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Role of the yeast neutral sphingomyelinase in mitochondria function and iron homeostasis

IBMC - Institute for Molecular and Cell Biology
Project classification

Scientific area

1.6 Biological sciences (Medical sciences go to scientific area 3.n; Agricultural sciences go to scientific area 4.n)

Discipline(s)

Biochemistry and molecular biology

Project description

Project title

Role of the yeast neutral sphingomyelinase in mitochondria function and iron homeostasis

Scientific Coordinator's name:

Vítor Costa

Scientific Coordinator's e-mail:

vcosta@ibmc.up.pt

Principal R&D Unit:

Redox Cell Signalling

Other R&D Units involved in the project:

Other R&D units involved in the project

Project keyword(s)

Sphingolipids; Mitochondria; Apoptosis; Iron

Short abstract and comments

Mitochondria play a vital role in energy production through oxidative phosphorylation and have an important function in the regulation of various other processes, including stress responses and cell death. They are considered the major source of reactive oxygen species, and an abnormal cellular redox homeostasis due to mitochondrial dysfunction has been implicated in the ageing process and increases the incidence of age-related disorders. In recent years, interest into the role of sphingolipids in mitochondria function, redox homeostasis and lifespan has greatly increased, since the regulation of sphingolipid metabolism may be of potential therapeutic relevance in pathologies associated with oxidative stress and ageing. Ceramide is a bioactive sphingolipid that modulates cellular processes such as apoptosis and ageing. Several protein targets, including ceramide-activated protein phosphatases, have been suggested to mediate the effects of ceramide but the signalling pathways involved remain poorly characterized. The yeast Saccharomyces cerevisiae has a well-defined genome and is a genetically tractable organism. Therefore, studies in this simple genetic model system may be helpful in defining the role of sphingolipids in mitochondrial function. The neutral sphingomyelinase nSMase2 is considered a major candidate for mediating ceramide signalling during stress responses and ageing. We have previously shown that Isc1, the yeast orthologue of mammalian nSMase2, plays a key role in oxidative stress resistance and chronological lifespan. Isc1 deficiency affects redox status and iron homeostasis and increases cell death by apoptosis. This project aims to uncover the role of Isc1 in the modulation of mitochondria function. We propose that Isc1 finely tunes ceramide levels and, therefore, modulates ceramide signalling pathways that control mitochondria morphology and functional properties, as well as mitochondria-mediated cell death pathways. We expect to identify protein targets and mediators of signalling pathways that are deregulated in isc1 cells and to characterize how these changes relate to isc1 phenotypes.

Potential uses/indications

This project will contribute to the characterization of the role of neutral sphingomyelinases and sphingolipid signalling in the modulation of mitochondria function and iron homeostasis and to our understanding of processes associated with lipid-related disorders, including ageing.

Status

Ongoing

Partner Status: Seeking Partners?

Yes

Grant number (QREN, FP7, Eureka, etc)

PTDC/BBB-BQB/1850/2012

Last edited on

2013-02-01 16:21:42

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