Abstract
<jats:p>The past decade has seen remarkable progress in the molecular resolution of the influx and efflux components of mitochondrial Ca2+ handling, but little progress in matrix Ca2+ chelation that is central to mitochondrial calcium signaling. Among possible chelators, inorganic phosphate (Pi) is dynamic, and its uptake can lessen during Ca2+ uptake the rundown of the membrane potential, the primary driving force for Ca2+ uptake. Thus, PiC, the major mitochondrial Pi transporter, is well-positioned to regulate mitochondrial Ca2+ handling. To test this, we depleted (KD) PiC in murine skeletal muscle. We show that PiC depletion enhances the matrix free Ca2+ rise across a range of Ca2+ uptake activities, and surprisingly, causes elevated mitochondrial Ca2+ uptake, which seems to arise from an increased abundance of the mitochondrial Ca2+ uniporter. With protein levels of non-mitochondrial Ca2+ handling proteins unaltered, the greater mitochondrial Ca2+ uptake may drive a suppressed cytoplasmic Ca2+ response to tetanic stimulation, via lesser Ca2+-mediated positive feedback on Ca2+ release channels, contributing to an exercise deficit in KD mice. Alternatively, less buffering of matrix Ca2+ might be beneficial. We test these possibilities by lowering MCU, the uniporter pore forming subunit, in skeletal muscle of adult PiC KD mice, and find a worsened exercise deficit. This study establishes the requirement for PiC to maintain a bound fraction of Ca2+ in the matrix, and reveals a fitness benefit for elevated [Ca2+]m in striated muscle depleted of PiC.</jats:p>