Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis

Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization and dynamics of the inter-organellar contact established by sheets of curved rough endoplasmic reticulum closely wrapped around the mitochondria (wrappER). To elucidate the in vivo function of this contact, mouse liver fractions enriched in wrappER-associated mitochondria are analyzed by transcriptomics, proteomics, and lipidomics. The biochemical signature of the wrappER points to a role in the biogenesis of very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion and increases hepatic fatty acids, lipid droplets, and neutral lipid content. Conversely, acute liver-specific ablation of Mttp, the most upstream regulator of VLDL biogenesis, recapitulates this hepatic dyslipidemia phenotype and promotes remodeling of the wrappER-mitochondria contact. The discovery that liver wrappER-mitochondria contacts participate in VLDL biology suggests an involvement of inter-organelle contacts in systemic lipid homeostasis.Fil: Anastasia, Irene. Laval University; Canadá. Brain Research Center; CanadáFil: Ilacqua, Nicolò. Laval University; Canadá. Brain Research Center; CanadáFil: Raimondi, Andrea. San Raffaele Scientific Institute; ItaliaFil: Lemieux, Philippe. Brain Research Center; CanadáFil: Ghandehari-Alavijeh, Rana. Brain Research Center; CanadáFil: Faure, Guilhem. Broad Institute of MIT and Harvard; Estados Unidos. National Center For Biotechnology Information; Estados UnidosFil: Mekhedov, Sergei L.. National Center For Biotechnology Information ; Estados UnidosFil: Williams, Kevin J.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Caicci, Federico. Università di Padova; ItaliaFil: Valle, Giorgio. Università di Padova; ItaliaFil: Giacomello, Marta. Università di Padova; ItaliaFil: Quiroga, Ariel Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. University of Alberta; CanadáFil: Lehner, Richard. University of Alberta; CanadáFil: Miksis, Michael J.. Northwestern University; Estados UnidosFil: Toth, Katalin. University of Ottawa; CanadáFil: de Aguiar Vallim, Thomas Q.. University of California at Los Angeles. School of Medicine; Estados UnidosFil: Koonin, Eugene V.. National Center For Biotechnology Information ; Estados UnidosFil: Scorrano, Luca. Università di Padova; ItaliaFil: Pellegrini, Luca. Laval University; Canad

Dual role of Miro protein clusters in mitochondrial cristae organisation and ER-Mitochondria Contact Sites

Mitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts (MEF) we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and endoplasmic reticulum-mitochondria contacts sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality

Infiltration of ambient PM 2.5 and levels of indoor generated non-ETS PM 2.5 in residences of four European cities

Ambient fine particle (PM 2.5) concentrations are associated with premature mortality and other health effects. Urban populations spend a majority of their time in indoor environments, and thus exposures are modified by building envelopes. Ambient particles have been found to penetrate indoors very efficiently (penetration efficiency P≈1.0), where they are slowly removed by deposition, adsorption, and other mechanisms. Other particles are generated indoors, even in buildings with no obvious sources like combustion devices, cooking, use of aerosol products, etc.. The health effects of indoor generated particles are currently not well understood, and require information on concentrations and exposure levels. The current work apportions residential PM 2.5 concentrations measured in the EXPOLIS study to ambient and non-ambient fractions. The results show that the mean infiltration efficiency of PM 2.5 particles is similar in all four cities included in the analysis, ranging from 0.59 in Helsinki to 0.70 in Athens, with Basle and Prague in between. Mean residential indoor concentrations of ambient particles range from 7 (Helsinki) to 21 μg m -3 (Athens). Based on PM 2.5 decay rates estimated in the US, estimates of air exchange rates and indoor source strengths were calculated. The mean air exchange rate was highest in Athens and lowest in Prague. Indoor source strengths were similar in Athens, Basle and Prague, but lower in Helsinki. Some suggestions of possible determinants of indoor generated non-ETS PM 2.5 were acquired using regression analysis. Building materials and other building and family characteristics were associated with the indoor generated particle levels. A significant fraction of the indoor concentrations remained unexplained. © 2004 Elsevier Ltd. All rights reserved

Indoor time-microenvironment-activity patterns in seven regions of Europe

Personal exposure to environmental substances is largely determined by time-microenvironment-activity patterns while moving across locations or microenvironments. Therefore, time-microenvironment-activity data are particularly useful in modeling exposure. We investigated determinants of workday time-microenvironment-activity patterns of the adult urban population in seven European cities. The EXPOLIS study assessed workday time- microenvironment-activity patterns among a total of 1427 subjects (age 19-60 years) in Helsinki (Finland), Athens (Greece), Basel (Switzerland), Grenoble (France), Milan (Italy), Prague (Czech Republic), and Oxford (UK). Subjects completed time-microenvironment-activity diaries during two working days. We present time spent indoors - at home, at work, and elsewhere, and time exposed to tobacco smoke indoors for all cities. The contribution of sociodemographic factors has been assessed using regression models. More than 90% of the variance in indoor time-microenvironment-activity patterns originated from differences between and within subjects rather than between cities. The most common factors that were associated with indoor time-microenvironment-activity patterns, with similar contributions in all cities, were the specific work status, employment status, whether the participants were living alone, and whether the participants had children at home. Gender and season were associated with indoor time-microenvironment-activity patterns as well but the effects were rather heterogeneous across the seven cities. Exposure to second-hand tobacco smoke differed substantially across these cities. The heterogeneity of these factors across cities may reflect city-specific characteristics but selection biases in the sampled local populations may also explain part of the findings. Determinants of time-microenvironment-activity patterns need to be taken into account in exposure assessment, epidemiological analyses, exposure simulations, as well as in the development of preventive strategies that focus on time-microenvironment-activity patterns that ultimately determine exposures. © 2007 Nature Publishing Group All rights reserved.link_to_subscribed_fulltex

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

Abstract Background In mouse liver hepatocytes, nearly half of the surface area of every mitochondrion is covered by wrappER, a wrapping-type of ER that is rich in fatty acids and synthesizes lipoproteins (VLDL) (Anastasia et al. in Cell Rep 34:108873, 2021; Hurtley in Science (80- ) 372:142–143, 2021; Ilacqua et al. in J Cell Sci 135:1–11, 2021). A disruption of the ultrastructure of the wrappER-mitochondria contact results in altered fatty acid flux, leading to hepatic dyslipidemia (Anastasia et al. 2021). The molecular mechanism that regulates the extent of wrappER-mitochondria contacts is unknown. Methods We evaluated the expression level of the mitochondrial protein Synj2bp in the liver of normal and obese (ob/ob) mice. In addition, we silenced its expression in the liver using an AAV8 vector. We coupled quantitative EM morphometric analysis to proteomics and lipid analyses on these livers. Results The expression level of Synj2bp in the liver positively correlates with the extent of wrappER-mitochondria contacts. A 50% reduction in wrappER-mitochondria contacts causes hepatic dyslipidemia, characterized by a gross accumulation of lipid droplets in the liver, an increased hepatic secretion of VLDL and triglycerides, a curtailed ApoE expression, and an increased capacity of mitochondrial fatty acid respiration. Conclusion Synj2bp regulates the extent of wrappER-mitochondria contacts in the liver, thus contributing to the control of hepatic lipid flux