Olkkonen, V. | bioRxiv Science

bioRxiv2019

ORP5 REGULATES TRANSPORT OF LIPIDS AND CALCIUM TO MITOCHONDRIA AT ENDOPLASMIC RETICULUM-MITOCHONDRIA MEMBRANE CONTACT SITES

Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membranes (MAMs) subdomains, physically linked to the MIB/MICOS complexes that bridge the two mitochondrial membranes. We also show that ORP5/8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a novel physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membranes contacts maintained by the MIB/MICOS complexes.

cell biology↗

bioRxiv2018

Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

ObjectiveLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically-induced ANGPTL3 deficiency in fasting and postprandial state.\n\nApproach and ResultsWe studied individuals carrying S17X loss-of-function mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between loss-of-function carriers and noncarriers in fasting state and after a high fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in low-density lipoprotein cholesterol (0.74 SD-units lower concentration per loss-of-function allele [95%CI 0.42-1.06]) as observed for many triglyceride-rich lipoprotein measures, including very-low-density lipoprotein cholesterol (0.75 [0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within triglyceride-rich lipoproteins and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [0.21-0.89]). Homozygous ANGPTL3 loss-of-function carriers showed essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids, without evidence for adverse compensatory metabolic effects.\n\nConclusionsIn addition to overall triglyceride and low-density lipoprotein cholesterol lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within triglyceride-rich lipoproteins and their remnants. Further, ANGPTL3 loss-of-function carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.\n\nHIGHLIGHTSO_LIANGPTL3 deficiency results in similar reductions in LDL cholesterol and many triglyceride-rich lipoprotein lipids measures, such as VLDL cholesterol, with no evidence of substantial adverse effects on the comprehensive panel of circulating metabolite biomarkers tested here.\nC_LIO_LIIn particular, ANGPTL3 deficiency results in reduction of cholesterol content in triglyceride-rich lipoproteins and their remnants, which have been highlighted as risk factor for cardiovascular disease independently of LDL levels.\nC_LIO_LIHomozygous ANGPTL3 loss-of-function carriers show essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids in response to a fat challenge, and display consistently elevated postprandial levels of ketone bodies and lactate when compared to noncarriers, suggesting enhanced hepatic fatty acid beta-oxidation.\nC_LI

genetics↗