Cardiolipin helps fruit flies take flight
Researchers at New York University have shown that cardiolipin, a phospholipid component of the inner mitochondrial membrane in fruit flies, exists for more than 30 days and may allow these flies to sustain wing-beat frequencies of more than 100 beats per second. In addition, they found that cardiolipin lengthens the lifetimes of fruit fly mitochondrial respiratory protein complexes. Their work was published recently in the Journal of Biological Chemistry.
Cardiolipin stabilizes mitochondrial electron transport complexes by interacting with oxidative phosphorylation, or OXPHOS, proteins, which are critical for cellular energy generation. OXPHOS is the primary mechanism that fruit fly muscles use to generate adenosine triphosphate, a cell’s energy currency.
Previous studies have shown that cardiolipin interacts with OXPHOS proteins via noncovalent interactions and that the mitochondria require this connection to work at their best. Among mitochondrial proteins, OXPHOS proteins have exceptionally long lifetimes. Most phospholipids boast a half-life of a few days. However, Mindong Ren, a research associate professor of anaesthesiology and lead author on the study, and his team showed that cardiolipin’s half-life is more than three times as long.
Ren compared proteins with cardiolipins: “Like long-lived proteins, cardiolipin can also be referred to as a long-lived lipid.”
This prompted researchers at NYU to wonder if the presence of cardiolipin impacts the longevity of OXPHOS proteins.
The team fed fruit flies, or Drosophila melanogaster, stable isotopes to measure the half-life of proteins and lipids. After feeding, these isotopes are incorporated into the flies’ existing muscle and other tissues.
“The fact that mature flies do not experience a change in their body mass makes Drosophila an excellent model organism for this experiment,” Ren said.
Since adult flies do not gain weight or grow new flight muscles, the heavy isotopes in their bodies can only be broken down by protein and lipid recycling inside their cells.
Because not all mitochondrial proteins are long-lived, Ren and his team decided to focus their work on a fruit fly tissue with minimal regeneration: the postmitotic flying muscle.
When the researchers ablated cardiolipin, the half-lives of respiratory protein complexes in the Drosophila flight muscle decreased by almost half.
These results indicate that respiratory proteins and cardiolipins live for a very long time, which is consistent with the notion that OXPHOS-containing domains in mitochondrial crista membranes are quite stable.
Ren said tightly packed cristae may explain cardiolipin and other proteins’ longevity. Crowding causes strong lipid–protein and protein–protein interactions but slows diffusion and molecular motion. Limited exposure to proteases and lipases, caused by strong interaction and slow diffusion, could increase the lifetimes of lipids and proteins.
Michael Schlame, a professor of anaesthesiology at NYU and supervising author of the study, compared cardiolipin and OXPHOS proteins to collaborators.
“We proved that cardiolipin and OXPHOS complexes last a long time and showed that they rely on each other,” Schlame said.
Ren said he was amazed at how much energy fruit flies can generate using complexes packed into small spaces.
Ren and Schlame agree that fruit flies could be useful models for researching cardiolipins and their functions in human diseases. Alterations in cardiolipin metabolism are associated with a plethora of disorders including ischemia or reperfusion injury, heart failure, cardiomyopathy and cancer.
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