MTDH inhibits CrAT to promote mitochondrial damage in palmitic acid-induced renal tubular cells.

PURPOSE

Mitochondrial dysfunction leading to impaired energy metabolism has been recognized as a pivotal factor contributing to renal tubular epithelial cells (RTECs) damage in the context of dyslipidemia conditions in diabetic kidney disease (DKD). The primary objective of this study is to elucidate the role and underlying mechanism of the proto-oncogene Metadherin (MTDH) in mediating mitochondrial damage within this specific pathological context in vitro.

METHODS

The expression of MTDH in RTECs was modulated by transfecting small interfering RNA and plasmid, while palmitic acid (PA) was employed to simulate diabetic lipid metabolism disorder. Mitochondrial damage was evaluated by examining various parameters including mitochondrial morphology, membrane potential, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, as well as morphological and structural alterations. Additionally, Carnitine acetyltransferase (CrAT) expression was assessed using Western blotting and quantitative real-time polymerase chain reaction, and CrAT activity was quantified.

RESULT

MTDH expression was upregulated in PA-induced RTECs, while CrAT expression and activity were inhibited. Downregulation of MTDH mitigated PA-induced mitochondrial damage, as demonstrated by the preservation of mitochondrial membrane potential, reduction in mitochondrial ROS production, prevention of ATP depletion, and maintenance of mitochondrial structure. This was accompanied by an upregulation in CrAT expression and activity. Conversely, overexpression of MTDH exacerbated mitochondrial dysfunction by impairing membrane potential, augmenting mitochondrial ROS production, inhibiting ATP synthesis, and suppressing CrAT expression and activity.

CONCLUSION

In the context of dyslipidemia conditions, MTDH is upregulated and suppresses the expression and activity of CrAT in RTECs, thereby inducing mitochondrial dysfunction and perturbing energy metabolism. These alterations exacerbate the injury to RTECs, consequently promoting the progression of DKD.