PUFA is incompatible with and directly toxic to mammalian mitochondria
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This is one of the few studies that presents direct and largely indisputable biochemical evidence for the negative effects of PUFA on human (and mammalian) health. Namely, it demonstrates that PUFA is truly an “alien” lipid species for mammalian mitochondria, largely due to the negative effects PUFA administration has on the lipid structure/function of mammalian cells such as the cell membrane and the crucial mitochondrial protein known as cardiolipin (CL). CL structure largely determines the speed of oxidative metabolism, and any perturbations in the lipid composition of CL has been shown to not only have detrimental effects on the metabolic rate, but has already been implicated in a diverse set of pathologies including cancer, heart disease, Parkinson Disease and various motor neuron diseases such as ALS. As the study states, PUFA are primarily plant lipids and are incompatible with CL stability and function. Namely, when human CL was exposed to linoleic or linoleinic acids, it results in both remodeling of CL structure associated with reduction in MUFA and SFA lipids, combined with increase mitochondrial fragmentation. Moreover, the degree of mitochondrial fragmentation and CL instability and dysfunction correlated with the degree of lipid unsaturation to which human CL was exposed. In other words, omega-3 PUFA, which are much more unsaturated than the omega-6 PUFA used in this study, are expected to have a much bigger detrimental effect on human CL On the same line of thought, several studies have already demonstrated that CL unsaturation increases progressively with aging (or severity of a chronic disease), resulting in greatly reduced metabolic rate. Conversely, administration of either fully hydrogenated/saturated lipids or an anti-oxidant targeting CL restored metabolism back to youthful rates. As the study itself states, plants and mammals have evolved to have preferences for different lipids, and exposure of one kindgom (e.g. animals) to the very different lipids (e.g. PUFA) predominantly used by another kingdom (e.g. plants) is unlikely to lead to good health outcomes.
https://pubmed.ncbi.nlm.nih.gov/40016208/
“…Finally, we tested if human CI could withstand engineered changes in unsaturation of fatty acyl chains in IMM-lipids. Recently, Oemer et al. demonstrated modulation of molar composition and unsaturation of various lipids including CL in mammalian cells treated with different fatty acids57,58. Increased incorporation of 18:2 fatty acyl chains in CL has also been linked to efficient OxPhos58 while increase in 18:3 fatty acid perturbs mitochondrial respiration59,60. We treated Hs-A1 cells with BSA conjugated 18:2 linoleic acid and 18:3 alpha-linolenic acid and performed mass spectrometry of the mitochondrial CLs (Fig. 6a). CL species 64:4, 66:1, 72:4, 66:5, 70:5 with 16:1, 18:1 and 18:2 fatty acids were rich in BSA-treated cells (Fig. 6a) suggesting their natural abundance in HEK293T mitochondria. Treatment with linoleic acid resulted in replacement of at least one of the fatty acyl chains with 18:2 resulting in CL 70:6, 70:7, 72:7, 72:8 etc. CL 72:8 with all four 18:2 fatty acyl chains were highly abundant in these cells (Fig. 6a). Alpha-linolenic acid treatment resulted in multiple unique CLs with 18:3 fatty acyl chains that were absent in both BSA and linoleic acid treated cells while CLs with 16:1, 18:1 and 18:2 fatty acyl chains were prominently reduced (Fig. 6a). Microscopy indicated fragmented mitochondria correlating with the degree of unsaturation of CLs (Supplementary Fig. 7a). Simultaneously, in-gel EGFP fluorescence assays revealed efficient entry of Hs-A1 in CI-HC and SCs in BSA-treated and 18:2 treated cells but only partial entry was observed in 18:3 treated cells (Fig. 6b). Interestingly, the cleaved product of Ch-A1 was reduced when cells were treated with 18:2 and 18:3 fatty acids suggesting slightly better stability of the trans-IMM helix in presence of unsaturated lipids (Fig. 6c). However, Ch-A1 was never integrated with CI-assemblies as probed by in-gel EGFP fluorescence assay (Supplementary Fig. 7c) correlating with perturbation of endogenous assemblies of CI in 18:3 fatty acid treated cells as probed by Ndufs1 western blots and in-gel CI-activity assay (Figs. 6d–e and Supplementary Fig. 7c). Together, these results suggested that the chemistry of the exposed amino acids in the trans-IMM helix of Ndufa1 with the surrounding saturated or unsaturated lipids determined the integration of the subunit in CI assemblies in different forms of eukaryotic life (Fig. 7).”
“…The balance of saturated and unsaturated phospholipids regulates curvature, fluidity, protein stability, and crowding in all cellular membranes6,70. Plant lipid metabolism has been evolved to favor polyunsaturated fatty acids (PUFA) which provide membrane plasticity to cope up with diverse habitats71. PUFA is also prevalent in aqueous metazoans to maintain membrane fluidity72. Accordingly, investigating evolution of lipid unsaturation in non-mitochondrial membranes and correlated sequence divergence in membrane-embedded proteins would be interesting.”
https://www.nature.com/articles/d44151-025-00073-7
“…Proteins interact with proteins to form stable complexes. But little is known about lipid-protein interactions. The scientists, led by Swasti Raychaudhuri, studied Complex I, the largest of the five respiratory complexes in mitochondria in plants, fungi and animals. They noticed a surprising number of mutations on the lipid-facing surfaces of Complex I proteins — parts not involved in protein-protein interactions. Next, the researchers probed cardiolipin, a key lipid in the inner mitochondrial membrane. In plants, cardiolipin has more unsaturated fatty acid chains than in animals. This difference affects how lipids pack and interact with proteins. Using various tools, including molecular dynamics simulations, they showed that protein helices from humans and plants function optimally in their own lipid environments. Exposure to plant-type lipids destabilised the human respiratory Complex I, the researchers found.”