Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

Abstract

Background: Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases.

Scope of review: In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), nonalcoholic hepatosteatosis (NASH), insulin resistance, and type 2 diabetes (T2D). We also discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic.

Major conclusions: Rodent and non-human primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide therapeutic index. Despite this, further characterization of the tissue- and cell-specific effects of mitochondrial uncouplers is needed. We propose targeting the dosing of mitochondrial uncouplers to specific tissues such as the liver and/or developing molecules with self-limiting properties to induce a subtle and sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.

Keywords: Diabetes; Insulin resistance; Liver fibrosis; MAFLD; Metabolic syndrome; Mitochondrial uncouplers; NAFLD/NASH.

Figure 1

Mitochondrial respiration and uncoupling. During cellular respiration, the oxidation of substrates such as glucose and fatty acids [1] yields electrons (e⁻) in the form of reduced hydrogen carriers, NADH and FADH₂, which are donated to a series of enzyme complexes embedded in the inner mitochondrial membrane (IMM), ultimately reducing oxygen to water [2]. As electrons are transferred along the electron transport chain (ETC), a fixed number of protons (H⁺) are pumped across the IMM, generating a membrane potential (Δψm) and proton motive force that is subsequently used to drive the synthesis of ATP from ADP and inorganic phosphate [3]. Proton leak induced by chemical uncouplers [4] or uncoupling proteins (UCPs) [5] competes for the same proton gradient, resulting in lower Δψm and diminished production of ATP, accelerating mitochondrial respiration to maintain energy homeostasis. This figure was adapted from “Electron Transport Chain” by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates.

Figure 2

Metabolic effects of mitochondrial uncouplers. Diagram highlighting the beneficial metabolic effects of mild mitochondrial uncoupling and how uncouplers can be leveraged to treat obesity and associated comorbidities.

Figure 3

Mechanism(s) by which liver-targeted mitochondrial uncouplers prevent metabolic syndrome. Liver-targeted mitochondrial uncoupling agents hold therapeutic promise for the treatment of MAFLD, NASH, and T2D by promoting increased hepatic cellular energy expenditure [1]. Uncoupling-mediated increases in hepatic fat oxidation lower hepatic triglycerides (TAGs), plasma membrane (PM) sn-1,2-DAG content, and PKCε translocation, which increase hepatic insulin sensitivity [2]. Subtle sustained increases in hepatic mitochondrial inefficiency also reduce hepatic acetyl-CoA content, pyruvate carboxylase (PC) activity, and gluconeogenesis [3]. Collectively, this leads to reduced fasting and postprandial hyperglycemia. Liver-targeted uncoupling also leads to reduced hepatic VLDL production [4], reducing intramyocellular plasma membrane sn-1,2-DAG content and PKCθ/PKCε activity and reversing muscle insulin resistance [5]. Overall, these improvements in dyslipidemia and whole-body insulin sensitivity in rodent and non-human primate models of MAFLD/NASH and T2D reduce the risk of developing atherosclerotic CVD [6] and suggest that liver-targeted mitochondrial uncoupling agents may be a viable therapy for treating cardiometabolic disease in humans.