A mitochondrial pathway for biosynthesis of lipid mediators

Abstract

The central role of mitochondria in metabolic pathways and in cell death mechanisms requires sophisticated signaling systems. Essential in this signaling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin, are oxidized by the intermembrane space hemoprotein, cytochrome c. We show that an assortment of oxygenated cardiolipin species undergoes phospholipase A2-catalyzed hydrolysis thus generating multiple oxygenated fatty acids, including well known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway including oxidation of polyunsaturated cardiolipins and accumulation of their hydrolysis products – oxygenated linoleic, arachidonic acids and monolyso-cardiolipins – is activated in vivo after acute tissue injury.

Minimalist Model Systems Reveal Similarities and Differences between Membrane Interaction Modes of MCL1 and BAK

“…The latter are not unprecedented, because CL microdomains have been described in bacterial membranes (33). Of note, although the role of CL during apoptosis is still unsettled, recent reports indicate that CL and/or its derivatives accumulate at the MOM early in the course of apoptotic cell death (34,35). It should also be taken into account that the BCL2-like structural folds of MCL1, BAK, and cBID are primarily oriented toward the cytosol-facing leaflet of the MOM, which should be enriched in CL relative to the intermembrane-facing leaflet of the MOM in accord with the asymmetrical interleaflet distribution of negatively charged lipids commonly found in biomembranes (32).…”

“…Although the physiological relevance of the latter set of results can be put into question due to the high CL amounts required to observe such effects, recent studies indicate that CL and its derivatives become enriched at the MOM early during the apoptotic process (34,35). Interestingly, further evidence indicates that lipids other than CL accumulate at the MOM during apoptosis and interact selectively with specific BCL2 family members (22).…”

NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

“…60 Mono-lyso-CL formed in PLA 2 -driven reaction was analyzed by LC/MS using a Dionex Ultimate 3000 HPLC coupled on-line to a Q-Exactive hybrid quadrupole-orbitrap mass spectrometer (ThermoFisher Scientific) as previously described. 62 Mono-lyso-CLs were separated on a normal phase column (Silica Luna 3 μm, 100 A, 150 × 2 mm, Phenomenex) with flow rate 0.2 ml/min using gradient solvents containing 5 mM CH 3 COONH 4 (A -n-hexane:2-propanol:water, 43:57:1 (v/v/v) and B -n-hexane:2-propanol:water, 43:57:10 (v/v/v). Mono-lyso-CL (tri-myristoyl-lyso-CL) was prepared from tetra-myristoyl-CL (Avanti polar lipids) by PLA 2 hydrolysis and used as internal standard.…”

Structural Re-arrangement and Peroxidase Activation of Cytochrome c by Anionic Analogues of Vitamin E, Tocopherol Succinate and Tocopherol Phosphate

“…with alternate proportions of hemolytic versus heterolytic activation of peroxide substrates, resulting in diversified stereospecificity of CL peroxidation products. Physiologically, the significance of these alternate pathways may be realized through the hydrolysis of peroxidized CL leading to the production of different lipid mediators, oxygenated fatty acids, and oxygenated or non-oxygenated lyso-CLs with yet to be explored signaling functions (51). ␣-TOS (and its mitochondrially targeted counterpart, mito-VES) and ␣-TOP can serve as activators of peroxidase activity of cytochrome c leading to CL oxidation as a step in the execution of the apoptotic program.…”