Altered insulin pathway compromises mitochondrial function and quality control both in in vitro and in vivo model systems

Abstract

Altered insulin signaling and insulin resistance are considered the link between Alzheimer's disease (AD) and metabolic syndrome. Here, by using an in vitro and an in vivo model, we investigated the relationship between these disorders focusing on neuronal mitochondrial dysfunction and mitophagy. In vitro Aβ insult induced the opening of mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (ΔΨm) loss, and apoptosis while insulin addition ameliorated these dysfunctions. The same alterations were detected in a 16 weeks of age mouse model of diet-induced obesity and insulin resistance. In addition, we detected an increase of fission related proteins and activation of mitophagy, proved by the rise of PINK1 and Parkin proteins. Nevertheless, in vitro, the increase of p62 and LC3 indicated an alteration in autophagy, while, in vivo decreased expression of p62 and increase of LC3 suggested removing of damaged mitochondria. Finally, in aged mice (28 and 48 weeks), the data indicated impairment of mitophagy and suggested the accumulation of damaged mitochondria. Taken together these outcomes indicate that alteration of the insulin pathway affects mitochondrial integrity, and effective mitophagy is age-dependent.