Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, ML 1010, Cincinnati, OH 45229-3039, USA.
Hum Pathol. 2012 Aug;43(8):1249-57. doi: 10.1016/j.humpath.2011.09.016. Epub 2012 Jan 25.
The purpose of this study was to evaluate relationships between subsarcolemmal mitochondrial aggregates and electron transport chain deficiencies in skeletal muscle with the objective of establishing an association between mitochondrial accumulation and electron transport chain complex deficiency. We conducted a large-scale, retrospective study to evaluate factors associated with subsarcolemmal mitochondrial aggregates (percent) in pediatric patients who received muscle biopsies for suspected respiratory chain disorders. Patients were included if they had histochemical stains for assessment of mitochondrial pathology and had biochemical testing for muscle electron transport chain complex activities. Significant positive bivariate correlations (n = 337) were found between subsarcolemmal mitochondrial aggregate percentage and electron transport chain complexes II, IV, I + III, and II + III activities. Evaluation showed that a cutoff value of > 2% subsarcolemmal mitochondrial aggregates had poor overall diagnostic accuracy (mean, 32%), compared with a < 5% cutoff (mean, 60%). To better evaluate the effects of subsarcolemmal mitochondrial aggregates percentages, patients were stratified according to lower one-third (group 1, n = 120 plus ties) and upper one-third (group 2, n = 115 plus ties) of subsarcolemmal mitochondrial aggregates values. Although only minor clinical and pathologic differences were observed, group 1 participants had significantly lower electron transport chain complex activities than group 2 for all enzymes except complex III. Logistic regression showed over 2-fold greater odds of deficiency for electron transport chain complexes I + III (P = .01) and II + III (P = .03) for group 1 participants compared with group 2. We conclude that, contrary to the previous > 2.0% subsarcolemmal mitochondrial aggregates cutoff for respiratory chain disorder, patients with a low subsarcolemmal mitochondrial aggregates percentage (≤4%) are significantly more likely to have electron transport chain complex deficiency than patients with increased subsarcolemmal mitochondrial aggregates percentage (≥10%). This morphological approach for assessment of mitochondrial proliferation may assist clinicians to select further testing to rule out an electron transport chain complex deficiency in children by other methods, including direct biochemical testing of electron transport chain complex activities, measurement of muscle coenzyme Q10 content, or evaluation for a mitochondrial DNA depletion syndrome.
本研究的目的是评估骨骼肌下肌膜线粒体聚集体与电子传递链缺陷之间的关系，旨在建立线粒体堆积与电子传递链复合物缺陷之间的关联。我们进行了一项大规模的回顾性研究，以评估在疑似呼吸链障碍的患者中接受肌肉活检的儿科患者中与下肌膜线粒体聚集体（百分比）相关的因素。如果患者有评估线粒体病理学的组织化学染色且有肌肉电子传递链复合物活性的生化检测，则将其纳入研究。在 337 名患者中发现下肌膜线粒体聚集体百分比与电子传递链复合物 II、IV、I+III 和 II+III 活性之间存在显著的正相关关系。评估显示，与<5%的截止值（平均值为 60%）相比，>2%的下肌膜线粒体聚集体的截止值对整体诊断准确性（平均值为 32%）的预测效果较差。为了更好地评估下肌膜线粒体聚集体百分比的影响，根据下肌膜线粒体聚集体值的较低三分之一（组 1，n=120 例+并列）和较高三分之一（组 2，n=115 例+并列）对患者进行分层。尽管观察到的临床和病理差异较小，但与组 2 相比，组 1 患者的所有酶除复合物 III 外，电子传递链复合物的活性均显著降低。逻辑回归显示，与组 2 相比，组 1 患者的电子传递链复合物 I+III（P=0.01）和 II+III（P=0.03）缺陷的可能性高出两倍以上。我们的结论是，与先前用于呼吸链障碍的>2.0%下肌膜线粒体聚集体截止值相反，电子传递链复合物缺陷的可能性显著高于下肌膜线粒体聚集体百分比增加（≥10%）的患者。这种评估线粒体增殖的形态学方法可以帮助临床医生通过其他方法（包括直接生化检测电子传递链复合物活性、测量肌肉辅酶 Q10 含量或评估线粒体 DNA 耗竭综合征）选择进一步的检测来排除电子传递链复合物缺陷。
