Human Mfn2 M393I and R400Q induce Drosophila cardiomyopathy/heart failure phenotypes recapitulating those caused by suppression of mitochondrial fusion.

(A, B) Negative geotaxis exercise capacity (A) and optical coherence tomography (OCT) of heart tube fractional shortening (B) of flies deficient in endogenous mitofusin (dMfn RNAi) or expressing wild-type, M393I, or R400Q mutant human Mfn2. Dotted lines and arrows indicate time of OCT study. R400Q induces cardiomyopathy by 21 days, whereas M393I effects are less severe at that time. (C, D) As in A and B, except the wild-type and mutant human Mfn2s are expressed in mitofusin-deficient Drosophila heart tubes. Wild-type hMfn2 almost completely rescues loss of exercise capacity (C) and depressed heart tube contraction (D), whereas M393I and R400Q Mfn2 are similar to dMfn2 RNAi alone. OCT data are presented as mean ± SEM. Asterisk = pE) Representative OCT images from (D).