Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

• Published in: The EMBO journal Vol. 39; no. 23; pp. e105364 - n/a
• Main Authors: Hathazi, Denisa, Griffin, Helen, Jennings, Matthew J, Giunta, Michele, Powell, Christopher, Pearce, Sarah F, Munro, Benjamin, Wei, Wei, Boczonadi, Veronika, Poulton, Joanna, Pyle, Angela, Calabrese, Claudia, Gomez‐Duran, Aurora, Schara, Ulrike, Pitceathly, Robert D S, Hanna, Michael G, Joost, Kairit, Cotta, Ana, Paim, Julia Filardi, Navarro, Monica Machado, Duff, Jennifer, Mattman, Andre, Chapman, Kristine, Servidei, Serenella, Della Marina, Adela, Uusimaa, Johanna, Roos, Andreas, Mootha, Vamsi, Hirano, Michio, Tulinius, Mar, Giri, Mamta, Hoffmann, Eric P, Lochmüller, Hanns, DiMauro, Salvatore, Minczuk, Michal, Chinnery, Patrick F, Müller, Juliane S, Horvath, Rita
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2020; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Adolescent; Amino acids; Aminoacylation; Availability; Biochemistry & Molecular Biology; Biosynthesis; Cell Biology; Cell Line; Cellular stress response; Chains; citric-acid cycle; Clinical Medicine; Deoxyribonucleic acid; digenic inheritance; DNA; DNA, Mitochondrial - genetics; Electron transport; EMBO20; EMBO21; Evolution; fatty-acid; Female; Gene Expression; Genes; glutaminase; Glutamine; homoplasmic tRNA mutation; Humans; Infant; Infants; key role; Klinisk medicin; Lipid metabolism; Lipid peroxidation; Lipids; Male; Medicin och hälsovetenskap; Metabolism; Mitochondria; Mitochondria - metabolism; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial DNA; Mitochondrial Myopathies - genetics; Mitochondrial Myopathies - metabolism; mitochondrial myopathy; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; mitochondrial translation; Muscles; Mutation; Myopathy; Oxidation; Pediatrics; Pediatrik; Pedigree; Proteomics; Quadriceps Muscle - metabolism; reaction-mechanism; regulator; reversible infantile respiratory chain deficiency; rna; Serine; Spontaneous recovery; stress-response; TOR protein; tRNA Methyltransferases - genetics; tRNA Methyltransferases - metabolism; mitochondrial myopathy; homoplasmic tRNA mutation; digenic inheritance; reversible infantile respiratory chain deficiency
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2020105364

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.
Synopsis
Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy associated with homoplasmic mutation in mt‐tRNAGlu. Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response (ISR) and metabolic rearrangements that reduce penetrance and promote spontaneous RIRCD recovery in infants.
Nuclear gene variants that affect glutamate/glutamine metabolism or mt‐tRNAGlu aminoacylation contribute to manifestation of RIRCD, when co‐occurring with the mtDNA m.14674T>C variant.
Analysis of diseased muscles reveals that recovery from RIRCD occurs in a stepwise manner in infants.
During phase one, ISR signaling increases FGF21 and GDF15 expression and enhances lipid and amino acid metabolism.
In a second phase, patients present activation of mTOR, leading to increased mitochondrial biogenesis.
ISR and increased mitochondria number facilitate a metabolic shift that improves amino acid availability and contribute to the spontaneous recovery in phase three.
Graphical Abstract
Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response and metabolic rearrangements, reducing penetrance and promoting spontaneous recovery in a rare mitochondrial myopathy.