Efeito do nocaute fígado-específico da Mitofusina 2 sobre o acúmulo de DNA mitocondrial NZB/BINJ em camundongos

Abstract

The mammalian mitochondrial DNA (mtDNA) shows a high mutation frequency, which can lead to severe diseases in humans. However, disease development relies on the mutation load, which is tissue specific. This is explained by the existence of multiple mtDNA copies in every cell, leading to the coexistence of mutant and wild-type mtDNAs (known as heteroplasmy). Importantly, the liver shows a rapid age-dependent increase of the mutation load. Mitochondria are constantly fusing and dividing, enabling the exchange of their content within the mitochondrial network. However, this mitochondrial dynamics also facilitate a mtDNA mutation to spread through the mitochondrial network, which can prevent the cell to eliminate it. Using heteroplasmic knockout mice for mitofusin 2 (Mfn2), we show that liver accumulation of a specific mtDNA haplotype takes place regardless of Mfn2. Provided that Mfn2 plays a key role in mitochondrial dynamics, this finding indicates that liver mtDNA segregation does not rely on mitochondrial dynamics.