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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. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. 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. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) 1 inhibition represents a precision medicine approach in the treatment of Aicardi–Goutières syndrome (AGS), through targeting of type I interferon‐mediated cell signalling. Blood interferon mRNAseq has been proposed as a biomarker of disease with utility in therapeutic monitoring. Objective cerebrospinal fluid (CSF) biomarkers tracking treatment efficacy are currently lacking. Here, we report a retrospective case series of 13 patients (median age 6y, range 2y 6mo–17y; five females, eight males) with AGS demonstrating significantly elevated CSF neopterin levels at first sampling (median 200nmol/L, range 45–2024nmol/L), compared to 13 age‐matched controls with non‐inflammatory neurological conditions (median 23nmol/L, range 5–34nmol/L, p<0.001). Five patients with AGS treated with JAK inhibitors demonstrated a median 81.5% reduction of CSF neopterin (range –36% to –88% change from baseline), compared to eight untreated patients with AGS demonstrating a median 7% reduction in CSF neopterin (range –63% to +117% change) (p=0.047). Our data indicate a biological effect of JAK inhibitors, and the potential role of CSF neopterin as a biomarker of treatment response. [ABSTRACT FROM AUTHOR]