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.

Sex‐ and strain‐specific effects of mitochondrial uncoupling on age‐related metabolic diseases in high‐fat diet‐fed mice

“…Some of the beneficial effects of mild mitochondrial uncoupling have previously been attributed to activation of AMPK and alterations in mitochondrial biogenesis (Demine et al, 2019 ; Goedeke & Shulman, 2021 ). To determine whether CRMP‐mediated reductions in ectopic lipid content and improvements in hepatic insulin sensitivity were due to mitochondrial adaptations, we next evaluated the effects of CRMP treatment on several static markers of mitochondrial content in the livers of HFD‐fed aging mice treated with 20 mg/(kg‐day) CRMP for 4 weeks.…”

Altered Mitochondrial Quality Control in Rats with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Induced by High-Fat Feeding

“…Recent studies have indicated that a reduction of the hepatic mitochondrial function and abnormalities of lipid metabolism are associated with increases in ectopic fat deposition and insulin resistance in humans with MAFLD [ 42 , 43 , 44 , 45 ]. In particular, mitochondrial dysfunction includes impaired oxidative phosphorylation (OXPHOS), and increased production of ROS [ 46 ]. A gene expression analysis suggested that the observed mitochondrial dysfunction might be attributable to the downregulation of genes related to the mitochondrial quality control, which has been demonstrated to operate through the coordination of biogenesis, dynamics, and mitophagy to ensure cell homeostasis [ 47 ].…”

Insulin resistance and insulin sensitizing agents

“…To overcome its adverse effects, the liver-targeted agents DNP-methyl ether (DNPME) and controlled-release mitochondrial protonophore (CRMP) were developed. Both agents enhance hepatic FAO and reduce ectopic lipid deposition without changes in BW, resulting in improved hepatic steatosis and whole-body IR in rodent models and nonhuman primates [148]. Conversely, BAM15 decreases BW without affecting food intake, and improves whole-body insulin sensitivity, hepatic FAO, steatosis and inflammation in obese mice [148].…”