Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

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.

Peripheral neuropathy linked mRNA export factor GANP reshapes gene regulation in human motor neurons

“…Mitochondrial transcripts are among the most abundant mRNAs in axons [2,5,14,40,52,60], indicating their importance in local maintenance of axonal and synaptic mitochondria. We also observed a transcriptional upregulation of the serine and one carbon biosynthesis, an early-stage of integrated stress response, which may be caused by mitochondrial dysfunction [7,11,16]. These neuronal compensatory responses may be of relevance in patients who have the permanent impairment of GANP but have not been observed in studies of transient GANP depletion [1,58].…”

“…Related to energy metabolic changes, CKB (brain-type creatine kinase) involved in compartmentalized ATP production and consumption was also upregulated [47]. Furthermore, upregulation of the serine and one-carbon biosynthesis pathway (PHGDH, PSAT1, SHMT2, MTHFD2) was detected, which is commonly observed in mitochondrial defects and as part of the integrated stress response [11,16].…”

The molecular pathology of pathogenic mitochondrial tRNA variants

“…Very recently, digenic inheritance of mtDNA and nuclear variants has been demonstrated for reversible infantile respiratory chain deficiency, which is associated with the homoplasmic m.14674T>C mt-tRNA Glu variant, but shows reduced penetrance [158,159]. In affected patients, Hathazi et al discovered additional rare, heterozygous nuclear mutations in EARS2 and TRMU, which encode proteins responsible for aminoacylation of mt-tRNA Glu and mt-tRNA Gln and cysteine-dependent thiouridylation of mt-tRNA Glu , as well as other genes involved in glutamate or glutamine metabolism.…”

Genetic basis of mitochondrial diseases

“…Indeed, such approach was recently utilized to decipher the molecular mechanism behind complete spontaneous recovery observed in patients with reversible infantile respiratory chain deficiency. Here, digenic inheritance of homoplasmic m.14674T>C variant with heterozygous pathogenic variants in nuclear genes, EARS2 and TRMU variants, respectively, leads to the clinical manifestation of the disease, activating the three-phase metabolic events that eventually lead to recovery [249]. Concerning the mtDNA, it has been postulated that the phenotypic variability of mtDNA homoplasmic variants could be explained by additional low-level heteroplasmic variants [250].…”