Deficiency of Cardiolipin Synthase Causes Abnormal Mitochondrial Function and Morphology in Germ Cells of Caenorhabditis elegans

Abstract

Background: Cardiolipin is required for maintaining optimal mitochondrial function. Results: Cardiolipin depletion selectively obstructed proliferation, mitochondrial function, and morphology in germ cells. Conclusion: The contribution of cardiolipin to mitochondrial function and morphology varies among the different cell types in vivo.Significance: This provides a biological basis for understanding the different sensitivities of organelles to changes in the lipid environment.Cardiolipin (CL) is a major membrane phospholipid specifically localized in mitochondria. At the cellular level, CL has been shown to have a role in mitochondrial energy production, mitochondrial membrane dynamics, and the triggering of apoptosis. However, the in vivo role of CL in multicellular organisms is largely unknown. In this study, by analyzing deletion mutants of a CL synthase gene (crls-1) in Caenorhabditis elegans, we demonstrated that CL depletion selectively caused abnormal mitochondrial function and morphology in germ cells but not in somatic cell types such as muscle cells. crls-1 mutants reached adulthood but were sterile with reduced germ cell proliferation and impaired oogenesis. In the gonad of crls-1 mutants, mitochondrial membrane potential was significantly decreased, and the structure of the mitochondrial cristae was disrupted. Contrary to the abnormalities in the gonad, somatic tissues in crls-1 mutants appeared normal with respect to cell proliferation, mitochondrial function, and mitochondrial morphology. Increased susceptibility to CL depletion in germ cells was also observed in mutants of phosphatidylglycerophosphate synthase, an enzyme responsible for producing phosphatidylglycerol, a precursor phospholipid of CL. We propose that the contribution of CL to mitochondrial function and morphology is different among the cell types in C. elegans. Cardiolipin (CL)2 is an anionic phospholipid with a unique diphosphatidylglycerol structure containing four acyl groups (1-3). In eukaryotic cells, CL localizes predominantly to the mitochondrial inner membrane, where it serves specific roles in mitochondrial structure and function. CL biosynthesis occurs via three enzymatic reactions, all catalyzed by enzymes present in the mitochondria (Fig. 1A) (4). The first step, catalyzed by phosphatidylglycerophosphate (PGP) synthase, is the synthesis of PGP from cytidine diphosphate-diacylglycerol (CDP-DAG) and glycerol 3-phosphate. PGP phosphatase dephosphorylates PGP to phosphatidylglycerol (PG). In the final step, CL synthase catalyzes the formation of CL from PG and CDP-DAG. These enzymes are highly conserved in eukaryotes (Figs. 1A, 2B, and 9B) (5).So far, in vitro analysis has revealed that CL interacts with a number of mitochondrial proteins and is required for the optimal activity of several enzymes in the mitochondrial electron transport chain, including NADH dehydrogenase (complex I) (6), ubiquinol:cytochrome c reductase (complex III) (7-10), cytochrome c oxidase (complex IV) (11,12), and ATP synthase (complex V) (13). Consi...

Cardiolipin or MTCH2 can serve as tBID receptors during apoptosis

“…Indeed, these mitochondria exhibited increased electron density with less and disorganized cristae (Figure 2e), which is in agreement with previously published results. [33][34][35][36][37] In addition to reduction in cyt c, we also observed a decrease in the protein level of MTCO1 (Figure 2b). A reduction in the amount of this labile protein suggests a defect in respiratory chain complex IV assembly.…”

APOOL Is a Cardiolipin-Binding Constituent of the Mitofilin/MINOS Protein Complex Determining Cristae Morphology in Mammalian Mitochondria

“…In a mouse model for human Barth syndrome which is characterized by low tetralinoleoyl CL levels mitochondrial morphology as well as cristae ultrastructure were greatly distorted [55]. Cristae alterations were further observed in C. elegans when CL synthesis is impaired [56]. Taken together, APOOL may well be required for proper transport of CL e.g.…”

Emerging roles for specific fatty acids in developmental processes

“…A strain carrying a mutation in crls-1, the homolog of cardiolipin synthases, produced a very small brood compared with wild type. Further studies revealed defects in germ cell proliferation in the crls-1 mutants, even though somatic cells divided normally in the same animals (Sakamoto et al 2012). This suggests that the contribution of cardiolipin to mitochondrial function varies among cell types and indicates that proper membrane lipid composition in mitochondria is vital for the optimal proliferation of germ cells.…”