New Insights into the Role of Mitochondria-Associated Endoplasmic Reticulum Membrane

Fujimoto, Michiko; Hayashi, Teruo

doi:10.1016/b978-0-12-386033-0.00002-5

Cited by 92 publications

(86 citation statements)

References 246 publications

(269 reference statements)

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“…For instance, a mitochondrial fusion protein, Mfn2, tethers mitochondria and the ER (53). In addition, many proteins are enriched at the mitochondrion-associated ER membrane (54). OM-IM contact sites are also formed by multiple mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Role for Two Conserved Intermembrane Space Proteins, Ups1p and Up2p, in Intra-mitochondrial Phospholipid Trafficking

Tamura

Onguka

Hobbs

et al. 2012

Journal of Biological Chemistry

103

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Background: Specific phospholipid composition in mitochondria is essential for mitochondrial activities. Results: Two intermembrane space proteins, Ups1p and Ups2p, antagonistically regulate conversion of phosphatidylethanolamine to phosphatidylcholine. Conclusion:The endoplasmic reticulum-mitochondria tethering complex and Ups proteins have related functions in phospholipid metabolism and trafficking. Significance: Deciphering regulation of phospholipid metabolism is vital for understanding the biogenesis of mitochondrial membranes and functions.

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Section: Discussionmentioning

confidence: 99%

Role for Two Conserved Intermembrane Space Proteins, Ups1p and Up2p, in Intra-mitochondrial Phospholipid Trafficking

Tamura

Onguka

Hobbs

et al. 2012

Journal of Biological Chemistry

103

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“…Although the initial steps and the majority of de novo ceramide formation clearly take place in the ER ( 7,8 ), the enzymes involved in the fi nal steps of ceramide formation (CerS and dihydroceramide desaturase) were also found in mitochondria ( 14,84,85 ). Moreover, Ardail and colleagues provided evidence that MAM, the specialized ER compartment involved in the transfer of lipids and Ca 2+ between the ER and mitochondria (86)(87)(88), contains glucosylceramide and lactosylceramide synthases which tunnel glycosphingolipids to mitochondria ( 89 ). On the catabolic side of ceramide metabolism, mitochondrial association of NCDase ( 9-11 ) and sphingosine kinase 2 ( 10,15 ) were also demonstrated.…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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“…22,23 The proteins involved in this contact region are still a subject of investigation and appear to be subject to dynamic changes. 23 {M} fraction contains some proteins that have been suggested to be part of the MAM (ACAT1, ATP2A2, ATP2A3, CALR, CANX, CYB5R1, CYB5R3, CYP1A1, ERLIN2, ERP44, HSPA5, HSPA9, PDIA3, TMX1), but not others (DGAT2, ERLIN1, HMOX1, ITPR1, MFN1, MFN2, PACS2, PEMT, PTDSS1, PTDSS2, RYR1). Many of these proteins have other known functions outside the MAM, but this suggests that there could be partial capture of endoplasmic reticulum proteins in this specialized region from the mitochondrial side even though there is not general contamination of the mitochondria with endoplasmic reticulum.…”

Section: Hierarchical Analysis Of Subcellular Distribution With Explimentioning

confidence: 99%

Spatial Distribution of Cellular Function: The Partitioning of Proteins between Mitochondria and the Nucleus in MCF7 Breast Cancer Cells

et al. 2012

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New Insights into the Role of Mitochondria-Associated Endoplasmic Reticulum Membrane

Cited by 92 publications

References 246 publications

Role for Two Conserved Intermembrane Space Proteins, Ups1p and Up2p, in Intra-mitochondrial Phospholipid Trafficking

Role for Two Conserved Intermembrane Space Proteins, Ups1p and Up2p, in Intra-mitochondrial Phospholipid Trafficking

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Spatial Distribution of Cellular Function: The Partitioning of Proteins between Mitochondria and the Nucleus in MCF7 Breast Cancer Cells

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