Biology subjects

Andreu-Carbo, M.

Publications and source records attributed to Andreu-Carbo, M..

5 recordsLinked to original sources

bioRxiv2026

Gαq-mediated contact release is required for efficient mitochondrial quality control

Lysosomes and mitochondria are highly dynamic organelles whose coordinated interactions are essential for cellular homeostasis, while their dysfunction contributes to numerous human diseases. Here, we identify the mitochondrial outer membrane protein Fis1 and the RabGAPs TBC1D15 and TBC1D17 as novel interacting partners of the heterotrimeric G protein -subunit Gq. Using mitochondrial proteomics, co-immunoprecipitation, proximity ligation assays, and in vitro binding studies with purified proteins, we demonstrate that Gq forms a complex with Fis1 and TBC1D15/TBC1D17 through a non-canonical interaction interface. Gq localizes to mitochondria-lysosome contact sites, where it regulates the dynamic balance between contact formation and dissociation. Loss of Gq resulted in enlarged and clustered lysosomes and increased the extent and duration of mitochondria-lysosome contacts. Live-cell imaging revealed prolonged organelle tethering in Gq-deficient cells, while proximity ligation and three-dimensional reconstruction analyses localized Gq and TBC1D15 to mitochondrial tips closely associated with lysosomes. This localization, together with increased mitochondrial fission and altered mitophagic turnover following Gq loss, links the regulation of contacts at mitochondrial tips to mitochondrial fragmentation and quality control. Re-expression of Gq, but not the non-canonical interaction-deficient mutant, restored normal lysosomal morphology, contact-site dynamics, mitochondrial fragmentation, and mitophagy. Together, these findings identify a Gq as a dynamic regulator of mitochondria-lysosome untethering and connect contact site turnover with mitochondria fragmentation and mitophagy. Our work uncovers a novel link between G protein signaling, organelle communication, and mitochondrial quality control.

cell biology↗

bioRxiv2024

Trace Amines are Essential Metabolites for the Autocrine Regulation of β-Cell Signaling and Insulin Secretion

Secretion of insulin in response to extracellular stimuli, such as elevated glucose levels and small molecules that act on G-protein coupled receptors (GPCRs), is the hallmark of {beta}-cell physiology. Trace amines (TAs) are small aromatic metabolites that were identified as low-abundant ligands of the trace amine-associated receptor 1 (TAAR1) in the central nervous system (CNS), a GPCR that is also expressed by pancreatic {beta}-cells. In the present work, we identify TAs as essential autocrine signaling factors for {beta}-cell activity and insulin secretion. We find that {beta}-cells are producing TAs in significant amounts and that the modulation of endogenous TA levels by the selective inhibition of TA biosynthetic pathways directly translated into changes of oscillations of the intracellular Ca2+ concentration ([Ca2+]i oscillations) and insulin secretion. Selective TAAR1 agonists or inhibitors of monoamine oxidases increased [Ca2+]i oscillations and insulin secretion. Opposite effects were mediated by selective TAAR1 antagonists, by recombinant monoamine oxidase action and by the inhibition of amino acid decarboxylase. As the modulation of TA biochemical pathways immediately translated into changes of [Ca2+]i oscillations, we inferred high metabolic turnover rates of TAs and autocrine feedback. We found that psychotropic drugs modulate [Ca2+]i oscillations and insulin secretion, either directly acting on TAAR1 or by altering endogenous TA levels. Our combined data support the hypothesis of TAs as essential autocrine signaling factors for {beta}-cell activity and insulin secretion as well as TAAR1 as an important mediator of amine-modulated insulin secretion.

biochemistry↗

bioRxiv2022

Running Kinesin-1 shapes the microtubule acetylation gradient

The properties of single microtubules within the microtubule network can be modulated through posttranslational modifications (PTMs), including acetylation within the lumen of microtubules. To access the lumen, the enzymes could either enter through the microtubule ends or at damage sites along the microtubule shaft. Here we show that the acetylation profile depends on damage sites, which can be caused by the motor protein kinesin-1. Indeed, the entry of the deacetylase HDAC6 into the microtubule lumen depends on kinesin-1-induced damage sites. In contrast, activity of the microtubule acetylase TAT1 is independent of kinesin-1 and shaft damage. On a cellular level, our results show that microtubule acetylation distributes in an exponential gradient. This gradient results from tight regulation of microtubule (de-)acetylation and scales with the size of the cells. The control of shaft damage represents a novel mechanism to regulate PTM inside the microtubule by giving access to the lumen.

cell biology↗

bioRxiv2022

The effect of motor-induced shaft dynamics on microtubule stability and length

Control of microtubule abundance, stability, and length is crucial to regulate intracellular transport as well as cell polarity and division. How microtubule stability depends on tubulin addition or removal at the dynamic ends is well studied. However, microtubule rescue, the event when a microtubule switches from shrinking to growing, occurs at tubulin exchange sites along the shaft. Molecular motors have recently been shown to promote such exchanges. Using a stochastic theoretical description, we study how microtubule stability and length depends on motor-induced tubulin exchange and thus rescue. Our theoretical description matches our in vitro experiments on microtubule dynamics in presence of kinesin-1 molecular motors. Although the average microtubule dynamics can be captured by an effective rescue rate, the dynamics of individual microtubules differs dramatically when rescue occurs only at exchange sites. Furthermore, we study in detail a transition from bounded to unbounded microtubule growth. Our results provide novel insights into how molecular motors imprint information of microtubule stability on the microtubule network. SIGNIFICANCEThe microtubule network is essential for vital cellular processes like the organization of intracellular transport and division. Although microtubule assembly occurs at its tips, it has recently been reported that tubulin is exchanged along the microtubule shaft. Tubulin exchange plays an essential role in regulating microtubule dynamics and can be induced by molecular motors. Here, we provide the first systematic study of the impact of shaft dynamics on the regulation of rescue events, where a microtubule switches from shrinking to growing. Our results illustrate how the usage of microtubules as tracks for intracellular transport regulates the microtubule network and thus offers a novel perspective on intracellular organization.

biophysics↗

bioRxiv2021

Motor usage imprints microtubule stability in the shaft

Tubulin dimers assemble into dynamic microtubules which are used by molecular motors as tracks for intracellular transport. Organization and dynamics of the microtubule network is commonly thought to be regulated at the polymer ends, where tubulin-dimers can be added or removed. Here we show that molecular motors running on microtubules cause exchange of dimers along the shaft. These sites of dimer exchange act as rescue sites where depolymerising microtubules stop shrinking and start re-growing. Consequently, the average length of microtubules increases depending on how frequently they are used as motor tracks. An increase of motor activity densifies the cellular microtubule network and enhances cell polarity. Running motors leave marks in the shaft serving as traces of microtubule usage to organize the polarity landscape of the cell.

cell biology↗