1. Cell Biology

Reducing proton leak restores function in aging heart cells

Blocking proton leaks in mitochondria via a crucial mitochondrial transport protein can rejuvenate aging heart cells and helps reverse aging heart dysfunction.
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Scientists have revealed a mechanism that causes heart cells to age and identified a drug currently in clinical trials that can rejuvenate them, according to a study published this week in eLife.

The results provide the first direct evidence that aging increases proton leakage in heart cells and could lead to new treatments to shore up the leaky membranes and restore heart function.

Tiny structures in heart cells called mitochondria produce the energy the heart needs to beat and pump blood effectively. They achieve this through a precisely controlled process involving the movement of ions – protons – across their inner membranes. If mitochondria start to leak protons, they become much less energy efficient and consume excessive oxygen.

“Increased mitochondrial proton leak has been found in various organs, including the heart, but its functional significance, and exactly where the protons leak from, has remained unclear,” explains lead author Huiliang Zhang, an Acting Instructor at the University of Washington Nathan Shock Center for Excellence in the Basic Biology of Aging, Seattle, US. “We set out to investigate whether a drug that improves heart function, called elamipretide (SS-31), has beneficial effects on aging heart cells and the mitochondrial proton leak.”

The team began by looking at the effect of elamipretide treatment on mitochondrial function in young and aged heart cells by studying oxygen consumption. In untreated aged heart cells, there was a much higher oxygen consumption, attributed to proton leak. But when they treated cells with elamipretide, oxygen consumption shifted closer to that of the young cells.

Next, they tested whether elamipretide could protect against mitochondrial stress caused by an increased proton gradient (pH) across the inner membrane. In aged cells, the natural resistance of heart cells to changes in pH was reduced, but treatment with elamipretide restored it. This provided the first direct evidence that aging increases proton leak in the mitochondria inner membrane.

To find out exactly where the protons were leaking from, the team turned their attention to a molecule called adenine nucleotide translocase (ANT), a crucial transport molecule in mitochondria recently implicated as the source of proton leaks in several other tissues. To test ANT’s involvement in the observed proton leak, the team repeated their first experiments with two chemicals that block ANT. In the absence of ANT function, there was no excess proton leak from the mitochondria, and the heart cells were more resistant to pH stress, implicating this molecule as the source of the proton leak

“Although previous studies have suggested the aged heart might have increased mitochondrial proton leak, the site of this leak has remained a puzzle,” concludes senior author Peter Rabinovitch, Co-Director of the University of Washington Nathan Shock Center for Excellence in the Basic Biology of Aging. “We’ve now shown that protons leak in aged heart cells via ANT, and that blocking this leak with a novel drug, now in clinical trials, rejuvenates mitochondria function and reverses aging heart dysfunction.”

The authors add that their work provides the mechanistic basis for the functional benefits of elamipretide to the aging heart, which was recently reported in a previous eLife paper*.

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This study was carried out in collaboration with Stealth BioTherapeutics (Needham, Massachusetts, US), licensee of elamipretide (SS-31).

It will be published as part of eLife's upcoming Special Issue on aging, geroscience and longevity.

*The paper ‘Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice’ is available to read at https://doi.org/10.7554/eLife.55513.

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