Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

Moshi Song, Antonietta Franco, Julie A. Fleischer, Lihong Zhang, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence. Mitochondrial dynamism and mitophagy maintain mitochondrial fitness. The impact of fission/fusion activity versus balance is unknown. Song et al. reported that mice with hearts with adynamic mitochondria live longer than fission- or fusion-defective parents, but develop mitochondrial senescence and heart failure from defective mitophagy, mitochondrial superabundance, and distorted sarcomeric architecture.

Original languageEnglish
Pages (from-to)872-883.e5
JournalCell metabolism
Volume26
Issue number6
DOIs
StatePublished - Dec 5 2017

Keywords

  • cardiomyopathies
  • mice
  • mitochondria
  • mitochondrial accumulation
  • mitochondrial dynamics
  • mitochondrial fission
  • mitochondrial fusion
  • mitochondrial quantity control
  • mitochondrial senescence

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