(A) Left ventricular section obtained from a 23-year-old patient (patient 3). Cardiac myocyte hypertrophy is associated with prominent perinuclear vacuolization (hematoxylin and eosin, x20). (B) The vacuoles contain granular material that stains with periodic acid Schiff (arrows, x40). (C) Ultrastructural analysis reveals patchy areas characterized by absence of myofibrils and accumulation of osmiophilic granular and fibrillar material consistent with glycogen (uracyl acetate lead citrate, x3,150). (D) Proliferation of polymorphic mitochondria causes displacement of sarcomere. Note a giant mitochondria (arrow; uracyl acetate lead citrate, x5,000).

(A) The mitochondrial deoxyribonucleic acid (mtDNA) amount is significantly increased in MIC compared with NF hearts. *p < 0.001 versus NF, DCM, and IHD. (B) The mRNA levels of PGC1-, NRF1, NRF2, and Tfam are coordinately up-regulated in MIC and down-regulated in DCM and IHD. *p < 0.001 versus NF; p < 0.05 versus NF. (C) Expression levels of PGC1-ß are slightly increased in MIC and IHD and decreased in DCM respect to NF. *Differences between each group and all the others are statistically significant (p < 0.001). (D) Both PPAR- and its targets mCPT-I, MCAD, and LCAD are up-regulated in MIC and down-regulated in DCM and IHD hearts. *p < 0.001 versus NF; p < 0.01 versus NF. Yellow = NF; red = MIC; blue = DCM; green = IHD. DCM = dilated cardiomyopathy; FAO = fatty acid oxidation; IHD = ischemic heart disease; LCAD = long-chain acyl-CoA dehydrogenasey; MCAD = medium-chain acyl-CoA dehydrogenase; mCPT-I = carnitine palmitoyl transferase muscle isoform; MIC = maternally inherited cardiomyopath; NF = nonfailing; NRF = nuclear respiratory factor; PGC = peroxisome proliferator activated receptor coactivator; PPAR = peroxisome proliferator activated receptor; Tfam = transcription and mitochondrial deoxyribonucleic acid maintenance factor.

(A) GLUT1 (orange) and GLUT4 (green) were up-regulated in mitochondrial cardiomyopathy (MIC) compared with NF hearts; GLUT1 was markedly reduced in DCM and slightly reduced in IHD compared with controls; GLUT4 shows a slight reduction in DCM and IHD. *p < 0.001 versus NF. (B) UCP2 (orange) and UCP3 (green) were up-regulated in MIC compared with NF hearts. Both isoforms were down-regulated in DCM and IHD failing hearts, UCP2 showing the lowest amount. *p < 0.001 versus NF. Abbreviations as in Figure 2.

(A) Nicotinamide adenine dinucleotide 3-phosphate (NADPH)-dependent superoxide production is increased in all failing hearts compared with control samples. The increase is more striking in MIC. *p < 0.05 versus NF; p < 0.001 versus NF; p < 0.001 versus DCM and IHD. (B) Effect of specific inhibitors of enzymatic reactive oxygen species production or of the superoxide scavenger Tiron. *p < 0.05 versus baseline; p < 0.01 versus baseline. DPI = diphenyleneiodonium; MLU = mean light units; other abbreviations as in Figure 2.

(A) Both MnSOD and GPX mRNA levels are increased in MIC compared with NF hearts. Expression of both genes is slightly reduced in DCM and IHD hearts. *p < 0.01 versus NF; p < 0.05 versus NF. Orange = MnSOD; green = GPX. (B) MnSOD activity didn’t show any changes in MIC, DCM, and IHD compared with control samples. (C) A significant reduction of GPX activity was observed in IHD hearts. *p < 0.01 versus NF. GPX = glutathione peroxidise; MnSOD = manganese superoxide dismutase; other abbreviations as in Figure 2.