Journal article
Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease
JJ Crameri, CS Palmer, T Stait, TD Jackson, M Lynch, A Sinclair, LE Frajman, AG Compton, D Coman, DR Thorburn, AE Frazier, D Stojanovski
Molecular and Cellular Biology | TAYLOR & FRANCIS INC | Published : 2024
Abstract
TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data se..
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Grants
Awarded by Mito Foundation
Funding Acknowledgements
We thank the patient and family for their participation in this research study. This research was supported by MRFF Genomics Health Futures Mission-2020 Genomics Health Futures Mission Grant Opportunity (MRF2007959) to DS, DRT and DC; NHMRC Ideas Grant (APP2021085) to DS, DRT and AEF; Mito Foundation funding (Booster Grant to DS; large equipment grants to AEF and DRT) and the Victorian Government's Operational Infrastructure Support Program. DRT was supported by an NHMRC Principal Research Fellowship (GNT1155244) and JC was supported by an Australian Government Research Training Program (RTP) scholarship and by a Mito Foundation PhD Top-Up scholarship. We thank the Biological Optical Microscopy Platform and Bio21 Mass Spectrometry and Proteomics Facility for the provision of instrumentation, training, and technical support.