Thursday, 16 November 2017

Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

Song M, Franco A, Fleischer JA, Zhang L, Dorn II GW

  • Mitochondrial fragmentation is often considered as harmful. This is often determined by inhibiting fusion fission proteins such as Mfn2 and Opa1. However, such conclusions are confounded by Mfn2 functioning in mitophagy and Opa1 functioning in cristae organisation. The authors sought to determine the role of fusion/fission dynamics in maintaining healthy heart function
  • The authors overexpressed the pro-fission protein Drp1 in cardiomyocytes (10 & 25 wild-type expression levels). This induced fragmentation of the network without affecting the expression of other mitochondrial proteins. The fragmented mitochondria appeared healthy
  • Through 93 weeks of age, Drp1 overexpression resulted in no phenotype
  • Previous work by the authors found that overexpression of Mfn2 induces enlargement of mitochondria in the heart, without any other clear phenotype
  • The authors conclude that increased or decreased mitochondrial size alone is not necessarily a mechanism of heart dysfunction
  • The authors then investigated a mouse model where Mfn1, Mfn2 and Drp1 expression could be switched off in the adult heart (since knockouts of these proteins are embryonic lethal)
  • Abolishing mitochondrial dynamics resulted in: fragmentation of the network, partial depolarisation of mitochondria, parkin aggregation and impaired mitophagy
  • Surprisingly, such mice were able to survive 14 weeks after mitochondrial dynamics abrogation (whereas a cardiac knockout of any single one of the 3 genes is rapidly lethal in mice)
  • The hearts of such mice were enlarged, and had a mitophagy defect resulting in suppressed elimination of defective mitochondria

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