Plant Polyprenols Disrupt the IP3R-GRP75-VDAC-MCU Axis to Restore Mitochondrial Motility Defects Associated with Alzheimer’s Disease

Abstract

Standardized Plant Polyprenols (SPP) were shown to ameliorate cognitive function in a rat model of Alzheimer’s Disease (AD) but we lack understanding of its mechanism of action. The increasing prevalence of AD with age makes it a major health burden in economically developed countries. Mitochondria dysfunctions are highly associated with the pathophysiology of AD. We aimed at better understanding the biological processes by which SPP target mitochondrial behavior and function to improve AD-associated phenotype in a patient-derived cell model. We found that SPP dose-dependently rescued AD-associated defects in mitochondrial motility, restoring docking capabilities in the “sentry” mitochondrial sub-population. SPP also restored mitochondrial bioenergetics, particularly increasing ATP production from the mitochondrial electron transfer chain. Rescue of the mitochondrial motility phenotype was independent from the SPP-mediated increase in de novo protein synthesis and reduced EIF2α activation. Instead we found that SPP modulated MAMs occurrence & signaling, engaged in the control of mitochondrial motility by modulating Ca2+ flux and ER-stress, both processes being impaired in AD. SPP limited the interactions between SERCA1 and the IP3R-GRP75-VDAC-MCU axis, which controlled mitochondrial Ca2+ flux. Disruption of the IP3R-GRP75-VDAC-MCU axis at MAMs by SPP provided a rationale for the control of mitochondrial movements and suggested a mechanism by which SPP increased bioenergetics efficiency and restored ATP production in AD-cells. Other biological processes that may explain SPP activity were discussed including the possibility that the TRACK-Miro interaction may be involved. Our data support clinical testing of SPP as a food supplement to sustain cognitive function in the elderly.