2023 Volume 82 Issue 5 Pages 263-270
The main function of mitochondria is to produce energy, and the respiratory chain complex embedded in theinner membrane of mitochondria is the site of energy production. Its disorder leads to dysfunction in variousorgans, a condition called mitochondrial respiratory chain complex deficiency (MRCD), or simply, mitochondrialdisease. Over 1,500 proteins are involved in respiratory chain reactions, and only 13 of them are encoded bymitochondrial DNA (mtDNA). The rest are coded by nuclear genes. Currently, there are more than 420 genes recognized to cause MRCD, and many of them are nuclear. MRCD caused by mtDNA mutations is maternally inherited, while that caused by nuclear genes is inherited in an autosomal recessive, autosomal dominant, or X-linkedmanner. Over 3,000 cases of pediatric MRCD have been analyzed in Japan since 2007, and over 480 cases havebeen genetically diagnosed. The most frequent genetic causes of MRCD in Japan are MT-TL1, MT-ATP6, PDHA1,ECHS1, and MT-ND6. Cases with younger onset are more likely to be caused by mutations in nuclear genes.Recently, novel nuclear genes such as GTPBP3, IARS and ATAD3 have been reported to cause MRCD. We arenow aware that MRCD may be the cause of many diseases in children, including cardiomyopathies, neonatal fatalhyperlactatemia, and hepatopathies. Neonatal-onset mitochondrial disease is defined as any MRCD with onsetin the neonatal period. Since initial symptoms often appear within the first two days of life, MRCD should besuspected in any neonates not doing well in this period. Mitochondrial nephropathy is also gaining attention, andit can be suspected by a characteristic pathological finding called granular swollen epithelial cells. Large-scaleepidemiologic studies have revealed outcomes and risk factors for mitochondrial cardiomyopathies, neonatalonset mitochondrial disease, and Leigh disease. With genetic analysis of MRCD now covered by public healthinsurance, research is expected to accelerate even more in the near future.
