Targeting antioxidants to mitochondria

Why aren’t antioxidants magic cure-alls?

It’s not a silly question, when one sees how oxidative stress and reactive oxygen species have been implicated in so many diseases, ranging from hypertension and atherosclerosis to neurodegenerative disorders. Yet large-scale clinical trials supplementing participants’ diets with antioxidants have showed little benefit.

Emory University School of Medicine scientists have arrived at an essential insight: the cell isn’t a tiny bucket with all the constituent chemicals sloshing around. To modulate reactive oxygen species effectively, an antioxidant needs to be targeted to the right place in the cell.

Sergei Dikalov and colleagues in the Division of Cardiology have a paper in the July 9 issue of Circulation Research, describing how targeting antioxidant molecules to mitochondria dramatically increases their effectiveness in tamping down hypertension.

Mitochondria are usually described as miniature power plants, but in the cells that line blood vessels, they have the potential to act as amplifiers. The authors describe a “vicious cycle” of feedback between the cellular enzyme NADPH oxidase, which produces the reactive form of oxygen called superoxide, and the mitochondria, which can also make superoxide as a byproduct of their energy-producing function.

The positive charge keeps mitoTEMPO embedded in mitochondria

Taking an antioxidant (TEMPOL) that sops up superoxide, and attaching a mitochondrial anchor (forming mitoTEMPO), makes the antioxidant work effectively at a concentration that is 1000 times lower, compared to the same antioxidant without the anchor. In animal models, the approach works to counteract both hypertension induced by the hormone angiotensin II and by the combination of a steroid hormone and salt.

In an editorial accompanying the Circulation Research article, Paul O’Connor and David Gutterman from Medical College of Wisconsin write that the results “provide renewed hope that through their focused site of action, this class of chemical agents may be more effective than traditional global antioxidants in treating hypertension in humans.”

The tactic of targeting drugs to mitochondria by attaching a positively charged, lipophilic (oil-preferring) anchor is not new, Dikalov notes. Russian biochemist Vladimir Skulachev first identified molecules with suitable properties in the 1960s, he says.

Mitochondria naturally have a negative charge inside because they pump out positively charged ions as part of their energy generation function. That means positively charged molecules are attracted into mitochondria like moths to a lamp on the porch, while the oil-preferring context keeps a molecule embedded inside.

There are so many drugs for blood pressure – why is there a need for more? Dikalov points out that several existing blood pressure medications have limited effectiveness for a fraction of the population.
“Many patients are taking more than one drug, but still their blood pressure is poorly controlled,” he says.

More broadly, the mitochondrial targeting approach may be applicable for treating other conditions besides hypertension, such as atherosclerosis, complications of diabetes, lung and eye diseases.

Dikalov says he is collaborating with colleagues at the Novosibirsk Institute of Organic Chemistry to follow up.

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Quinn Eastman

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