP ases. Gimap3 is a membrane-anchored GTP ase with a critical role in T cell development. Here, we summarize our genetic findings and postulate how Gimap3 might regulate mtDNA genetics.