Lack of Mitochondrial Anionic Phospholipids Causes an Inhibition of Translation of Protein Components of the Electron Transport Chain

Abstract

Reduction of mitochondrial cardiolipin (CL) levels has been postulated to compromise directly the function of several essential enzymes and processes of the mitochondria. There is limited genetic evidence for the critical roles with which CL and its precursor phosphatidylglycerol (PG) have been associated. A null allele of the PGS1 gene from Saccharomyces cerevisiae, which encodes the enzyme responsible for the synthesis of the CL precursor PG phosphate, was created in a yeast strain in which PGS1 expression is exogenously regulated by doxycycline. The addition of increasing concentrations of doxycycline to the growth medium causes a proportional decrease to undetectable levels of PGS1 transcript, PG phosphate synthase activity, and PG plus CL. The doubling time of this strain with increasing doxycycline increases to senescence in non-fermentable carbon sources or at high temperatures, conditions that do not support growth of the pgs1⌬ strain. Doxycycline addition also causes mitochondrial abnormalities as observed by fluorescence microscopy. Products of four mitochondrial encoded genes (COX1, COX2, COX3, and COB) and one nuclear encoded gene (COX4) associated with the mitochondrial inner membrane are not present when PGS1 expression is fully repressed. No translation of these proteins can be detected in cells lacking the PGS1 gene product, although transcription and splicing appear unaffected. Protein import of other nuclear encoded proteins remains unaffected. The remaining proteins encoded by mitochondrial DNA are expressed and translated normally. Thus, the molecular basis for the lack of mitochondrial function in pgs1⌬ cells is the failure to translate gene products essential to the electron transport chain.

Role of cardiolipin in cytochrome c release from mitochondria

“…A similar correlation between lowered cardiolipin content and release of cytochrome c from the IMM has previously been found in palmitate-induced apoptosis of cardiomyocytes. 35 Growing cells in the presence of this fatty acid in the culture medium resulted in a decreased mitochondrial cardiolipin content and a compensatory increase in its biosynthetic precursor, phospatidylglycerol, as well as enhanced rate of cell death. In contrast, cultivating cells in the presence of an unsaturated fatty acid, oleate, did not cause a decrease in cardiolipin content, provoke cytochrome c release or affect death rate in cardiomyocytes.…”

Lipids, cardiolipin and apoptosis: a greasy licence to kill

“…For instance, a major PC species in mouse liver mitochondria has one palmitate and one arachidonate. Most membrane lipids follow a similar balance of saturated and unsaturated fatty acids, 1,6 but not cardiolipin, which is the most unsaturated (i.e. oxidised) lipid of our body.…”

Isc1p Plays a Key Role in Hydrogen Peroxide Resistance and Chronological Lifespan through Modulation of Iron Levels and Apoptosis

“…The activation of Isc1p is dependent on Pgs1p, which catalyzes the committed step in the synthesis of phosphatidylglycerol and cardiolipin in the mitochondria. Loss of either ISC1 or PGS1 results in down-regulation of the mitochondrial cytochrome c oxidase subunits Cox3p and Cox4p, suggesting that Isc1p mediates at least some functions downstream of phosphatidylglycerol/cardiolipin (Ostrander et al, 2001;Vaena de Avalos et al, 2005).…”