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YME1L1 Degrades Mitochondria Protein Import Complex TIMM17A and TIMM23 Subunits and Protects Cells upon Import Plugging

ABSTRACT: Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase (DHFR) fused to the N-terminus of the inner membrane protein MIC60. While stabilization of the DHFR domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, surprisingly, plugging the channel of translocase of the outer membrane (TOM) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 appears to play a crucial role in mitochondrial quality control to counteract precursor stalling in the TOM complex and unoccupied TIM23 channels.

INSTRUMENT(S): UltiMate 3000 RSLCnano system (Thermofisher) coupled with Orbitrap Fusion Lumos Mass Spectrometer (Thermofisher)

ORGANISM(S): Human

SUBMITTER: Koji Yamano Meng-Chieh Hsu Richard youle

PROVIDER: MSV000096201 | MassIVE | Thu Oct 24 14:39:00 BST 2024

SECONDARY ACCESSION(S): PXD057163

REPOSITORIES: MassIVE

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