Setting the curve: the biophysical properties of lipids in mitochondrial form and function

Venkatraman K, Lee CT, and Budin I. (2024) Setting the curve: the biophysical properties of lipids in mitochondrial form and function. Journal of Lipid Research

Mitochondria are double-membraned organelles that are the production site of adenosine triphosphate (ATP), a source of energy in a cell. The two membrane layers, outer membrane (OMM) and invaginated inner membrane (IMM), have distinctly different functions. The IMM’s morphology is made up of folds called cristae which is where ATP synthesis occurs. Alternatively, the OMM acts as a barrier for metabolites, cations, and other molecules from getting into or out of the mitochondria. In addition, the OMM has important roles in mitophagy, fission and fusion, and maintains interactions with other organelles. For the two mitochondrial membrane layers to have such separate functions, different and tightly regulated lipid compositions are required. This review explores the presence of non-bilayer phospholipids in the IMM, phospholipid metabolism pathways, acyl chain homeostasis, and cardiolipin, however this blog will focus on their discussion of the role of plasmalogens in the mitochondrial membranes.

Plasmalogens are a unique lipid class that contain a vinyl-ether bond at the sn1 position which causes the lipid to have a more compact conformation. This double bond allows plasmalogens to influence membrane structure, fluidity, and function. The presence of plasmalogens in membranes is vital as an antioxidant and for proper vesicular fusion. Plasmalogen levels vary between tissues which could explain some of the discrepancies in the levels of plasmalogens reported to be in mitochondria. Plasmalogens have been found to be anywhere from 10-40% of the lipid pool of mitochondria, but these differences could be due to different types of sources being uses. In addition, since they are antioxidants and the vinyl-ether bond scavenges radical oxygen species, which are generated by mitochondria, plasmalogens could be acting as a regulator of lipid peroxidation. This is also why plasmalogen levels are reduced in states of inflammation and aging. One property that the vinyl-ether bond provides to plasmalogens is a reduced Lα to HII transition temperature which results in a higher tendency to form non-lamellar structures, which is essential for the IMM.

It is well known that there is an association between plasmalogens and maintenance of the function of mitochondria. In a cell model of plasmalogen deficiency (PEX26 knockout cells), researchers found that there was also a reduction in mitochondrial volume and an increase in cardiolipin levels, which may be a compensatory response to the lack of plasmalogens in the membrane. Interestingly, supplementation with plasmalogens was able to recover plasmalogen levels and corrected mitochondrial morphology, further confirming their role in the structure of mitochondrial membranes. A Barth Syndrome (BTHS) lymphoblast model, which has a mutation in the phospholipid acyltransferase tafazzin gene resulting in an inability to remodel cardiolipin, has also been evaluated. A tafazzin deficiency is associated with alterations to other lipids including plasmalogens and a group administered plasmalogen precursors to BTHS lymphoblasts and were able to recover the mitochondrial lipid defects compared to the lymphoblasts that were not treated with the precursors. (This study can be read about further here).

Venkatraman et al explored the lipidomic differences between the inner and outer membranes of mitochondria and their role within the membranes and their functions. Although these lipids have been studied for many decades, there are still many questions about how lipid properties affect the structure and function of membranes, especially in specialized organelles. In this review Venkatraman et al explained the benefits and interesting characteristics that the double bond in plasmalogens provides to mitochondrial membranes. These include their antioxidant properties which is likely employed against ROS produced by mitochondria, their necessity for vesicular fusion, and the reduced Lα to HII transition temperature leading to a higher likelihood of forming non-lamellar structures. Plasmalogen deficiencies have been shown to reduce mitochondria volume and affect their function, and supplementing with plasmalogens has been determined to be able to recover these defects, further supporting the importance of plasmalogens in mitochondrial membranes. Continuing to elucidate the role of plasmalogens in mitochondrial function would be important in understanding pathologies in mitochondrial disorders and provide useful insights for drug development.