Focusing on the Apolipoprotein M-Mitophagy Axis: A Mechanism for Renal Protection in Diabetic Nephropathy.

Abstract

Diabetic nephropathy (DN), a predominant cause of end-stage renal disease (ESRD), is primarily driven bfigolic disturbances and mitochondrial dysfunction. Apolipoprotein M (ApoM), a protein associated with high-density lipoprotein (HDL), is notably downregulated in DN and is correlated with a decline in renal function. Recent studies have identified a protective bidirectional axis between ApoM and mitophagy, the selective autophagy of mitochondria. ApoM, chiefly through its role as a carrier for sphingosine-1-phosphate (S1P), enhances mitophagy by activating the silent information regulator 1 (SIRT1) and parkin induced kinase 1 (PINK1)/Parkin pathways, thereby improving mitochondrial quality control. Conversely, mitophagy facilitates ApoM synthesis by supplying sufficient adenosine triphosphate (ATP) for its production and the assembly of HDL. In the context of DN, hyperglycemia disrupts this reciprocal relationship, leading to a detrimental cycle of impaired mitophagy and reduced ApoM, which exacerbates renal injury. Targeting the ApoM-mitophagy axis through ApoM enhancement or mitophagy activation emerges as a promising therapeutic approach for personalized renal protection in DN. This review synthesizes the mechanistic interplay between lipid metabolism and mitochondrial quality control, emphasizing its translational potential and the necessity for further investigation.