bims-mecosi 2023-06-25 papers

Issue of 2023‒06‒25
three papers selected by
Verena Kohler

bioRxiv. 2023 Jun 06. pii: 2023.06.05.543771. [Epub ahead of print]

An obligate intracellular bacterial pathogen forms a direct, interkingdom membrane contact site.

Yamilex Acevedo-Sánchez, Patrick J Woida, Stephan Kraemer, Rebecca L Lamason.

Interorganelle communication regulates cellular homeostasis through the formation of tightly-associated membrane contact sites 1-3 . Prior work has identified several ways that intracellular pathogens alter contacts between eukaryotic membranes 4-6 , but there is no existing evidence for contact sites spanning eukaryotic and prokaryotic membranes. Here, using a combination of live-cell microscopy and transmission and focused-ion-beam scanning electron microscopy, we demonstrate that the intracellular bacterial pathogen Rickettsia parkeri forms a direct membrane contact site between its bacterial outer membrane and the rough endoplasmic reticulum (ER), with tethers that are approximately 55 nm apart. Depletion of the ER-specific tethers VAPA and VAPB reduced the frequency of rickettsia-ER contacts, suggesting these interactions mimic organelle-ER contacts. Overall, our findings illuminate a direct, interkingdom membrane contact site uniquely mediated by rickettsia that seems to mimic traditional host MCSs.

DOI: https://doi.org/10.1101/2023.06.05.543771

Science. 2023 Jun 23. 380(6651): eadh9351

Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.

Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.

DOI: https://doi.org/10.1126/science.adh9351

Research (Wash D C). 2023 ;6 0175

LonP1 Links Mitochondria-ER Interaction to Regulate Heart Function.

Yujie Li, Dawei Huang, Lianqun Jia, Fugen Shangguan, Shiwei Gong, Linhua Lan, Zhiyin Song, Juan Xu, Chaojun Yan, Tongke Chen, Yin Tan, Yongzhang Liu, Xingxu Huang, Carolyn K Suzuki, Zhongzhou Yang, Guanlin Yang, Bin Lu.

Interorganelle contacts and communications are increasingly recognized to play a vital role in cellular function and homeostasis. In particular, the mitochondria-endoplasmic reticulum (ER) membrane contact site (MAM) is known to regulate ion and lipid transfer, as well as signaling and organelle dynamics. However, the regulatory mechanisms of MAM formation and their function are still elusive. Here, we identify mitochondrial Lon protease (LonP1), a highly conserved mitochondrial matrix protease, as a new MAM tethering protein. The removal of LonP1 substantially reduces MAM formation and causes mitochondrial fragmentation. Furthermore, deletion of LonP1 in the cardiomyocytes of mouse heart impairs MAM integrity and mitochondrial fusion and activates the unfolded protein response within the ER (UPRER). Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming and pathological heart remodeling. These findings demonstrate that LonP1 is a novel MAM-localized protein orchestrating MAM integrity, mitochondrial dynamics, and UPRER, offering exciting new insights into the potential therapeutic strategy for heart failure.

DOI: https://doi.org/10.34133/research.0175