Zeviani M, Mariotti C, Antozzi C, Fratta G M, Rustin P, Prelle A
Istituto Nazionale Neurologico Carlo Besta, Milano, Italy.
Muscle Nerve Suppl. 1995;3:S170-4. doi: 10.1002/mus.880181433.
Defects of the mitochondrial respiratory chain in cardiac muscle are an important, yet still overlooked cause of heart failure. In 16 of 32 endocardial biopsies from infants affected by "idiopathic" hypertrophic cardiomyopathy we demonstrated a remarkable decrease of activity of either complex I, or complex IV, or both, relative to complex II + III activity which was taken as an index of mitochondrial proliferation. At the molecular level, several mtDNA mutations have been associated with cardiomyopathy. For instance, MIMyCa is a maternally inherited syndrome presenting with a variable combination of skeletal and heart muscle failure associated with a heteroplasmic A3260G transition in the tRNALeu(UUR) gene. To study the effects of the mutation in a controlled system, we prepared clones of transmitochondrial cybrids by fusing mutant cytoplasts with mtDNA-less tumor cells. Two groups of clones were identified: nearly 100% mutant (M group) and nearly 100% wild-type (WT group). The means of complex I and IV in the M group were 63% and 67% relative to the WT group. The O2 consumption in the M group was 36%, and the lactate production was 218% of that in the WT group. MtDNA-specific translation was defective in M clones. The study of transmitochondrial cybrids is an important clue to test the pathogenicity of mtDNA mutations.
心肌线粒体呼吸链缺陷是心力衰竭的一个重要但仍被忽视的原因。在32例受“特发性”肥厚型心肌病影响的婴儿的心内膜活检样本中，有16例显示相对于作为线粒体增殖指标的复合物II + III活性，复合物I或复合物IV或两者的活性显著降低。在分子水平上，几种线粒体DNA（mtDNA）突变与心肌病有关。例如，MIMyCa是一种母系遗传综合征，表现为骨骼肌和心肌功能衰竭的不同组合，与tRNALeu(UUR)基因中的异质性A3260G转换有关。为了在可控系统中研究该突变的影响，我们通过将突变细胞质体与无mtDNA的肿瘤细胞融合制备了线粒体杂交细胞克隆。鉴定出两组克隆：近100%突变型（M组）和近100%野生型（WT组）。M组中复合物I和IV的平均值相对于WT组分别为63%和67%。M组的氧气消耗量为WT组的36%，乳酸产量为WT组的218%。M克隆中的mtDNA特异性翻译存在缺陷。线粒体杂交细胞的研究是测试mtDNA突变致病性的重要线索。
