Caveolin-1 impairs PKA-DRP1-mediated remodelling of ER–mitochondria communication during the early phase of ER stress

Abstract

Close contacts between endoplasmic reticulum and mitochondria enable reciprocal Ca exchange, a key mechanism in the regulation of mitochondrial bioenergetics. During the early phase of endoplasmic reticulum stress, this inter-organellar communication increases as an adaptive mechanism to ensure cell survival. The signalling pathways governing this response, however, have not been characterized. Here we show that caveolin-1 localizes to the endoplasmic reticulum-mitochondria interface, where it impairs the remodelling of endoplasmic reticulum-mitochondria contacts, quenching Ca transfer and rendering mitochondrial bioenergetics unresponsive to endoplasmic reticulum stress. Protein kinase A, in contrast, promotes endoplasmic reticulum and mitochondria remodelling and communication during endoplasmic reticulum stress to promote organelle dynamics and Ca transfer as well as enhance mitochondrial bioenergetics during the adaptive response. Importantly, caveolin-1 expression reduces protein kinase A signalling, as evidenced by impaired phosphorylation and alterations in organelle distribution of the GTPase dynamin-related protein 1, thereby enhancing cell death in response to endoplasmic reticulum stress. In conclusion, caveolin-1 precludes stress-induced protein kinase A-dependent remodelling of endoplasmic reticulum-mitochondria communication.

Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells

“…Furthermore, by means of TMRE (a potentiometric probe that can be used for direct measurement of the mitochondria membrane potential ∆Ψm) [45], we evaluated the RM preservation of ∆Ψm ( Figure 5D,E) and concomitant increase in TMRE-ER-tracker co-localization ( Figure 5D,F). This increase in ER-mitochondria proximity [62] and in TMRE fluorescence suggests that RM can modulate both mitochondrial bioenergetics and ER-mitochondria contacts. We want to highlight how the quantitative cytometric data help to interpret the co-localization frameworks: in fact, the increase of co-localization for lysosomes and ER happens in parallel to a significant and relevant decrease of ER-tracker fluorescence ( Figure 4C) (attesting a decrease in ER cisternae and tubules), and a strong increase in lysosome-LTDR fluorescence (for ATCC 33291 lysate-treated cells only).…”

Caveolin-1 suppresses tumor formation through the inhibition of the unfolded protein response

“…Indeed, CAV1 is located at the mitochondria-associated ER membrane fraction (MAMs) 31 and genetic ablation of CAV1 has detrimental effects on mitochondrial function 64,65 . Moreover, we recently showed that CAV1 impairs the remodeling of ER-mitochondria contacts by precluding protein kinase A signaling, as evidenced by alterations in organelle distribution and impaired phosphorylation of the GTPase dynamin-related protein 1, thus enhancing cell death in response to ER stress 66 . Alternatively, CAV1 has recently been implicated as a core component of the calcium-dependent apoptotic pathway that regulates critical mitochondrial functions during tumor development 67 .…”

Imbalance in mitochondrial dynamics induced by low PGC-1α expression contributes to hepatocyte EMT and liver fibrosis

“…Dnm1/Drp1 assemble on the surface of mitochondria and drive membrane constriction and the scission of the inner and outer mitochondrial membranes in a GTP-dependent manner. The endoplasmic reticulum (ER), ER-bound inverted-formin 2 (INF2), and actin assembly at mitochondria-ER contact sites are required for mitochondrial fission [15][16][17] . An increase in phospho-Drp1 levels was detected in mitochondrial outermembrane and forms a large ring-like complex to exert fission activity in sporadic Parkinson's disease cellular models, implicating increased mitochondrial fission in the pathophysiology of Parkinson's diseases 18,19 .…”