ZDHHC8-mediated S-palmitoylation of RAD21 causes mitochondrial dysfunction in diabetic nephropathy via inhibiting...

Tubulointerstitial injury exerts a key role in diabetic nephropathy (DN) development; however, its potential mechanism is still unclear. We explored the role and molecular mechanisms of RAD21 cohesin complex component (RAD21) in mitochondrial dysfunction during tubulointerstitial injury of DN. We found that RAD21 was down-regulated, but its S-palmitoylation level was up-regulated in DN. RAD21 overexpression attenuated renal tubulointerstitial injury, fibrosis and mitochondrial dysfunction in DN. In addition, zinc finger DHHC-type palmitoyltransferase8 (ZDHHC8) served as a key acetyltransferase that catalyzed RAD21 S-palmitoylation at C78 site, which led to heat shock protein member 8 (HSPA8)-mediated lysosomal degradation of RAD21. Down-regulation of RAD21 repressed the transcription and expression of ACSM3. ACSM3 deficiency abrogated the beneficial effect of RAD21 overexpression on mitochondrial dysfunction during tubulointerstitial injury in DN. In conclusion, ZDHHC8-mediated S-palmitoylation of RAD21 favored its lysosomal degradation with assistance of HSPA8, which repressed ACSM3 transcription to cause mitochondrial dysfunction, thereby accelerating DN progression.