The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease

Authors

Li Li
Jianyin Long
Koki Mise
Naravat Poungavrin
Philip L Lorenzi
Iqbal Mahmud
Lin Tan
Pradip K Saha
Yashpal S Kanwar
Benny H Chang
Farhad R Danesh

Publication Date

9-1-2023

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2023.105185

PMID

37611830

PMCID

PMC10506103

PubMedCentral® Posted Date

8-21-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Diabetes Mellitus, Diabetic Nephropathies, Gene Expression Regulation, Kidney, Lipidomics, Transcription Factors, lipid metabolism, mitochondria, phospholipid, kidney metabolism, diabetic nephropathy

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.

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