MARF and Opa1 Control Mitochondrial and Cardiac Function in Drosophila

Abstract

Rationale Mitochondria interact via actions of outer and inner membrane fusion proteins. The role of mitochondrial fusion on functioning of the heart, where mitochondria comprise ~30% of cardiomyocyte volume and their inter-myofilament 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 RNAi for Mitochondrial Assembly Regulatory Factor (MARF) and Optic atrophy 1 (Opa1). 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-ER interactions mediated uniquely by mfn2 appear dispensable to functioning of the fly heart.

Cardiolipin and Mitochondrial Phosphatidylethanolamine Have Overlapping Functions in Mitochondrial Fusion in Saccharomyces cerevisiae

“…The role of mitochondrial phospholipids in fusion is relevant to studies that implicate function of mitochondrial fusion in cardiac function (57). Fragmented mitochondria are associated with the loss of Opa1 (the human homolog of Mgm1p) in mitochondrial myopathies involving cardiac and skeletal muscle (53) and in ischemic cardiomyopathy (58).…”

Drosophila Erect wing (Ewg) controls mitochondrial fusion during muscle growth and maintenance by regulation of the Opa1-like gene

“…8). Myopathological conditions involving mitochondrial fusions have been studied with respect to Mitofusin (Chen et al, 2011;Dorn et al, 2011;Fang et al, 2007). However, the only reported case of Opa1 depletion in a myopathy is that of ischaemic cardiomyopathy in humans .…”

OPA1 in Cardiovascular Health and Disease

“…Cardiac-specific RNA-knockdown of OPA1 in the heart tube of Drosophila had the following detrimental effects; mitochondrial clustering, fragmentation, a 30% decrease in mitochondrial sizefeatures which were associated with severe contractile impairment, cardiac dilatation and death, underscoring the requirement of OPA1 in cardiac development (59). Genetic ablation of OPA1 in Zebrafish was shown to reduce both cardiac contractions and heart rate (60).…”