Transglutaminase and its role in Alzheimer's disease: focus on mitochondria, aging, defective mitophagy, synaptic degeneration, and metabolomics.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline driven by amyloid-β plaques, tau neurofibrillary tangles, and extensive neuronal loss. Emerging evidence highlights mitochondrial dysfunction, defective mitophagy, and disrupted proteostasis as pivotal events in disease progression. Transglutaminase TG2, a multifunctional calcium-dependent enzyme, has gained attention for its capacity to link these pathological processes. Beyond catalyzing ε-(γ-glutamyl)-lysine crosslinks that stabilize amyloid and tau aggregates, TG2 interacts with mitochondrial membranes, altering permeability and bioenergetic efficiency. In neurons, aberrant TG2 activity promotes oxidative stress, impairs mitophagy through crosslinking of PINK1 and Parkin, and exacerbates calcium dyshomeostasis via modification of VDAC and ANT1, culminating in energy failure and apoptosis. Aging-related increases in ROS and inflammatory cytokines further amplify TG2 activation, reinforcing proteostatic collapse and synaptic degeneration. Recent metabolomic studies reveal that TG2-mediated dysregulation extends to lipid and amino acid metabolism, affecting mitochondrial respiration and neuronal signaling. Therapeutically, selective TG2 inhibition restores autophagic flux, mitigates mitochondrial damage, and reduces aggregate burden in preclinical models. This integrative review underscores TG2 as a central orchestrator connecting mitochondrial dysfunction, aging, mitophagy failure, and metabolic imbalance in AD. Targeting TG2's transamidase activity while preserving its regulatory roles may offer a promising strategy for neuroprotection and disease modification.