The transcription factor ChREBP links mitochondrial lipidomes to mitochondrial morphology and progression of diabetic kidney disease
Issued Date
2023-09-01
Resource Type
ISSN
00219258
eISSN
1083351X
Scopus ID
2-s2.0-85170642989
Pubmed ID
37611830
Journal Title
Journal of Biological Chemistry
Volume
299
Issue
9
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Biological Chemistry Vol.299 No.9 (2023)
Suggested Citation
Li L., Long J., Mise K., Poungavrin N., Lorenzi P.L., Mahmud I., Tan L., Saha P.K., Kanwar Y.S., Chang B.H., Danesh F.R. The transcription factor ChREBP links mitochondrial lipidomes to mitochondrial morphology and progression of diabetic kidney disease. Journal of Biological Chemistry Vol.299 No.9 (2023). doi:10.1016/j.jbc.2023.105185 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/90256
Title
The transcription factor ChREBP links mitochondrial lipidomes to mitochondrial morphology and progression of diabetic kidney disease
Other Contributor(s)
Abstract
A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase, a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD.