Loss of mitochondrial phosphate carrier in skeletal muscle: dissociation of muscle dysfunction from lower ADP phosphorylating potential

Many mutations in the mitochondrial genome and in nuclear genes that encode mitochondrial proteins hamper oxidative phosphorylation (oxphos) and lead to tissue dysfunction. Yet, whether an energy deficit is necessarily a direct cause of tissue dysfunction is not clear. We addressed this question in mice in which the mitochondrial phosphate carrier, PiC, was depleted from skeletal muscle (skm) by tamoxifen‐induced excision of nuclear gene SLC25A3 encoding PiC (Cre+). Three weeks after tamoxifen injections, PiC protein in skm was <5% of levels found in control (Ctrl) wild‐type mice (tamoxifen‐treated). Oxphos, measured in mitochondria isolated from skm, was greatly suppressed to <2%, 35% or 50% of Ctrl, depending on substrate, with essentially no oxphos when succinate (+rotenone) was supplied and the highest residual oxphos when fatty acid substrate and malate were supplied; the residual oxphos may be driven by alternate Pi uptake on the dicarboxylate carrier. Residual oxphos was similar at 3 and 9 wks of PiC depletion, suggesting that the oxphos defect was stable for this interval. Furthermore, subunits of the oxphos machinery were robustly upregulated (50–70% rise) at both time points. Nonetheless, treadmill running capacity worsened during this time. Time‐to‐exhaustion was ~50 mins in Cre+ mice with PiC absent for 3 wks, but ~25 mins when PiC was absent for 9 wks, whereas Ctrl mice ran for the scheduled 80 mins. Thus, deteriorating treadmill running in Cre+ mice seems unrelated to suppressed oxphos per se. Stress signaling via transcription factor ATF4 as well as elevated mTORC1 signaling have been associated with oxphos defects caused by mitochondrial DNA depletion in cell models and in mouse skm. These models have also suggested a causal relationship between persistent mTORC1 activation/stress signaling and cell dysfunction. Yet we found little evidence for stress signaling via ATF4 (or ATF2, ATF3, or ATF5) after 3 or 9 wks of PiC depletion, and evidence for only mild mTORC1 activation after 9 wks of PiC loss. Overall, these observations suggest that skm dysfunction is not related to an oxphos deficit in a simple way. Rather, the oxphos deficit may drive adaptive mechanisms that either become exhausted or turn maladaptive when ongoing over a longer term, or trigger additional processes that are deleterious for muscle function. Furthermore, the model presented here suggests that a mechanism other than stress signaling through ATFs is responsible for tissue dysfunction in the context of a severe oxphos defect. Support or Funding Information Funding: R01 GM123771 to ELS This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .