Oxa1L-Mediated Co-translational Protein Insertion Maintains Mitochondrial Function in Parkinson's Disease Models

Abstract

Mitochondrial respiratory chain integrity relies on the coordinated synthesis and membrane insertion of mitochondrially encoded proteins. How limitations in this process contribute to mitochondrial dysfunction under stress remains poorly understood. Here, we identify the mitochondrial insertase Oxa1L as a key buffering factor that modulates mitochondrial vulnerability under Parkinsonian stress conditions. Transcriptomic analyses and cellular stress models reveal pronounced disruption of oxidative phosphorylation pathways accompanied by reduced Oxa1L abundance. Functional gain- and loss-of-function analyses demonstrate that Oxa1L actively influences mitochondrial membrane potential, reactive oxygen species levels, and ATP production during stress. Notably, Oxa1L selectively governs the abundance of mitochondrially encoded respiratory chain subunits, indicating that co-translational membrane insertion represents a rate-limiting step in mitochondrial protein biogenesis. Structural analyses position Oxa1L at the mitoribosomal exit site, providing a spatial framework for coupling translation to inner membrane insertion. Together, our findings uncover a critical layer of mitochondrial quality control at the level of co-translational insertion and establish Oxa1L as a determinant of mitochondrial resilience under stress.