Summary Mitochondria are key organelles for cellular energetics, metabolism, signaling, and quality control and have been linked to various diseases. Different views exist on the composition of the human mitochondrial proteome. We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). We identified interactors of translocases, respiratory chain, and ATP synthase assembly factors. The abundance of MitoCoP proteins covers six orders of magnitude and amounts to 7% of the cellular proteome with the chaperones HSP60-HSP10 being the most abundant mitochondrial proteins. MitoCoP dynamics spans three orders of magnitudes, with half-lives from hours to months, and suggests a rapid regulation of biosynthesis and assembly processes. 460 MitoCoP genes are linked to human diseases with a strong prevalence for the central nervous system and metabolism. MitoCoP will provide a high-confidence resource for placing dynamics, functions, and dysfunctions of mitochondria into the cellular context.

ObjectiveTo assess whether chronic white matter inflammation in multiple sclerosis (MS) patients - as detected in-vivo by paramagnetic rim MRI lesions (PRL) - is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuro-axonal damage.MethodsIn 118 MS patients with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathological evaluation was performed in 25 MS lesions from 20 additional autopsy MS patients.ResultsIn univariable analyses, participants with ≥2 PRL (“PRL ≥2”, n=43) compared to those with ≤1 PRL (“PRL 0–1,” n=75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p<0.001) and higher MS disease severity scale (MSSS median, 4.3 and 2.4; p=0.003). In multivariable analyses, sNfL percentile levels were higher in PRL ≥2 cases (βadd: 16.3; 95% CI: 4.6–28.0; p<0.01), whereas disease-modifying treatment (DMT), EDSS, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRL (n=30; βadd: 30.4; 95% CI, 15.6–45.2; p<0.01). Subsequent multivariable analysis revealed that PRL ≥2 cases had also higher MSSS (βadd: 1.1; 95% CI, 0.3–1.9; p<0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p=0.004 and p=0.0002, respectively).InterpretationChronic white matter inflammation was associated with increased levels of sNfL and disease severity in non-acute MS patients, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.