Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria

Abstract

Extensive complementation between fused mitochondria is indicated by recombination of 'parental' mitochondrial (mt) DNA (ref. 1,2) of yeast and plant cells. It has been difficult, however, to demonstrate the occurrence of complementation between fused mitochondria in mammalian species through the presence of recombinant mtDNA molecules, because sequence of mtDNA throughout an individual tends to be uniform owing to its strictly maternal inheritance. We isolated two types of respiration-deficient cell lines, with pathogenic mutations in mitochondrial tRNAIle or tRNALeu(UUR) genes from patients with mitochondrial diseases. The coexistence of their mitochondria within hybrids restored their normal morphology and respiratory enzyme activity by 10-14 days after fusion, indicating the presence of an extensive and continuous exchange of genetic contents between the mitochondria. This complementation between fused mitochondria may represent a defence of highly oxidative organelles against mitochondrial dysfunction caused by the accumulation of mtDNA lesions with age.

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

“…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). Therefore, mitochondrial fusion should not be the limiting factor for functional complementation between mitochondria carrying different mutants of mtDNA.…”

“…Studies on intermitochondrial complementation have been performed with respiration-deficient cell lines devoid of mtDNA ( 0-cells) or with 0-derived cells that had been repopulated with mutant mtDNA from patients (Enriquez et al, 2000;Ono et al, 2001). To investigate whether a functional respiratory chain is necessary for mitochondrial fusion, we generated 143B-0 cells stably expressing mtGFP or mtRFP.…”

A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells

“…15,16 The majority of the mitochondrial genome consists of genes; thus, mtDNA mutations in irradiated cells lead to mitochondrial dysfunction and radiation toxicity. To control the quality of mitochondria, IR-induced defects in this organelle are attenuated by mitochondrial fusion, in which the contents of damaged and healthy mitochondria are mixed, 17,18 or by the selective degradation of mitochondria (mitophagy). 19,20 The E3 ubiquitin ligase parkin recognizes abnormal mitochondria with low mitochondrial membrane potential (DCm) and promotes their clearance via mitophagy.…”

Mdm30 Is an F-Box Protein Required for Maintenance of Fusion-competent Mitochondria in Yeast

“…For example, fusion of mitochondria is important for sperm development in Drosophila (Hales and Fuller, 1997) and for maintenance of mitochondrial DNA (mtDNA) in yeast (Berger and Yaffe, 2000). Furthermore, fusion is required for the formation of intracellular mitochondrial networks that allow the dissipation of energy in the cell (Skulachev, 2001) and for complementation of mitochondrial gene products, a mechanism thought to constitute a defense against cellular aging (Ono et al, 2001). Mitochondrial fission is an important step in apoptosis (Frank et al, 2001) and is required for embryonic development in nematodes (Labrousse et al, 1999).…”