Abstract
Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
Highlights
Mitochondrial diseases are a large and clinically heterogeneous group of disorders that result from deficiencies in cellular energy production and affect at least one in 4,300 of the population (Gorman et al, 2016)
We studied 42 individuals (27 affected, 15 unaffected) from 19 families from eight countries (UK, Germany, Sweden, Estonia, Italy, USA, Canada, Brazil) carrying the homoplasmic m.14674T>C mttRNAGlu mutation (Table EV1, Fig EV1A)
The skeletal muscle and fibroblast samples were stored in the Newcastle Biobank of the Medical Research Council (MRC) Centre for Neuromuscular Diseases (Reza et al, 2017)
Summary
Mitochondrial diseases are a large and clinically heterogeneous group of disorders that result from deficiencies in cellular energy production and affect at least one in 4,300 of the population (Gorman et al, 2016). Defective oxidative phosphorylation is the common pathway behind the disease, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue-specific clinical presentations. We have previously studied a rare and unique group of mitochondrial diseases, where life-threatening symptoms present in infancy, but recover spontaneously after 6 months of age (infantile reversible mitochondrial diseases) (Boczonadi et al, 2015). Heteroallelic EARS2 (mitochondrial glutamic acid tRNA synthetase, OMIM*612799) mutations show partial recovery of neurological and muscle symptoms around 1 year of age in two-third of patients (Steenweg et al, 2012; Talim et al, 2013). We utilised unbiased genomic sequencing, transcriptomic and proteomic approaches to explore the reasons for the markedly reduced penetrance and define the molecular mechanism of the reversibility in RIRCD associated with the homoplasmic m.14674T>C mutation
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