5.2. Therapeutic agents targeting the AMPK-OPA1 pathway
As several studies have noted a role for the AMPK-OPA1 pathway in mitophagy activation upon melatonin treatment (Zhang et al., 2019), targeting components of AMPK-OPA1 should help to strengthen melatonin-regulated mitophagy.
AMPK activators induce intracellular accumulation of either adenosine monophosphate (AMP) or Ca2+ and are thus termed “indirect activators”, whereas, some activators directly interact with AMPK to foster its kinase activity, thus being termed “direct activators” (Samant et al., 2014).
Substantial evidence indicates that metformin antidiabetic actions are attributed to AMPK activation. Mechanistically, metformin blocks complex I of the mitochondria, thus increasing AMP levels and activating AMPK (Owen, Doran & Halestrap, 2000). Thiazolidinediones are a class of pharmaceutical drugs including rosiglitazone, pioglitazone, and troglitazone, which activate AMPK via AMP accumulation due to the inhibition of mitochondrial respiratory complex I (Brunmair et al., 2004).
In addition to pharmaceutical agents, some naturally occurring agents can activate AMPK. Polyphenols including curcumin, quercetin, genistein, berberine, epigallocatechin-3-gallate, and resveratrol, which exist in fruits, vegetables, and plants, have been reported to switch on AMPK (Sharma & Kumar, 2017). Epigallocatechin-3-gallate, curcumin, quercetin, and resveratrol increase AMP levels by targeting the mitochondrial ATP synthase (Gledhill, Montgomery, Leslie & Walker, 2007; Zheng & Ramirez, 2000), whereas berberine increases AMP levels by targeting mitochondrial respiratory complex I (Turner et al., 2008).
Ginsenosides are extracted from ginseng and exhibit a favorable impact on type 2 diabetes, largely attributable to AMPK activation (Jeong, Kim & Chung, 2014). A naturally available dithiol agent, α-lipoic acid, generated from octanoic acid, can also activate AMPK likely by inducing Ca2+ accumulation, and, thereby, activation of the CAMKK1 (calcium/calmodulin dependent protein kinase kinase 1)-AMPK axis.
Several AMPK activators directly interact with AMPK complex and cause conformational changes, leading to its enzymatic activation. For example, 5-aminoimidazole-4-carboxamide riboside, thienopyridine, salicylate, compound-13, PT-1, and MT 63–78 are AMPK activators (Cool et al., 2006; Corton, Gillespie, Hawley & Hardie, 1995; Gómez-Galeno et al., 2010; Hawley et al., 2012; Pang et al., 2008; Zadra et al., 2014). Overall, a combinational therapeutic system comprising melatonin plus AMPK modulators might boost mitophagy activation and regulation in macrophages. Given that mitochondrial SIRT3 can deacetylate OPA1 and enhance its activity (Samant et al., 2014), SIRT3 modulators may confer OPA1 activation as well.