A Popular Science View of Mitochondrial Uncoupling

Mitochondrial uncoupling diverts the output of the electron transport chain into heat rather than the production of ATP. Induction of higher than usual levels of uncoupling is a calorie restriction mimetic strategy: it produces some of the same gains in health and longevity as the practice of calorie restriction, with some overlap in the processes affected and metabolic changes produced. Historically, the only available pharmacological approach to increased uncoupling, 2,4-dinitrophenol (DNP), has been regarded, correctly, as dangerous. Take a little too much and you will die, because your mitochondria generate enough heat to raise your body temperature to a lethal level. In recent years some progress has been made in finding safe ways to achieve the goal of mild, self-limiting mitochondrial uncoupling, but it is a little early to say how well these will fare as therapies.

In the past few years, there's been something of a renaissance in the mitochondrial uncoupling space. In 2019, the FDA gave Mitochon Pharmaceuticals permission to test DNP as a treatment for Huntington's disease. Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them. They suggest they might have some way of giving it as a prodrug with fewer side effects, but pharma companies are always saying this sort of thing.

Last year, an Australian team published a paper about a new mitochondrial uncoupler, BAM-15. They claim it's non-toxic, doesn't explode, and doesn't increase body temperature (all uncouplers produce heat, but the body has a certain capacity to adjust for that, and if the heat produced is below the body's adjustment capacity there's no fever). Everyone involved works for Continuum Biosciences, an ambitious-looking biotech startup including anti-aging expert David Sinclair, so I'm sure they're not missing the implications. But I haven't seen any clear signs of where they're going with this.

Closer to home, a team from UCSF recently figured out the specifics of natural mitochondrial uncoupling. All mitochondria contain certain uncoupling proteins - think of them as doors, in contrast to 2,4-DNP punching holes in the wall - for generating heat. These are well-understood in brown fat, a special kind of fat used to maintain body temperature, but most of the rest of the body is a mystery. The new paper suggests that uncoupling in other cells is orchestrated by the mitochondrial ADP/ATP carrier, a protein which helps shuffle the "depleted cellular battery" ADP into the mitochondria and the "recharged cellular battery" ATP out of it. At the same time, it lets a few protons escape the positively-charged side, uncoupling the mitochondrion a little bit. Depending on the relative level of ADP on either side, it might let more or fewer protons through. This forms a feedback loop that raises or lowers the level of uncoupling depending on the level of ATP in the cell.

This is a natural biological process - it's part of how your body generates heat. It seems pretty safe - if there's too little ATP, the feedback loop kicks in and closes the doors. A drug that modified this process could potentially replicate the fat-burning properties of DNP without its side effects. And if they targeted it to be a little less intense than DNP, it wouldn't be able to reach the point where it caused deadly fevers either. This group also hasn't missed the implications - they've started Equator Therapeutics, a biotech company focused on developing drugs to hit this target.

Link: https://astralcodexten.substack.com/p/shilling-for-big-mitochondria

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