| First Author | Miotto PM | Year | 2016 |
| Journal | Biochem J | Volume | 473 |
| Issue | 18 | Pages | 2831-43 |
| PubMed ID | 27402793 | Mgi Jnum | J:245088 |
| Mgi Id | MGI:5917780 | Doi | 10.1042/BCJ20160373 |
| Citation | Miotto PM, et al. (2016) In the absence of phosphate shuttling, exercise reveals the in vivo importance of creatine-independent mitochondrial ADP transport. Biochem J 473(18):2831-43 |
| abstractText | The transport of cytosolic adenosine diphosphate (ADP) into the mitochondria is a major control point in metabolic homeostasis, as ADP concentrations directly affect glycolytic flux and oxidative phosphorylation rates within mitochondria. A large contributor to the efficiency of this process is thought to involve phosphocreatine (PCr)/Creatine (Cr) shuttling through mitochondrial creatine kinase (Mi-CK), whereas the biological importance of alterations in Cr-independent ADP transport during exercise remains unknown. Therefore, we utilized an Mi-CK knockout (KO) model to determine whether in vivo Cr-independent mechanisms are biologically important for sustaining energy homeostasis during exercise. Ablating Mi-CK did not alter exercise tolerance, as the time to volitional fatigue was similar between wild-type (WT) and KO mice at various exercise intensities. In addition, skeletal muscle metabolic profiles after exercise, including glycogen, PCr/Cr ratios, free ADP/adenosine monophosphate (AMP), and lactate, were similar between genotypes. While these data suggest that the absence of PCr/Cr shuttling is not detrimental to maintaining energy homeostasis during exercise, KO mice displayed a dramatic increase in Cr-independent mitochondrial ADP sensitivity after exercise. Specifically, whereas mitochondrial ADP sensitivity decreased with exercise in WT mice, in stark contrast, exercise increased mitochondrial Cr-independent ADP sensitivity in KO mice. As a result, the apparent ADP Km was 50% lower in KO mice after exercise, suggesting that in vivo activation of voltage-dependent anion channel (VDAC)/adenine nucleotide translocase (ANT) can support mitochondrial ADP transport. Altogether, we provide insight that Cr-independent ADP transport mechanisms are biologically important for regulating ADP sensitivity during exercise, while highlighting complex regulation and the plasticity of the VDAC/ANT axis to support adenosine triphosphate demand. |
