Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency

Abstract

Mitochondrial complex I deficiency results in a plethora of often severe clinical phenotypes manifesting in early childhood. Here, we report on three complex-I-deficient adult subjects with relatively mild clinical symptoms, including isolated, progressive exercise-induced myalgia and exercise intolerance but with normal later development. Exome sequencing and targeted exome sequencing revealed compound-heterozygous mutations in TMEM126B, encoding a complex I assembly factor. Further biochemical analysis of subject fibroblasts revealed a severe complex I deficiency caused by defective assembly. Lentiviral complementation with the wild-type cDNA restored the complex I deficiency, demonstrating the pathogenic nature of these mutations. Further complexome analysis of one subject indicated that the complex I assembly defect occurred during assembly of its membrane module. Our results show that TMEM126B defects can lead to complex I deficiencies and, interestingly, that symptoms can occur only after exercise.

Recent Advances in Mitochondrial Disease

“…Following identification of TMEM126B as a complex I assembly factor, two groups reported biallelic mutations in a cohort of undiagnosed complex I-deficient patients. Mutations were identified by either whole-exome sequencing or targeted NGS, and their pathogenicity was validated by blue native polyacrylamide gel electrophoresis and Western blotting of patient tissues (1,77).…”

Sarcopenia, age, atrophy, and myopathy: Mitochondrial oxidative enzyme activities

“…Selection of muscles for the sarcopenia category was based only on muscle pathology features and patient age. Further study is required to test whether such individuals have specific clinical correlates of the abnormally reduced complex I activities such as weakness, fatigue, or myalgias . The reduction in complex I activities in the sarcopenia group was an overall shift in the population with age and atrophy as, along with more patients with reduced activities, there were fewer patients with higher activities in this group.…”

Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

“…The assembly factor TIMMDC1 has also been identified in association with the MCIA complex and stalled complex I intermediate (Andrews et al, 2013;Guarani et al, 2014). Pathogenic mutations have also been identified in NDUFAF1 (Dunning et al, 2007;Fassone et al, 2011), ACAD9 (Haack et al, 2010;Nouws et al, 2010), TMEM126B (Alston et al, 2016;Sánchez-Caballero et al, 2016b) and TIMMDC1 (Kremer et al, 2017). In addition, complexome analysiscorrelative analysis of proteins that migrate together on blue-native gelsrevealed that TMEM186 and COA1 co-migrate with complex I assembly intermediates that contain known MCIA complex components (Guerrero-Castillo et al, 2017).…”