PARTIAL INHIBITION OF MITOCHONDRIAL COMPLEX I ACTIVATES STRESS RESPONSE PATHWAYS INDUCING A PROTECTION AGAINST OXIDATIVE STRESS

Abstract

We have previously shown that partial inhibition of mitochondrial complex I activity with a small molecule tricycle pyrone compound (code name CP2) averted the development of cognitive and behavior phenotypes in multiple transgenic mouse models of Alzheimer’s disease (AD). One of the beneficial effects of CP2 involved the protection against oxidative stress in primary mouse neurons, human cells and in mice fed with a high fat diet. In the current study, I investigated the molecular mechanism of CP2-induced neuroprotection and established the translational potential of this therapeutics using murine, human and Drosophila model systems. Target identification revealed that CP2 competes with a flavin mononucleotide (FMN) for the binding to the redox subunit of mitochondrial complex I. Bioenergetics studies showed that CP2 mildly inhibits basal cellular respiration simultaneously leading to a dose-dependent generation of a sub-lethal level of reactive oxygen species (ROS). This increase in ROS rapidly activates cytosolic signaling pathways including the nuclear factor erythroid 2-related factor 2/antioxidant response element (NRF2/ARE) activation to induce a protection against oxidative stress. This retrograde response is known as mitohormesis, and the genetic validation of this phenomenon was done in the longevity studies in several model organisms including Drosophila and C. elegans. Mitohormetic nature of CP2-induced protection against oxidative stress was confirmed using pharmacological and genetic manipulations in human cells, in Drosophila, and in the ARE reporter mice in vivo, and validated in mouse models of the AD. CP2 treatment also reduced the extent of oxidative damage and enhanced the survival in wild-type (WT) mice fed with a high fat diet (HFD), which could be attributed to mitohormetic induction of the NRF2/ARE pathway. In summary, this study provides compelling evidence that mitohormetic activation of the NRF2/ARE pathway using small molecule partial inhibitor of mitochondrial complex I could be beneficial in multiple human conditions where oxidative stress contributes to the disease phenotype.