Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy causing severe infant metabolic issues.
• The condition is linked to the m.14674T>C mitochondrial DNA mutation, but only a small fraction of carriers develop symptoms, suggesting other factors are involved.

Purpose of the Study:

• Investigate the genetic basis of RIRCD and the mechanisms behind its spontaneous recovery.
• Identify genetic factors contributing to the variable penetrance of the m.14674T>C mutation.

Main Methods:

• Studied 27 affected and 15 unaffected individuals from 19 families.
• Performed genetic analysis to identify nuclear gene mutations.
• Conducted transcriptomic and proteomic analyses on patient muscle tissue.

Main Results:

• Identified additional heterozygous mutations in nuclear genes EARS2 and TRMU in most affected individuals, but not in healthy carriers, supporting digenic inheritance.
• Transcriptomic and proteomic data revealed a stepwise metabolic response involving integrated stress response, serine biosynthesis, one-carbon metabolism, and mTOR activation leading to mitochondrial biogenesis.
• These changes may modulate spontaneous recovery in infants with digenic mutations.

Conclusions:

• Digenic inheritance involving mitochondrial and nuclear genes plays a crucial role in RIRCD.
• A stepwise metabolic adaptation, including stress response and mTOR activation, is implicated in disease progression and recovery.
• Understanding these mechanisms may offer insights into variable penetrance of mitochondrial DNA mutations and potential therapeutic roles for amino acids.