ATP Synthase Deficiency due to TMEM70 Mutation Leads to Ultrastructural Mitochondrial Degeneration and Is Amenable to Treatment

Abstract

TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in the TMEM70 gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.

A dual function of TMEM70 in OXPHOS: assembly of complexes I and V

“…Our results describe a role of TMEM70 in the assembly of CI and CV of the OXPHOS system. This finding is in line with previous studies of patients harbouring mutations in TMEM70 , that did not always have an isolated CV deficiency but rather combined OXPHOS deficiencies or even an isolated CI deficiency 18,20,22,29 . The conclusions are supported by the results from BioID, complexome profiling analyses and enzyme measurements of the OXPHOS complexes.…”

“…An interaction of TMEM70 with CI and CV, as we observed in the BioID results, might explain why patients harbouring TMEM70 mutations have CI and CV deficiencies 20,22,29 . To obtain a detailed view on how the absence of TMEM70 affects those mitochondrial protein complexes, we performed complexome profiling on a TMEM70 knockout cell line and on controls.…”

“…Interestingly, defects in TMEM70 have not exclusively reported deleterious effects on CV but also that combined with less severe CI deficiency 22 , a combined OXPHOS deficiency 29 or even an isolated CI deficiency 20 . Furthermore, TMEM70 has been shown to co-migrate with an assembly intermediate that forms part of CI 6 , suggesting it might form part of its assembly process.…”

TMEM70 forms oligomeric scaffolds within mitochondrial cristae promotingin situassembly of mammalian ATP synthase proton channel

“…These topographic differences in the biogenesis of OXPHOS complexes may contribute to the preferential accumulation of Complex V at the edge of cristae (Davies et al , 2011; Dudkina et al , 2010), which is presumably important for shaping the mitochondrial inner membrane (Paumard et al , 2002; Strauss et al , 2008). Consistently, mitochondrial ultrastructure was found perturbed in our TMEM70 KO cells and in cells from a patient carrying a premature stop codon after TM2 that destabilizes TMEM70 (Fig.3 and 4), similarly to tissues from a mouse lacking this protein (Vrbacký et al , 2016, 70) and other TMEM70 patients (Braczynski et al , 2015; Diodato et al , 2015; Cameron et al , 2011).…”

“…Although a role for TMEM70 in mammalian ATP synthase biogenesis has been established in recent years (Braczynski et al , 2015; Cameron et al , 2011; Cízková et al , 2008; Jonckheere et al , 2011; Torraco et al , 2012; Vrbacký et al , 2016), its molecular function remained thus far poorly understood. We herein provide evidence that TMEM70 specifically interacts with Su.c before its assembly into the ATP synthase, protects Su.c from degradation, and facilitates its incorporation into the ATP synthase within cristae of the mitochondrial inner membrane.…”