Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice

Daniel L. Galvan, Jianyin Long, Nathanael Green, Benny H. Chang, Jamie S. Lin, Paul T Schumacker, Luan D. Truong, Paul Overbeek, Farhad R. Danesh*

*Corresponding author for this work

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)2807-2823
Number of pages17
JournalJournal of Clinical Investigation
Volume129
Issue number7
DOIs
StatePublished - Jan 1 2019

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Mitochondrial Dynamics
Diabetic Nephropathies
Serine
Phosphorylation
Dynamins
Actin-Related Protein 3
Proteins
Alanine
Actins
Mitochondria
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Galvan, Daniel L. ; Long, Jianyin ; Green, Nathanael ; Chang, Benny H. ; Lin, Jamie S. ; Schumacker, Paul T ; Truong, Luan D. ; Overbeek, Paul ; Danesh, Farhad R. / Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 7. pp. 2807-2823.
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title = "Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice",
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.",
author = "Galvan, {Daniel L.} and Jianyin Long and Nathanael Green and Chang, {Benny H.} and Lin, {Jamie S.} and Schumacker, {Paul T} and Truong, {Luan D.} and Paul Overbeek and Danesh, {Farhad R.}",
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Galvan, DL, Long, J, Green, N, Chang, BH, Lin, JS, Schumacker, PT, Truong, LD, Overbeek, P & Danesh, FR 2019, 'Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice', Journal of Clinical Investigation, vol. 129, no. 7, pp. 2807-2823. https://doi.org/10.1172/JCI127277

Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice. / Galvan, Daniel L.; Long, Jianyin; Green, Nathanael; Chang, Benny H.; Lin, Jamie S.; Schumacker, Paul T; Truong, Luan D.; Overbeek, Paul; Danesh, Farhad R.

In: Journal of Clinical Investigation, Vol. 129, No. 7, 01.01.2019, p. 2807-2823.

Research output: Contribution to journalArticle

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T1 - Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic mice

AU - Galvan, Daniel L.

AU - Long, Jianyin

AU - Green, Nathanael

AU - Chang, Benny H.

AU - Lin, Jamie S.

AU - Schumacker, Paul T

AU - Truong, Luan D.

AU - Overbeek, Paul

AU - Danesh, Farhad R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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