Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) is the third most common genetically-defined subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare, clinically heterogeneous disorders. The MPAN pathomechanism, including the link between C19orf12 mutations, iron accumulation, and metabolic alterations, is still poorly understood. While earlier research pointed to impaired autophagy in MPAN, a comprehensive understanding remains elusive. Here, we investigated the autophagy-linked proteome in primary fibroblasts derived from 18 MPAN patients and identified distinct alterations in autophagy-related protein expression. Importantly, a subset of these proteomic changes showed significant associations with disease severity, highlighting their potential relevance as biomarkers of clinical progression. Functional analyses further revealed increased lysosomal acidification as the most consistently affected autophagy-related process in MPAN fibroblasts. Notably, both proteomic and functional alterations were associated with C19orf12 mutation zygosity, underscoring its modulatory role in disease-relevant cellular pathways.