MARF and Opa1 control mitochondrial and cardiac function in Drosophila

Gerald W. Dorn, Charles F. Clark, William H. Eschenbacher, Min Young Kang, John T. Engelhard, Stephen J. Warner, Scot J. Matkovich, Casey C. Jowdy

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Rationale: Mitochondria interact via actions of outer and inner membrane fusion proteins. The role of mitochondrial fusion in functioning of the heart, where mitochondria comprise ≈30% of cardiomyocyte volume and their intermyofilament spatial arrangement with other mitochondria is highly ordered, is unknown. Objective: Model and analyze mitochondrial fusion defects in Drosophila melanogaster heart tubes with tincΔ4Gal4-directed expression of RNA interference (RNAi) for mitochondrial assembly regulatory factor (MARF) and optic atrophy (Opa)1. Methods and Results: Live imaging analysis revealed that heart tube-specific knockdown of MARF or Opa1 increases mitochondrial morphometric heterogeneity and induces heart tube dilation with profound contractile impairment. Sarcoplasmic reticular structure was unaffected. Cardiomyocyte expression of human mitofusin (mfn)1 or -2 rescued MARF RNAi cardiomyopathy, demonstrating functional homology between Drosophila MARF and human mitofusins. Suppressing mitochondrial fusion increased compensatory expression of nuclear-encoded mitochondrial genes, indicating mitochondrial biogenesis. The MARF RNAi cardiomyopathy was prevented by transgenic expression of superoxide dismutase 1. Conclusions: Mitochondrial fusion is essential to cardiomyocyte mitochondrial function and regeneration. Reactive oxygen species are key mediators of cardiomyopathy in mitochondrial fusion-defective cardiomyocytes. Postulated mitochondrial-endoplasmic reticulum interactions mediated uniquely by mfn2 appear dispensable to functioning of the fly heart.

Original languageEnglish
Pages (from-to)12-17
Number of pages6
JournalCirculation research
Volume108
Issue number1
DOIs
StatePublished - Jan 7 2011

Keywords

  • Cardiomyopathy
  • Mitochondrial fusion
  • Superoxide dismutase

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