Fatty acids trigger mitochondrion-dependent necrosis.
Obesity is characterised by lipid accumulation in non-adipose tissues, leading to organ degeneration and a wide range of diseases, including diabetes, heart attack and liver cirrhosis. Free fatty acids (FFA) are believed to be the principal toxic triggers mediating the adverse cellular effects of lipids. Here, we show that various cooking oils used in human nutrition cause cell death in yeast in the presence of a triacylglycerol lipase, mimicking the physiological microenvironment of the small intestine. Combining genetic and cell death assays, we demonstrate that elevated FFA concentrations lead to necrotic cell death, as evidenced by loss of membrane integrity and release of nuclear HMGB1. FFA-mediated necrosis depends on functional mitochondria and leads to the accumulation of reactive oxygen species. We conclude that lipotoxicity is executed via a mitochondrial necrotic pathway, challenging the dogma that the adverse effects of lipid stress are exclusively apoptotic.
Rockenfeller
Patrick
P
University of Graz, Institute for Molecular Biosciences, Austria.
Ring
Julia
J
Muschett
Vera
V
Beranek
Andreas
A
Buettner
Sabrina
S
Carmona-Gutierrez
Didac
D
Eisenberg
Tobias
T
Khoury
Chamel
C
Rechberger
Gerald
G
Kohlwein
Sepp D
SD
Kroemer
Guido
G
Madeo
Frank
F
D017209:Apoptosis; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D024243:HMGB1 Protein / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D024243:HMGB1 Protein; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D008049:Lipase