Figure 4.

Phenotypes of chimeras carrying deleterious mtDNA mutations. (A) Survival rate of chimeras with COXIII-81 (n = 12), ND6-100 (n = 35), ND2-50 (n = 34), ATP8-62 (n = 25), and control (n = 17) ESC lines at 21 days (dotted line). Premature death was observed in ATP8-62 chimeras, resulting in a significantly lower survival rate compared to controls. (B) Two hour blood glucose levels (mg/dl) in high contribution chimeras with COXIII-81 (n = 1), ND6-100 (n = 3), ND2-50 (n = 2), ATP8-62 (n = 2), and Control-1(n = 3) ESCs after 1 mg/g glucose injection. For each animal, two measurements were performed. Each dot represents biological replicates, ns denotes P ≥ 0.05. Reduced glucose tolerances were observed in ND6-100, ND2-50, and ATP8-62 chimeras compared to Control-1 animals. (C) Optokinetic response spatial frequency (c/d) of pigmented eye chimeras from COXIII-81 (n = 2), ND6-100 (n = 4), ND2-50 (n = 4), ATP8-62 (n = 1), and Control-1(n = 4) ESCs. Measurement was performed on both eyes of animals. Each dot represents biological replicates, ns denotes P ≥ 0.05. Optic neuropathy was observed as low optokinetic response in COXIII-81, ND6-100, and ND2-50 chimeras compared to Control-1 animals. (D–G) Mean cardiac ultrasound values documenting reduced ejection fraction (D) and increased left ventricular (LV) volume (E) in ATP8-62 chimeras (n = 6) compared with age- and sex-matched control PolG^wt/wt (n = 6). In tandem, right ventricles (RV) were significantly enlarged in ATP8-62 chimeric hearts (F–G). (H) Echocardiography of ATP8-62 chimeras showing biventricular chamber dilation and reduced pump function in hearts as dilated cardiomyopathy. LV/RV, left/right ventricle. Vertical scale bars = 2 mm.