University of Kansas Medical Center Kansas City, Kansas, United States
Ibtihal Alghusen (University of Kansas Medical Center)| Heather Wilkins (University of Kansas Medical Center)| Chad Slawson (University of Kansas Medical Center)
The accumulation of dysfunctional mitochondria is closely associated with Alzheimer Disease (AD). Mitochondrial dysfunction is an early feature of the disease and impaired turnover of damaged mitochondria increases cellular toxicity leading to neuronal damage. Importantly, AD exhibited a marked reduction in global post-translational modification β-N-acetylglucosamine (O-GlcNAc) level in post-mortem human brain tissue with AD and triple transgenic mouse model of AD (3xTg-AD). O-GlcNAc is a ubiquitous single sugar modification found on nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) respectively. Previously, we reported that sustained alterations in O-GlcNAcylation by pharmacologically or genetically manipulation impaired mitochondrial function. Here, we have established an essential role for O-GlcNAc in inducing the expression of several mitochondrial quality control mechanisms using cell lines and in vitro models of AD (differentiated organoids isolated from AD and control patients). We established that sustained alterations in O-GlcNAcylation by pharmacological inhibiting OGA induces the expression of two mitochondrial stress response proteins Activating Transcription Factor 4 (ATF4) and heat shock protein family A (GRP75). ATF4 is a key transcription factor to initiate mitophagy (mitochondria-selective autophagy). Consistence with the ATF4 induction, several mitophagy proteins are increased in the sustained alterations in O-GlcNAcylation. This post-translational modification plays crucial role in AD and restoring mitochondrial quality control mechanisms is important to prevent the accumulation of dysfunctional mitochondria.