How do mitochondrial protonophores (like DNP) differ from a brown-fat approach?

How do mitochondrial protonophores (like DNP) differ from a brown-fat approach?

Mitochondria are often described as the cell’s power plants, and they are central to this discussion. Cells use nutrients such as sugars and fats to produce the energy they need to function. Much of the breakdown of these nutrients happens in mitochondria, which are specialized structures inside cells. As nutrients are processed, protons are actively pumped across the inner mitochondrial membrane, creating stored energy much like water held behind a dam. Those protons then passively flow back through a protein called ATP synthase, which uses their energy to make adenosine triphosphate (ATP), the main form of energy that cells can use. When proton flow through ATP synthase leads to ATP production, mitochondrial function is said to be “coupled.”

Brown fat cells, or brown adipocytes, however, contain a protein called UnCoupling Protein-1 (UCP1). UCP1 provides an alternative pathway for protons to cross the mitochondrial membrane without going through ATP synthase. This “uncouples” mitochondrial function and releases the stored energy as heat rather than converting it into ATP. As a result, the cell must then burn more stored fat and sugar to meet its normal energy needs. Over time, if brown fat activity is sufficient, this can reduce fat stores and contribute to weight loss.

UCP1 activity is tightly regulated by the body, mainly by controlling how much of the protein the cells produce [1]. The formation and abundance of brown fat cells is also tightly regulated [1]. In this way, brown fat provides a natural and highly controlled mechanism for dissipating excess energy.

Protons can also be moved across the mitochondrial membrane without producing ATP through an artificial, drug-induced process. Certain compounds known as chemical uncouplers, or more recently as “mitochondrial protonophores”, can let protons cross the mitochondrial membrane in an uncontrolled fashion, creating a proton “leak”. In the 1930s, one such compound, 2,4-dinitrophenol (DNP), was used as a highly effective weight-loss agent. However, DNP and similar compounds act directly on mitochondria in virtually all cell types, not just brown fat, and create a proton leak that depends solely on their dose. Unlike UCP1, they are not subject to the body’s normal control mechanisms. In some people, this uncontrolled proton leak caused too little energy production for cells to carry out their normal functions, leading to organ dysfunction and, in a few cases, death. Because the margin between an effective dose and a dangerous one was very small, and the chances for overdose (and serious outcomes) in patients wishing to lose weight was high, DNP was removed from the market [2, 3].

A few companies are now developing newer mitochondrial protonophores, some derived from DNP or using a similar mechanism [4, 5, 6, 7, 8, 9]. Some are designed as prodrugs, meaning they are inactive at first and become active mainly in specific tissues such as the liver. Compared with DNP, these compounds are intended to produce lower peak levels in the blood and act more selectively. They are being developed for obesity and related conditions, including metabolic dysfunction-associated steatohepatitis (MASH), a serious form of liver disease, as well as heart failure. It remains to be seen however whether these newer compounds can be made substantially safer than DNP while still being effective enough for their intended uses.

Our approach is fundamentally different. Rather than directly uncoupling mitochondria like mitochondrial protonophores, it increases the body’s capacity to dissipate energy by recruiting additional brown fat cells, which are naturally designed to dissipate stored energy as heat and are tightly controlled by the body. In this way, it avoids creating an uncontrolled proton leak and instead amplifies the effects of the system that naturally developed to dissipate excess energy.

Preclinical Disclaimer: Energesis’ programs, including EGS-2632, are currently in preclinical development. They have been evaluated only in laboratory and animal models and have not yet been tested in humans. They are not approved by any regulatory authority, and preclinical results may not predict human safety or efficacy.

Sources

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3. Goldgof M, Xiao C, Chanturiya T, Jou W, Gavrilova O, and Reitman ML. The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality. J Biol Chem 289: 19341-19350, 2014.

4. Perry RJ, Zhang D, Zhang XM, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. 2015 Mar 13;347(6227):1253-6. doi: 10.1126/science.aaa0672.

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6. Goedeke L, Peng L, Montalvo-Romeral V, Butrico GM, Dufour S, Zhang XM, Perry RJ, Cline GW, Kievit P, Chng K, Petersen KF, Shulman GI. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Sci Transl Med. 2019 Oct 2;11(512):eaay0284. doi: 10.1126/scitranslmed.aay0284.

7. Pandey A, Kitzman D. Inquiry Regarding Body Temperature Data in HuMAIN-HFpEF Trial-Reply. JAMA Cardiol. 2025 Dec 1;10(12):1328. doi: 10.1001/jamacardio.2025.3682.

8. Noureddin M, Khan S, Portell F, Jorkasky D, Dennis J, Khan O, Johansson L, Johansson E, Sanyal AJ. Safety and efficacy of once-daily HU6 versus placebo in people with non-alcoholic fatty liver disease and high BMI: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol. 2023 Dec;8(12):1094-1105. doi: 10.1016/S2468-1253(23)00198-X.

9. Pandey A, Lewis GD, Borlaug BA, Shah SJ, Sauer AJ, Litwin S, Sharma K, Jorkasky DK, Tarka EA, Khan SM, Kitzman DW. Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF: The HuMAIN-HFpEF Randomized Clinical Trial. JAMA Cardiol. 2025 Jun 1;10(6):609-616. doi: 10.1001/jamacardio.2025.0103.