Mitochondrial fusion is essential for organelle function and cardiac homeostasis

Yun Chen, Yingqiu Liu, Gerald W. Dorn

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

Rationale: Mitochondria constitute 30% of myocardial mass. Mitochondrial fusion and fission appear essential for health of most tissues. Mitochondrial fission occurs in neonatal cardiomycyte and is implicated in cardiomyocyte death. Mitochondrial fusion has not been observed in postmitotic myocytes of adult hearts, and its occurrence and function in this context are controversial. Objective: Determine the consequences on organelle and organ function of disrupting cardiomyocyte mitochondrial fusion in vivo. Methods and Results: The murine mfn1 and mfn2 genes, encoding mitofusins (Mfn) 1 and 2 that mediate mitochondrial tethering and outer mitochondrial membrane fusion, were interrupted by Cre-mediated excision of essential exons in neonatal (Nkx2.5-Cre) and adult (MYH6 modified estrogen receptor-Cre-modified estrogen receptor plus tamoxifen or Raloxifene) hearts. Embryonic combined Mfn1/Mfn2 ablation was lethal after e9.5. Conditional combined Mfn1/Mfn2 ablation in adult hearts induced mitochondrial fragmentation, cardiomyocyte and mitochondrial respiratory dysfunction, and rapidly progressive and lethal dilated cardiomyopathy. Before heart failure developed, cardiomyocyte shortening and calcium cycling were unaffected by absence of Mfn1 and Mfn2. Based on the time course over which fusion-defective mitochondrial size decreases, a mitochondrial fusion/fission cycle in adult mouse hearts occurs approximately every 16 days. Conclusions: Mitochondrial fusion in adult cardiac myocytes is necessary to maintain normal mitochondrial morphology and is essential for normal cardiac respiratory and contractile function. Interruption of mitochondrial fusion causes lethal cardiac failure at a time corresponding to 3 or 4 cycles of unopposed mitochondrial fission.

Original languageEnglish (US)
Pages (from-to)1327-1331
Number of pages5
JournalCirculation Research
Volume109
Issue number12
DOIs
StatePublished - Dec 9 2011
Externally publishedYes

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Mitochondrial Dynamics
Organelles
Homeostasis
Cardiac Myocytes
Estrogen Receptors
Heart Failure
Mitochondrial Size
Membrane Fusion
Dilated Cardiomyopathy
Mitochondrial Membranes
Tamoxifen
Muscle Cells
Exons
Mitochondria
Calcium

Keywords

  • Dilated cardiomyopathy
  • Mitochondrial fragmentation
  • Mitochondrial fusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mitochondrial fusion is essential for organelle function and cardiac homeostasis. / Chen, Yun; Liu, Yingqiu; Dorn, Gerald W.

In: Circulation Research, Vol. 109, No. 12, 09.12.2011, p. 1327-1331.

Research output: Contribution to journalArticle

Chen, Yun ; Liu, Yingqiu ; Dorn, Gerald W. / Mitochondrial fusion is essential for organelle function and cardiac homeostasis. In: Circulation Research. 2011 ; Vol. 109, No. 12. pp. 1327-1331.
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