Disruption of Fusion Results in Mitochondrial Heterogeneity and Dysfunction*

By Hsiuchen Chen, A. Chomyn, D. C. Chan. Journal of Biological Chemistry, 2005

1,361 citations recorded by the source corpus.

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 fzoΔ 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.

Subfields: Clinical Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/df60a447dc67594f5a32b4cd1db7d354231b5f19

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Citations in the corpus

Mitochondria: In Sickness and in Health (2012, background): “In this context, it is possible that the mitochondrial motility defects associated with absent or altered MFN1 and MFN2 proteins result from the targeted degradation of Miro (Baloh et al., 2007; Chen et al., 2005).”
Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. (2008, background): “reduced mitochondrial size as well as reduced autophagy [58,59].”
Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “One way in which fusion could regulate MAVS signaling is through its effects on inner mitochondrial membrane potential, a critical source of energy for ATP synthesis (212).”
Mitochondrial dynamics in mammalian health and disease. (2009, background): “tected in permeabilized Mfn double KO cells (50).”
Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin (2012, background): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript MEF cells lacking the mitochondrial fusion proteins Mfn1 and Mfn2 have a mixed population of both healthy and damaged/depolarized mitochondria (Chen et al., 2005).”
Mitochondrial Fusion Protects against Neurodegeneration in the Cerebellum (2007, neutral): “Because lack of mitochondrial fusion causes loss of membrane potential (Chen et al., 2005), such selective transport may also shift the distribution of mitochondria away from synaptic termini in fusion-deficient neurons.”
SLP‐2 is required for stress‐induced mitochondrial hyperfusion (2009, positive): “Mfn1 (cid:2) / (cid:2) , Mfn2 (cid:2) / (cid:2) , Mfn1/2 (cid:2) / (cid:2) , and Opa1 (cid:2) / (cid:2) were generated as described (Chen et al , 2005; Song et al , 2007).”
Mitochondrial fragmentation in neurodegeneration (2008, background): “In yeast, inner membrane fusion requires Mgm1, suggesting that the mammalian orthologue OPA1 is also involved in this proces”
Fission and selective fusion govern mitochondrial segregation and elimination by autophagy (2008, background): “Conversely, Dcm is influenced when fusion is inhibited (Olichon et al, 2003; Chen et al, 2005), suggesting that reduced fusion capacity could be either the cause or the result of Dcm depolarization.”
Mitochondrial fusion and fission in mammals. (2006, background): “In cells lacking mitofusins or OPA1, mitochondrial function is greatly diminished (Chen et al. 2005).”
The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease (2015, background): “Genetic loss of Mfn1 and Mfn2 leads to a subset of mitochondria lacking membrane potential (Chen et al., 2005) that selectively recruit Parkin (Narendra et al., 2008).”