Cardiolipin is a key determinant for mtDNA stability and segregation during mitochondrial stress

Abstract

Mitochondria play a key role in adaptation during stressing situations. Cardiolipin, the main anionic phospholipid in mitochondrial membranes, is expected to be a determinant in this adaptive mechanism since it modulates the activity of most membrane proteins. Here, we used Saccharomyces cerevisiae subjected to conditions that affect mitochondrial metabolism as a model to determine the possible role of cardiolipin in stress adaptation. Interestingly, we found that thermal stress promotes a 30% increase in the cardiolipin content and modifies the physical state of mitochondrial membranes. These changes have effects on mtDNA stability, adapting cells to thermal stress. Conversely, this effect is cardiolipin-dependent since a cardiolipin synthase-null mutant strain is unable to adapt to thermal stress as observed by a 60% increase of cells lacking mtDNA (ρ0). Interestingly, we found that the loss of cardiolipin specifically affects the segregation of mtDNA to daughter cells, leading to a respiratory deficient phenotype after replication. We also provide evidence that mtDNA physically interacts with cardiolipin both in S. cerevisiae and in mammalian mitochondria. Overall, our results demonstrate that the mitochondrial lipid cardiolipin is a key determinant in the maintenance of mtDNA stability and segregation.

Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure

“…The latter is likely facilitated by the ability of elamipretide to permeate the outer MITO membrane and bind to CL, a signature phospholipid of the inner MITO membrane that plays an important role in cristae formation, activity of respiratory complexes, organization of the respiratory complexes into supercomplexes for oxidative phosphorylation, MITO fusion and MITO DNA stability and segregation (10–12, 14,31). CL is biosynthesized in a series of steps from phosphatidic acid and remodeled into a form which contains four 18:2 fatty acid chains, tetralinoleol CL [(18:2) 4 CL].…”

Role of Cardiolipin in Mitochondrial Signaling Pathways

“…A significant adaption of the CL pool to external stress signaling has been reported in several studies. In yeast, increased total CL levels were found under temperature stress (Luévano-Martínez et al, 2015 ). A recent study observed increased total levels of CL and increased linoleic acid (18:2) content in CL, in skeletal muscle in response to overload stimuli (Fajardo et al, 2017 ).…”

Specific degradation of phosphatidylglycerol is necessary for proper mitochondrial morphology and function

“…The crd1Δ yeast strain displays growth defects and decreased viability on both fermentable and nonfermentable carbon sources at elevated temperatures, decreased mitochondrial membrane potential, and decreased respiratory rates [8,9,24]. Respiratory chain supercomplexes are destabilized in crd1Δ cells [14,25,26] and the lack of CL leads to mitochondrial DNA instability [8,9,27]. …”