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.