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.