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Université de Fribourg

Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import

Finger, Yannik ; Habich, Markus ; Gerlich, Sarah ; Urbanczyk, Sophia ; Logt, Erik ; Koch, Julian ; Schu, Laura ; Lapacz, Kim Jasmin ; Ali, Muna ; Petrungaro, Carmelina ; Salscheider, Silja Lucia ; Pichlo, Christian ; Baumann, Ulrich ; Mielenz, Dirk ; Dengjel, Jörn ; Brachvogel, Bent ; Hofmann, Kay ; Riemer, Jan

In: The EMBO Journal, 2020, vol. 39, no. 19, p. e103889

Plasticity of the proteome is critical to adapt to varying conditions. Control of mitochondrial protein import contributes to this plasticity. Here, we identified a pathway that regulates mitochondrial protein import by regulated N-terminal processing. We demonstrate that dipeptidyl peptidases 8/9 (DPP8/9) mediate the N-terminal processing of adenylate kinase 2 (AK2) en route to mitochondria....

Université de Fribourg

The re-emerging pathophysiological role of the cystathionine-β-synthase - hydrogen sulfide system in Down syndrome

Szabo, Csaba

In: The FEBS Journal, 2020, p. -

Down syndrome (DS) is associated with significant perturbances in many morphological and biochemical features. Cystathionine‐β‐synthase (CBS) is one of the key mammalian enzymes that is responsible for the biological production of the gaseous transmitter hydrogen sulfide (H2S). When H2S is overproduced, it can exert detrimental cellular effects, in part due to inhibition of mitochondrial...

Université de Fribourg

Hypoxia enhances endothelial intercellular adhesion molecule 1 protein level through upregulation of arginase type II and mitochondrial oxidative stress

Liang, Xiujie ; Arullampalam, Prakash ; Yang, Zhihong ; Ming, Xiu-Fen

In: Frontiers in Physiology, 2019, vol. 10, p. -

Hypoxia plays a crucial role in the pathogenesis of cardiovascular diseases. Mitochondrial enzyme arginase type II (Arg-II) is reported to lead to endothelial dysfunction and enhance the expression of endothelial inflammatory adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, we investigate the role of Arg-II in...

Université de Fribourg

Phosphorylation of mitochondrial matrix proteins regulates their selective mitophagic degradation

Kolitsida, Panagiota ; Zhou, Jianwen ; Rackiewicz, Michal ; Nolic, Vladimir ; Dengjel, Jörn ; Abeliovich, Hagai

In: Proceedings of the National Academy of Sciences, 2019, vol. 116, no. 41, p. 20517–20527

Mitophagy is an important quality-control mechanism in eukaryotic cells, and defects in mitophagy correlate with aging phenomena and neurodegenerative disorders. It is known that different mitochondrial matrix proteins undergo mitophagy with very different rates but, to date, the mechanism underlying this selectivity at the individual protein level has remained obscure. We now present...

Université de Fribourg

Overproduction of H2S, generated by CBS, inhibits mitochondrial Complex IV and suppresses oxidative phosphorylation in Down syndrome

Panagaki, Theodora ; Randi, Elisa B. ; Augsburger, Fiona ; Szabo, Csaba

In: Proceedings of the National Academy of Sciences, 2019, p. 201911895

Down syndrome (DS) is associated with significant perturbances in mitochondrial function. Here we tested the hypothesis that the suppression of mitochondrial electron transport in DS cells is due to high expression of cystathionine-β-synthase (CBS) and subsequent overproduction of the gaseous transmitter hydrogen sulfide (H2S). Fibroblasts from DS individuals showed higher CBS expression...

Università della Svizzera italiana

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Genini, Davide ; Brambilla, Lara ; Laurini, Erik ; Merulla, Jessica ; Civenni, Gianluca ; Pandit, Shusil ; D'Antuono, Rocco ; Perez, Laurent ; Levy, David E. ; Pricl, Sabrina ; Carbone, Giuseppina M. ; Catapano, Carlo V.

In: Proceedings of the national academy of sciences of the United States of America, 2017, vol. 114, no. 25, p. E4924-E4933

In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The...

Université de Fribourg

Vectorial import via a metastable disulfide-linked complex allows for a quality control step and import by the mitochondrial disulfide relay

Habich, Markus ; Salscheider, Silja Lucia ; Murschall, Lena Maria ; Hoehne, Michaela Nicole ; Fischer, Manuel ; Schorn, Fabian ; Petrungaro, Carmelina ; Ali, Muna ; Erdogan, Alican J. ; Abou-Eid, Shadi ; Kashkar, Hamid ; Dengjel, Jörn ; Riemer, Jan

In: Cell Reports, 2019, vol. 26, no. 3, p. 759-774.e5

Disulfide formation in the mitochondrial intermembrane space (IMS) is an essential process. It is catalyzed by the disulfide relay machinery, which couples substrate import and oxidation. The machinery relies on the oxidoreductase and chaperone CHCHD4-Mia40. Here, we report on the driving force for IMS import and on a redox quality control mechanism. We demonstrate that unfolded reduced...

Université de Fribourg

Parvalbumin alters mitochondrial dynamics and affects cell morphology

Lichvarova, Lucia ; Henzi, Thomas ; Safiulina, Dzhamilja ; Kaasik, Allen ; Schwaller, Beat

In: Cellular and Molecular Life Sciences, 2018, vol. 75, no. 24, p. 4643–4666

The Ca2+-binding protein parvalbumin (PV) and mitochondria play important roles in Ca2+ signaling, buffering and sequestration. Antagonistic regulation of PV and mitochondrial volume is observed in in vitro and in vivo model systems. Changes in mitochondrial morphology, mitochondrial volume and dynamics (fusion, fission, mitophagy) resulting from modulation of PV were investigated in MDCK...