MAPK1 Mediates MAM Disruption and Mitochondrial Dysfunction in Diabetic Kidney Disease via the PACS-2-Dependent...

Area of Science:

• Nephrology
• Cell Biology
• Biochemistry

Background:

• Diabetic kidney disease (DKD) is a primary cause of end-stage renal disease (ESRD).
• Mitochondrial dysfunction in renal tubules is an early event in DKD pathogenesis, but the molecular mechanisms are not fully understood.
• The mitochondria-associated endoplasmic reticulum membrane (MAM) plays a crucial role in cellular health and is implicated in various diseases.

Purpose of the Study:

• To investigate the role of the mitochondria-associated endoplasmic reticulum membrane (MAM) in diabetic kidney disease (DKD).
• To identify the molecular pathways linking high glucose to mitochondrial dysfunction in DKD.
• To explore potential therapeutic targets for DKD.

Main Methods:

• Examined diabetic human and mouse kidneys, and human renal HK-2 cells under high glucose conditions.
• Assessed changes in MAM integrity, mitochondrial morphology, and the expression of key proteins like MAPK1 and PACS-2.
• Utilized cell culture experiments to manipulate PACS-2 levels and in vivo studies involving MAPK1 inhibition in diabetic mice.

Main Results:

• High glucose disrupts MAM and causes mitochondrial fragmentation in renal cells and tissues.
• High glucose increases mitogen-activated protein kinase 1 (MAPK1) activity, which reduces phosphofurin acidic cluster sorting protein 2 (PACS-2) levels.
• Restoring PACS-2 levels or inhibiting MAPK1 protected against MAM disruption and mitochondrial fragmentation in experimental models.

Conclusions:

• The MAPK1-PACS-2 signaling axis is a critical pathway in the pathogenesis of DKD.
• Disruption of MAM by high glucose, mediated by MAPK1-induced reduction of PACS-2, contributes to mitochondrial dysfunction in DKD.
• Targeting the MAPK1-PACS-2 pathway represents a promising therapeutic strategy for DKD.