Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA

Abstract

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.

Mitochondrial Fusion in Human Cells Is Efficient, Requires the Inner Membrane Potential, and Is Mediated by Mitofusins

“…The dependence of mitochondrial fusion on ⌬⌿m and ATP level indicates that its efficiency may be lowered in tissues of patients with mitochondrial diseases (Leonard and Schapira, 2000a,b). This may explain why complementation by wild-type mtDNA is hampered at high doses of mutant mtDNA in vivo (Boulet et al, 1992;Nakada et al, 2001). In contrast, fusion capacity should not be affected in clones of 0-cells repopulated with mutant mtDNA (Bakker et al, 2000;Enriquez et al, 2000;Ono et al, 2001), because they are expected to maintain a ⌬⌿m similar to that of parental 0-cells (Buchet and Godinot, 1998).…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…On one hand, mitochondrial fusion would either allow the complementation between different mitochondria that mix their matrix contents or the electric coupling of different mitochondria. On the other hand, fission would either generate small mitochondria that can be delivered to distant regions of the cell where energy is required, as the synaptic boutons in neuronal axons, or would allow the segregation of pre-existing mitochondria between daughter cells during mitosis (Nakada et al, 2001;Skulachev, 2001;Detmer and Chan, 2007;Twig et al, 2008a). Pioneering works from several laboratories have described some of the proteins involved in the fusion and fission events, amongst which the best characterized are: mitofusin1 and mitofusin 2 (Mfn1, Mfn2), that are involved in the fusion of the outer mitochondrial membrane; OPA1, that mediates mitochondrial inner membrane fusion; and Drp1, known to be essential for mitochondrial fission (reviewed in Chen and Chan, 2009;Sauvanet et al, 2010).…”

The mitochondrial theory of aging: dead or alive?

“…Mice with predominantly rearranged mtDNA do die prematurely, but as a result of renal failure. Preliminary analyses of mice carrying lower mutation loads indicate that 50% rearranged mtDNA is required to produce a deleterious phenotype in any tissue examined (Nakada et al ., 2001), strongly supporting the view that the level of sublimons seen in human aging is most unlikely to be phenotypically significant.…”