Cannabinoid-1 receptor regulates mitochondrial dynamics and function in renal proximal tubular cells

Aims: To evaluate the specific role of the endocannabinoid/cannabinoid type-1 (CB₁R) system in modulating mitochondrial dynamics in the metabolically active renal proximal tubular cells (RPTCs). Materials and methods: We utilized mitochondrially-targeted GFP in live cells (wild-type and null for the CB₁R) and electron microscopy in kidney sections of RPTC-CB₁R^-/- mice and their littermate controls. In both in vitro and in vivo conditions, we assessed the ability of CB₁R agonism or fatty acid flux to modulate mitochondrial architecture and function. Results: Direct stimulation of CB₁R resulted in mitochondrial fragmentation in RPTCs. This process was mediated, at least in part, by modulating the phosphorylation levels of the canonical fission protein dynamin-related protein 1 on both S637 and S616 residues. CB₁R-induced mitochondrial fission was associated with mitochondrial dysfunction, as documented by reduced oxygen consumption and ATP production, increased reactive oxygen species and cellular lactate levels, as well as a decline in mitochondrial biogenesis. Likewise, we documented that exposure of RPTCs to a fatty acid flux induced CB₁R-dependent mitochondrial fission, lipotoxicity and cellular dysfunction. Conclusions: CB₁R plays a key role in inducing mitochondrial fragmentation in RPTCs, leading to a decline in the organelle's function and contributing to the renal tubular injury associated with lipotoxicity and other metabolic diseases.