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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.
These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.
Of the approximate 1, mitochondrial proteins in human cells, only 13 are encoded by the mitochondrial genome mtDNA. A Depiction of the human TIM23 complex located in the inner mitochondrial membrane. Variant identified in this study is denoted in red.
Densitometric quantification right is presented as percentage of control average, normalized to Coomassie stained loading control. Following incubation for indicated times, all samples were treated with proteinase K. Coomassie staining is presented as loading control. Densitometric quantification below is presented as percentage of control values, normalized to Coomassie stained loading control.
