Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis

Kah Ying Ng, Uwe Richter, Christopher B Jackson, Sara Seneca, Brendan J Battersby

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
17 Downloads (Pure)

Abstract

Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogeneous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.

Original languageEnglish
Pages (from-to)1230-1241
Number of pages12
JournalHuman Molecular Genetics
Volume31
Issue number8
Early online date2021
DOIs
Publication statusPublished - 22 Apr 2022

Bibliographical note

© The Author(s) 2021. Published by Oxford University Press.

Fingerprint

Dive into the research topics of 'Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis'. Together they form a unique fingerprint.

Cite this