TRPV4 regulates mitochondrial Ca2+-status and physiology in primary murine T cells based on their immunological state

Abstract

T cell activation process is critically affected by temperature and intracellular Ca²⁺-signalling. Yet, the nature and the key molecules involved in such complex Ca²⁺-signalling is poorly understood. It is mostly assumed that ion channels present in the plasma membrane primarily regulate the cytosolic Ca²⁺-levels exclusively. TRPV4 is a non-selective Ca²⁺ channel which can be activated at physiological temperature. TRPV4 is involved in several physiological, pathophysiological process as well as different forms of pain. Here we demonstrate that TRPV4 is endogenously expressed in T cell and is present in the mitochondria of T cells. TRPV4 activation increases mitochondrial Ca²⁺-levels, and alters mitochondrial temperature as well as specific metabolisms. The TRPV4-dependent increment in the mitochondrial Ca²⁺ is context-dependent and not just passively due to the increment in the cytosolic Ca²⁺. Our work also indicates that mitochondrial Ca²⁺-level correlates positively with a series of essential factors, such as mitochondrial membrane potential, mitochondrial ATP production and negatively correlates with certain factors such as mitochondrial temperature. We propose that TRPV4-mediated mitochondrial Ca²⁺-signalling and other metabolisms has implications in the immune activation process including immune synapse formation. Our data also endorse the re-evaluation of Ca²⁺-signalling in T cell, especially in the light of mitochondrial Ca²⁺-buffering and in higher body temperature, such as in case of fever. Presence of TRPV4 in the mitochondria of T cell is relevant for proper and optimum immune response and may provide evolutionary adaptive benefit. These findings may also have broad implications in different pathophysiological process, neuro-immune cross-talks, and channelopathies involving TRPV4.

Keywords: ATP; Ca2+; Cardiolipin; ER-mito contact sites; Membrane potential; Mitochondria; Pain; T cell; TCR activation; TRPV4; Temperature.