Interplay of Impaired Cellular Bioenergetics and Autophagy in PMM2-CDG

Congenital disorders of glycosylation (CDG) and mitochondrial are multisystem with overlapping symptomatology. Pathogenic variants in the PMM2 gene lead to abnormal N-linked glycosylation. This disruption can induce endoplasmic reticulum stress, contributing disease pathology. Although impaired dysfunction has been reported some CDG, cellular bioenergetics never evaluated detail PMM2-CDG. prompted us evaluate function autophagy/mitophagy vitro patient-derived fibroblast lines differing genotypes from our natural history study. We found secondary was evidenced by decreased maximal ATP-linked respiration, as well complex I electron transport chain. Our study also revealed altered autophagy PMM2-CDG lines. marked an increased abundance autophagosome marker LC3-II. Additionally, changes proteins mitophagy pathways further indicated dysregulation these processes. Interestingly, serum sorbitol levels (a biomarker severity) CDG severity score showed inverse correlation suggests that may act a modulator biochemical clinical markers Overall, research sheds light on interplay between glycosylation, function, Manipulating alterations could offer therapeutic benefits when combined existing treatments for