Low phosphorus causes hepatic energy metabolism disorder through Drp1-mediated mitochondrial fragmentation: Low phosphorus causes hepatic energy metabolism disorder through Drp1-mediated mitochondrial fragmentation

The balance of mitochondrial fission/fusion plays an irreplaceable role in energy metabolism disorder, such as obesity, diabetes, and metabolic syndrome. However, the potential role of this balance in low phosphorus (LP)-induced energy metabolism disorder remains to be elucidated. Herein, in vivo and in vitro results exhibited that mitochondrial fragmentation, mediated by dynamin-related protein 1 (Drp1), was a key role in LP-induced glucolipid metabolism disorder. This disorder is characterized by mitochondrial dysfunction and elevated levels of triglyceride (TG) and lactic acid (LD). By using a Drp1 inhibitor (Mdivi-1, a mitochondrial fission inhibitor) or knocking out Drp1 in vitro, the results revealed that inhibition of Drp1-mediated mitochondrial fragmentation alleviated LP-induced glucolipid metabolism disorder. This is evidenced by enhanced mitochondrial function and reduced levels of TG and LD. Similar results were observed in zebrafish fed the Mdivi-1-supplemented diets. Furthermore, the application of plasmids that induces mutations at the s582 site of Drp1 (Drp1-s582D), which reduces Drp1 activity, blunted the above detrimental effects of Drp1. Mechanistically, the activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway targeted the phosphorylated Drp1 at s582 site, inhibiting mitochondrial excessive fission. This, in turn, alleviated LP-induced glucolipid metabolism disorder. These findings provide a possible mechanistic explanation for LP induces glucolipid metabolism disorder through the cAMP/PKA/Drp1-mediated mitochondrial fission signaling pathway.