Disruption of fusion results in mitochondrial heterogeneity and dysfunction.
Mitochondria undergo continual cycles of fusion and fission, and the balance of these opposing processes regulates mitochondrial morphology. Paradoxically, cells invest many resources to maintain tubular mitochondrial morphology, when reducing both fusion and fission simultaneously achieves the same end. This observation suggests a requirement for mitochondrial fusion, beyond maintenance of organelle morphology. Here, we show that cells with targeted null mutations in Mfn1 or Mfn2 retained low levels of mitochondrial fusion and escaped major cellular dysfunction. Analysis of these mutant cells showed that both homotypic and heterotypic interactions of Mfns are capable of fusion. In contrast, cells lacking both Mfn1 and Mfn2 completely lacked mitochondrial fusion and showed severe cellular defects, including poor cell growth, widespread heterogeneity of mitochondrial membrane potential, and decreased cellular respiration. Disruption of OPA1 by RNAi also blocked all mitochondrial fusion and resulted in similar cellular defects. These defects in Mfn-null or OPA1-RNAi mammalian cells were corrected upon restoration of mitochondrial fusion, unlike the irreversible defects found in fzodelta yeast. In contrast, fragmentation of mitochondria, without severe loss of fusion, did not result in such cellular defects. Our results showed that key cellular functions decline as mitochondrial fusion is progressively abrogated.
Chen
Hsiuchen
H
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Chomyn
Anne
A
Chan
David C
DC
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000502:physiology; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption; D011092:Polyethylene Glycols / Q000737:chemistry; D012313:RNA / Q000737:chemistry; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D013997:Time Factors
D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D012313:RNA; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D010100:Oxygen