Mitochondrial Fatty Acids and Neurodegenerative Disorders

Kastaniotis, Alexander J.; Autio, Kaija J.; Nair, R.

doi:10.1177/1073858420936162

Cited by 15 publications

(12 citation statements)

References 95 publications

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“…Several groups of disorders caused by of inborn errors leading in humans that affect lipoylation in mitochondria have been described [15]. The first group encompasses defects due to failures in synthesis of Fe-S clusters [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of the mitochondrial lipoylation pathway in yeast

et al. 2021

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Background Lipoylation of 2-ketoacid dehydrogenases is essential for mitochondrial function in eukaryotes. While the basic principles of the lipoylation processes have been worked out, we still lack a thorough understanding of the details of this important post-translational modification pathway. Here we used yeast as a model organism to characterize substrate usage by the highly conserved eukaryotic octanoyl/lipoyl transferases in vivo and queried how amenable the lipoylation system is to supplementation with exogenous substrate. Results We show that the requirement for mitochondrial fatty acid synthesis to provide substrates for lipoylation of the 2-ketoacid dehydrogenases can be bypassed by supplying the cells with free lipoic acid (LA) or octanoic acid (C8) and a mitochondrially targeted fatty acyl/lipoyl activating enzyme. We also provide evidence that the S. cerevisiae lipoyl transferase Lip3, in addition to transferring LA from the glycine cleavage system H protein to the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGD) E2 subunits, can transfer this cofactor from the PDH complex to the KGD complex. In support of yeast as a model system for human metabolism, we demonstrate that the human octanoyl/lipoyl transferases can substitute for their counterparts in yeast to support respiratory growth and protein lipoylation. Like the wild-type yeast enzyme, the human lipoyl transferase LIPT1 responds to LA supplementation in the presence of the activating enzyme LplA. Conclusions In the yeast model system, the eukaryotic lipoylation pathway can use free LA and C8 as substrates when fatty/lipoic acid activating enzymes are targeted to mitochondria. Lip3 LA transferase has a wider substrate specificity than previously recognized. We show that these features of the lipoylation mechanism in yeast are conserved in mammalian mitochondria. Our findings have important implications for the development of effective therapies for the treatment of LA or mtFAS deficiency-related disorders.

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Section: Introductionmentioning

confidence: 99%

Genetic dissection of the mitochondrial lipoylation pathway in yeast

et al. 2021

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“…Next, palmitic acid is further elongated and desaturated to generate complex fatty acids. Alternatively, d e novo synthesis also occurs in mitochondria but this pathway closely resembles the prokaryotic FA synthesis pathway [ 23 ]. However, this pathway has only one known product, lipoic acid, which functions as a cofactor for several important mitochondrial multienzyme complexes [ 24 ].…”

Section: Fatty Acid Biosynthesis In Healthy Cnsmentioning

confidence: 99%

“…Furthermore, lipoic acid reduces demyelization and axonal loss [ 152 ]. mtFAS deficiencies very specifically affect CNS function and lead to degeneration [ 23 , 153 ]. Thus, linoic acid metabolism is very promising as a therapeutic alternative in treating CNS disorders [ 151 , 154 , 155 , 156 ].…”

Section: Fa Synthesis In Neurological Diseasesmentioning

confidence: 99%

Fatty Acid Synthesis in Glial Cells of the CNS

Corrales

Haidar

Bogie

et al. 2021

IJMS

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Fatty acids (FAs) are of crucial importance for brain homeostasis and neural function. Glia cells support the high demand of FAs that the central nervous system (CNS) needs for its proper functioning. Additionally, FAs can modulate inflammation and direct CNS repair, thereby contributing to brain pathologies such Alzheimer’s disease or multiple sclerosis. Intervention strategies targeting FA synthesis in glia represents a potential therapeutic opportunity for several CNS diseases.

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“…Patients with MEPAN present in early childhood (1-6.5 years) with basal ganglia lesions leading to dystonia, chorea and other movement disorders, followed by progressive optic atrophy and occasional developmental delay. Finally, mtFAS dysfunction has also been implicated in Parkinson's disease 13,14 . Neurological symptoms in MEPAN indicates the importance of mtFAS in neuronal survival and maintenance, and raise an important question: how does mtFAS contribute to neuronal maintenance?…”

Section: Introductionmentioning

confidence: 99%

Loss of Mitochondrial Enoyl CoA Reductase causes elevated ceramide levels and impairs iron metabolism

Dutta

Kanca

Byeon

et al. 2023

Preprint

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In most eukaryotic cells fatty acid synthesis occurs in the cytoplasm as well as in mitochondria. However, the relative contribution of mitochondrial fatty acid synthesis (mtFAS) to the cellular lipidome of metazoans is ill-defined. Hence, we studied the function of the fly Mitochondria enoyl CoA reductase (Mecr), the enzyme required for the last step of mtFAS. Loss of mecr causes lethality while neuronal loss leads to progressive neurological defects. We observe an elevated level of ceramides, a defect in Fe-S cluster biogenesis and increased iron levels in mecr mutants. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes indicating that increased ceramides and iron metabolism are interrelated and play an important role in the pathogenesis. Mutations in human MECR cause pediatric-onset neurodegeneration and patient-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study shows an as-yet-unidentified role of mecr/MECR in ceramide and iron metabolism providing a mechanistic link between mtFAS and neurodegeneration

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Mitochondrial Fatty Acids and Neurodegenerative Disorders

Cited by 15 publications

References 95 publications

Genetic dissection of the mitochondrial lipoylation pathway in yeast

Genetic dissection of the mitochondrial lipoylation pathway in yeast

Fatty Acid Synthesis in Glial Cells of the CNS

Loss of Mitochondrial Enoyl CoA Reductase causes elevated ceramide levels and impairs iron metabolism

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