Activation of AMPK/mTORC1-Mediated Autophagy by Metformin Reverses Clk1 Deficiency-Sensitized Dopaminergic Neuronal Death

Abstract

The autophagy-lysosome pathway (ALP) plays a critical role in the pathology of Parkinson's disease (PD). Clk1 (coq7) is a mitochondrial hydroxylase that is essential for coenzyme Q (ubiquinone) biosynthesis. We have reported previously that Clk1 regulates microglia activation via modulating microglia metabolic reprogramming, which contributes to dopaminergic neuronal survival. This study explores the direct effect of Clk1 on dopaminergic neuronal survival. We demonstrate that Clk1 deficiency inhibited dopaminergic neuronal autophagy in cultured MN9D dopaminergic neurons and in the substantia nigra pars compacta of Clk mutant mice and consequently sensitized dopaminergic neuron damage and behavioral defects. These mechanistic studies indicate that Clk1 regulates the AMP-activated protein kinase (AMPK)/rapamycin complex 1 pathway, which in turn impairs the ALP and TFEB nuclear translocation. As a result, Clk1 deficiency promotes dopaminergic neuronal damage in vivo and in vitro, which ultimately contributes to sensitizing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal death and behavioral impairments in Clk1-deficient mice. Moreover, we found that activation of autophagy by the AMPK activator metformin increases dopaminergic neuronal survival in vitro and in the MPTP-induced PD model in Clk1 mutant mice. These results reveal that Clk1 plays a direct role in dopaminergic neuronal survival via regulating ALPs that may contribute to the pathologic development of PD. Modulation of Clk1 activity may represent a potential therapeutic target for PD.

The anti-tubercular activity of simvastatin is mediated by cholesterol-dependent regulation of autophagy via the AMPK-mTORC1-TFEB axis

“…Our pathway analysis of simvastatin-treated PBMC also identified upregulation of signaling pathways regulated by AMPK, a serine-threonine kinase that inhibits mTORC1 signaling and induces autophagy (55) and upregulated Liver kinase B1 (LKB1), a serine-threonine kinase that activates AMPK (56) (Table 2), as previously observed in squamous cell carcinoma (57). Since these two proteins participate in the energy-sensing cascade activated by an increased AMP:ATP ratio (56), we first asked whether simvastatin treatment alters cellular AMP:ATP ratios in M. tuberculosis -infected cells.…”

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

“…Autophagy is a self-digestion process that facilitates the turnover of damaged proteins 49 . Several studies have revealed that metformin is a potent activator of the AMPK signalling pathway, which mediates the induction of autophagy [50][51][52] . Although it has been reported that metformin treatment induces the phosphorylation of AMPK in HaCaT cells 43 , an immortalized human keratinocyte cell line, whether it induces this in primary normal keratinocytes such as NHEKs, has not been tested.…”

MicroRNA-337-3p suppresses cell viability, apoptosis, and autophagy by modulating PPARγ expression in androgen-dependent human prostate cancer

“…The mechanisms underlying the relationship bet ween AR inhibition and autophagy remain elusive; however, AMPK and mTORC1 might play vital roles in the regulation of autophagy (Carroll and Dunlop 2017;Yan Q et al 2017). Here, we found that the decrease in autophagy is not dependent on PPARγ degeneration caused by miR-337-3p and is instead associated with a change in AMPK phosphorylation after androgen deprivation.…”