TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia

Abstract

be (Y.A.A.); jeanmichel.rigo@uhasselt.be (J.-M.R.); annelies.bronckaers@uhasselt.be (A.B.); jerome.hendriks@uhasselt.be (J.J.A.H.) Highlights What are the main findings? • Trpv4 knockout exhibits mitochondrial fragmentation and increased fission. • Acute inhibition of TRPV4 increases non-mitochondrial respiration and does not induce fragmentation of the mitochondrial network. What is the implication of the main finding? • The constitutive absence of TRPV4 activity alters the morphology of the mitochondrial network without affecting the basal metabolic function of the organelle. Abstract Microglia perform surveillance and phagocytosis to maintain the homeostasis of the central nervous system (CNS). These processes are energetically demanding, and given the critical roles of mitochondria in providing ATP, the characteristics of the mitochondrial network can modulate microglial behavior. Although the Ca 2+-permeable Transient Receptor Potential Vanilloid 4 (TRPV4) is known for regulating microglial morphology and migration, and it is implicated in mitochondrial calcium uptake, it is unknown whether TRPV4 affects the mitochondrial network in microglia. Our study provides evidence that TRPV4 plays a role in the integrity and complexity of the mitochondrial network in microglia. Quantifi-cation of the Mitochondrial Fragmentation and Complexity Index (MFCI) and increased pDrp1 (Ser616) showed a shift towards mitochondrial network fragmentation, and lowered complexity in Trpv4 knockout versus wild-type primary murine microglia in vitro. The distribution of mitochondria within microglia showed significant differences in density at 10-32 µm away from the nucleus. Furthermore, acute pharmacological TRPV4 inhibition with GSK2193874 did not induce significant mitochondria network fragmentation. Our Cells 2026, 15, 341 https://doi.org/10.3390/cells15040341 Cells 2026, 15, 341 2 of 27 findings establish TRPV4 as a regulator of mitochondrial dynamics and adaptive responses, highlighting its importance for maintaining homeostasis in microglia and the entire CNS.