Wilnai Yael, Enns Gregory M, Niemi Anna-Kaisa, Higgins John, Vogel Hannes
Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children's Hospital, Stanford University Medical Center , Palo Alto, CA , USA and.
Ultrastruct Pathol. 2014 Oct;38(5):309-14. doi: 10.3109/01913123.2014.921657. Epub 2014 Jun 16.
Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.
甲基丙二酸血症（MMA）是最常见的支链有机酸血症之一。一些MMA患者出现的生化异常，如乳酸性酸中毒和三羧酸循环中间产物排泄增加，提示线粒体功能障碍。为了研究线粒体参与MMA的可能性，我们检查了肝组织以寻找线粒体超微结构异常的证据。对5例接受肝移植的MMA mut(0)患者的移植肝进行了活检。所有患者既往均有代谢性酸中毒、乳酸性血症、酮尿症和高氨血症发作。所有活检标本经电子显微镜检查均显示出明显的线粒体病变。线粒体在大小、形状和嵴的形态上有显著差异。线粒体内基质明显扩张，嵴变小且不连续。未发现晶体包涵体。该系列研究清楚地记录了接受移植的MMA患者肝组织样本中广泛的线粒体超微结构异常，为MMA mut(0)病理生理学中线粒体功能障碍提供了病理证据。考虑到线粒体异常增大的趋势，MMA的代谢效应可能会限制线粒体分裂或促进融合。MMA中线粒体功能障碍与形态异常之间的相关性可能为更好地理解和监测优化或新型治疗策略提供思路。
