Abstract
Phosphorylation of dynamin-related protein 1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here, we established the role of Drp1 serine 600 (Drp1S600) phosphorylation in mitochondrial fission in vivo and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in the progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus dependent but not cell type dependent. Mechanistically, we show that mitochondrial fission in high-glucose conditions occurs through concomitant binding of phosphorylated Drp1S600 with mitochondrial fission factor (MFF) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish the idea that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo and highlight the stimulus-specific consequences of Drp1S600 phosphorylation in mitochondrial dynamics.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2807-2823 |
| Number of pages | 17 |
| Journal | Journal of Clinical Investigation |
| Volume | 129 |
| Issue number | 7 |
| DOIs | |
| State | Published - 2019 |
Funding
This work was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (RO1DK078900 and R01DK091310, to FRD). We thank members of the Electron Microscopy Facility (UTMDACC, Houston, Texas, CCSG grant NIH P30CA016672); the Center for Advanced Imaging (Texas A&M University, Houston, Texas); the Mass Spectrometry Proteomics and Gene Vector Core Facilities at Baylor College of Medicine, Houston, Texas; the National Cancer Institute [NCI], NIH (P30CA125123); and the Houston Methodist Research Institute Intravital Core (HMRIIC). We also thank Enrica De Rosa (HMRIIC) for her assistance with intravital imaging.
ASJC Scopus subject areas
- General Medicine
