AMPK promotes lysosomal and mitochondrial biogenesis via folliculin:FNIP1

Abstract

The AMP-activated protein kinase (AMPK) is known to maintain the integrity of cellular mitochondrial networks by (i) promoting fission, (ii) inhibiting fusion, (iii) promoting recycling of damaged components via mitophagy, (iv) enhancing lysosomal biogenesis to support mitophagy, and (v) promoting biogenesis of new mitochondrial components. While the AMPK targets underlying the first three of these effects are known, a recent paper suggests that direct phosphorylation of the folliculin-interacting protein 1 (FNIP1) by AMPK may be involved in the remaining two.

Figure 1

Inhibition of the GAP activity of FLCN:FNIP1 GAP by AMPK induces lysosomal and mitochondrial biogenesis. Activation of AMPK by mitochondrial inhibition or damage, energy stress, allosteric activators that bind the ADaM site, or glucose starvation promotes phosphorylation of FNIP1 at five sites, rendering the GAP activity of the FLCN:FNIP1 complex for RagC/D inactive. RagC/D:GTP then accumulates in the cytosol, reversing the inhibitory phosphorylation of TFEB/TFE3 by mTORC1 and causing dissociation of the latter from the lysosome. Active TFEB/TFE3 translocates to the nucleus to induce the transcription of CLEAR genes promoting lysosome biogenesis and mitophagy (early response) and of NT-PGC1α promoting mitochondria biogenesis (secondary response). P, phosphorylation. (Created with BioRender.com.).