TRPV4 interacts with MFN2 and facilitates endoplasmic reticulum-mitochondrial contact points for Ca-buffering.

Aim: Mitochondrial fission-fusion events, distribution, and Ca-buffering abilities are relevant for several diseases, yet are poorly understood events. TRPV4 channels are a group of thermosensitive ion channel which regulate cellular and mitochondrial Ca-level. The underlying mechanisms of the change in mitochondrial dynamics upon modulation of TRPV4 channel are ill explored.

Main Methods: We have used TRPV4 expressing stable cell line CHO-K1-V4 and compared with CHO-K1-Mock as a control cell. We have also used mouse bone marrow derived mesenchymal stem cells and purified mitochondria from mouse brain for the interaction study.

Key Findings: Now we demonstrate that expression and/or pharmacological modulation of TRPV4 regulates mitochondrial morphologies and Ca-level. TRPV4 interacts with MFN1/MFN2, the mitochondrial regulatory factors. TRPV4 regulates ER-mito contact points. We used different cellular conditions where cytosolic or ER Ca-levels were pharmacologically altered. Analysis of ∼55,000 mitochondrial particles, ∼125,000 ER-mito contact points from ∼900 cells in 10 different cellular conditions suggest that ER-mito contact points are inversely regulated with mitochondrial Ca-levels where TRPV4 always elevates mitochondrial Ca-levels. These findings link TRPV4 with MFN2-mediated diseases and suggest that different TRPV4-induced channelopathies are likely due to mitochondrial abnormalities.