Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction

Metabolic syndrome is a cluster of abnormalities characterized by obesity and insulin resistance, which compromise energy metabolism, damage mitochondria, cause cardiomyocyte death, and eventually impair heart contraction and relaxation performance. Despite the increasing prevalence of heart complications in obese and diabetic patients, our knowledge on how obese and diabetes mellitus impair heart function is very limited. In this study, we used animal and cell culture models in rodents or monkeys and generated lipid overload models to mimic obesity conditions. We found that excessive lipid supply decreased nicotinamide adenine dinucleotide (oxidized) levels and increased the acetylation of a fission protein Drp1 at a specific lysine residue (K642). Drp1 acetylation at K642 activated Drp1 through phosphorylation, mitochondrial translocation, and oligomerization. The excessively activated Drp1 had higher GTPase activity, bound with VDAC1 on mitochondria, induced mitochondrial fission, and caused cardiomyocyte death. These findings provide new information regarding how lipid overload regulates redox environment, protein acetylation, and the function of mitochondrial fission protein Drp1 in the heart.

Methods
1. All source data and raw Western Blotting (WB) images corresponding to the research paper 'Increased Drp1 Acetylation by Lipid Overload Induces Cardiomyocyte Death and Heart Dysfunction’ published in Circulation Research. Methods are described in detail in the online supplemental materials of this paper.

2. The Excel files contain source data for the bar graphs of Figures 1–8, Online Figures I–VIII and Online Tables 1–2 of this paper. For clarity, each spreadsheet is labeled with its location (figure/panel) in the paper. The first cell in each spreadsheet contains a brief description of the contents.

3. The pdf file named: Raw WB images for Fig 1–8 S2 S6 & S7.pdf contains all the raw WB images in this paper, including images in Figures 1-8 and Online Figures II, VI, and VII. In some images, red rectangles are used to highlight the portion of the image used in the paper.