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. 1998 Nov;153(5):1501-10.
doi: 10.1016/S0002-9440(10)65738-0.

Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy

E Arbustini  1 , M Diegoli, R Fasani, M Grasso, P Morbini, N Banchieri, O Bellini, B Dal Bello, A Pilotto, G Magrini, C Campana, P Fortina, A Gavazzi, J Narula, M Viganò
Affiliations

Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy

E Arbustini et al. Am J Pathol. 1998 Nov.

Abstract

Mitochondrial (mt)DNA defects, both deletions and tRNA point mutations, have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles, angulated, tubular, and concentric cristae, and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques, automated DNA sequencing, restriction enzyme digestion, and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy, and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean, 43.5 +/- 12.7 years), 85 had ultrastructural evidence of giant organelles, with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA, and 4 missense, one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases, the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation, cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P = 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P = 0.0388), whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure.

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Figures

Figure 1.
Figure 1.
Electron micrographs showing characteristic ultrastructural changes of mitochondria in patients with pathological mtDNA mutations. a: Ring mitochondria; b: giant mitochondria with membrane fusion and circular cristae; c: concentric cristae; d and e: giant organelles with irregularly whorled and undulated cristae. Uranyl acetate, lead citrate; magnification, ×5600 and (a and d), ×16,000 (b) and ×9600 (c and e).
Figure 2.
Figure 2.
Enzyme cuts show higher amount of mutants in heart than in blood DNA. 1: Middle, A3260G, tRNALeuUUR; left, XmnI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with inclusion polygonal bodies. 2: Middle, T4314A, tRNAIle; left, MseI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with ring organelles. 3: Middle, A4315G, tRNAIle; left, MseI digestion in blood and inheart DNA; right, ultrastructural characteristics of the heart mitochondria with crystallized compacted cristae and osmiophilic bodies. 4: Middle, A5600T, tRNAAla; left, HinfI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with large organelles, devoid of cristae and often full of glycogen. 5: Middle, T7581C, tRNAAsp; left, MnlI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with giant organelles, peripheral cristolysis, and central compacted cristae. 6: Middle, C14684T, tRNAGlu; left, NlaIII digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with concentrically arranged and undulated cristae. Uranyl acetate, lead citrate; magnification, ×6000.
Figure 3.
Figure 3.
Left column shows the heteroplasmy and the higher amount of mutant in heart than in blood DNA. 1: Middle, T15889C, tRNAThr; left, AvaII + digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with concentric cristae and giant mitochondria. 2: Middle, A15902G, tRNAThr; left, MaeI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with giant organelles and undulated cristae. 3: Middle, A15935G, tRNAThr; left, MboII digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with undulated, compacted cristae. 4: Middle, A1692T, 16 S rRNA; left MnlI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with giant organelles and crystallized compacted cristae. 5: Middle, C1703T, 16 S rRNA; left, PflMI digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with giant organelles, peripheral cristolysis, and central compacted cristae. 6: Middle, T3197C, 16 S rRNA; left, MaeII digestion in blood and in heart DNA; right, ultrastructural characteristics of the heart mitochondria with giant organelles and undulate, swollen cristae. Uranyl acetate, lead citrate; magnification, ×6000.
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