TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulator

Abstract

TRPV4 has been linked with the development of sensory defects, neuropathic pain, neurodegenerative disorders such as Charcot Marie Tooth disease and various muscular dystrophies. In all these cases mitochondrial abnormalities were tagged as cellular hallmarks and such abnormalities have been reported as key factor for the pathophysiological conditions. Mitochondria also have the unique ability to sense and regulate their own temperature. Here, we demonstrate that TRPV4, a thermosensitive ion channels, localizes to a subpopulation of mitochondria in various cell lines, in primary cells and also in sperm cells. Improper expression and/or function of TRPV4 induce several mitochondrial abnormalities such as low oxidative potential, high Ca 2+ -influx and changes in electron transport chain functions. TRPV4 is also involved in regulation of mitochondrial morphology, smoothness, and fusion -fission events. The C-terminal cytoplasmic region of TRPV4 can localize it to mitochondria and interacts with mitochondrial proteins including Hsp60, Mfn1 and Mfn2. Regulation of mitochondria by TRPV4 may contribute to previously uncharacterized mitochondria-specific functions observed in various cell types. This discovery may help to link TRPV4-mediated channelopathies with mitochondria-mediated diseases.

Mitochondria regulate TRPV4‐mediated release of ATP

“…TRPV4 generates an inward (Na + and Ca 2+ ) current, which may act to depolarise the plasma membrane potential resulting in pannexin channel opening and ATP release. TRPV4 channels are also reported to interact with mitochondria proteins including Hsp60 and Mfn1/2 to regulate mitochondrial structure and function (Kumar et al, 2018). Perhaps this forms a link allowing mitochondria to regulate TRPV4 activity.…”

“…We sought to determine if mitochondria regulate TRPV4‐mediated Ca 2+ signalling. Previous studies have shown that TRPV4 interacts with mitochondrial proteins including Hsp60 and Mfn1/2 to regulate mitochondrial structure and function (Kumar et al, 2018). This observation highlights a potential interaction between mitochondria and TRPV4 in regulating intracellular signalling.…”

Anterograde Axonal Transport in Neuronal Homeostasis and Disease

“…Indeed, disruption of the ER network has been shown to result in axonal degeneration (Yalçın et al, 2017 ). Mitochondrial Ca 2+ uptake is required for correct intracellular signaling, homeostasis, and mitochondrial integrity and transport, therefore mutations in Ca 2+ channels also lead to mitochondrial dysfunction (Kumar et al, 2018 ). The integral ER membrane protein vesicle-associated membrane protein-associated protein B (VAPB), which is associated to ALS (Nishimura A. L. et al, 2004 ; Chen et al, 2010 ), interacts with the outer mitochondrial membrane and its mutation impacts mitochondrial Ca 2+ uptake and induces the formation of abnormal ER inclusions (De Vos et al, 2012 ).…”

Defects in Axonal Transport in Inherited Neuropathies

“…Whereas, decrease of VAPB MOM protein, causes a perturbation of the uptake of Ca 2+ by mitochondria, which is required to maintain an intracellular homeostasis as well as mitochondrial transport. Ca 2+ is an important factor for various other functions such as cell signaling as well as regulating mitochondrial function and structure [77]. Therefore, mutations in Ca 2+ -channels such VDAC or TRPV4 lead to mitochondrial dysfunction in IPN [77].…”

“…Ca 2+ is an important factor for various other functions such as cell signaling as well as regulating mitochondrial function and structure [77]. Therefore, mutations in Ca 2+ -channels such VDAC or TRPV4 lead to mitochondrial dysfunction in IPN [77].…”