Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice

Abstract

There has been a growing interest toward mitochondrial fatty acid synthesis (mtFAS) since the recent discovery of a neurodegenerative human disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is caused by mutations in the mitochondrial enoyl-CoA/ACP (acyl carrier protein) reductase (MECR) carrying out the last step of mtFAS. We show here that MECR protein is highly expressed in mouse Purkinje cells (PCs). To elucidate mtFAS function in neural tissue, here, we generated a mouse line with a PC-specific knock-out (KO) of Mecr, leading to inactivation of mtFAS confined to this cell type. Both sexes were studied. The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age. These animals exhibited balancing difficulties ϳ7 months of age and ataxic symptoms were evident from 8 -9 months of age on. Our data show that impairment of mtFAS results in functional and ultrastructural changes in mitochondria followed by death of PCs, mimicking aspects of the clinical phenotype. This KO mouse represents a new model for impaired mitochondrial lipid metabolism and cerebellar ataxia with a distinct and well trackable cellular phenotype. This mouse model will allow the future investigation of the feasibility of metabolite supplementation approaches toward the prevention of neurodegeneration due to dysfunctional mtFAS.We have recently reported a novel neurodegenerative disorder in humans termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration) (Heimer et al., 2016). The cause of neuron degeneration in MEPAN patients is the dysfunction of the highly conserved mitochondrial fatty acid synthesis (mtFAS) pathway due to mutations in MECR, encoding mitochondrial 2-enoyl-CoA/ACP reductase. The report presented here describes the analysis of the first mouse model suffering from mtFASdefect-induced neurodegenerative changes due to specific disruption of the Mecr gene in Purkinje cells. Our work sheds a light on the mechanisms of neurodegeneration caused by mtFAS deficiency and provides a test bed for future treatment approaches.

Mitochondrial Fatty Acids and Neurodegenerative Disorders

“…Consequently, ISC biogenesis defects can affect LA biosynthesis and have been shown to result in neurological symptoms (Lebigot and others 2017). Depletion of mtFAS in mammalian cells has shown to result in mitochondrial fission in mammals (Monteuuis and others 2017; Nair and others 2018) and hence mitochondrial morphology dysregulation appears to be an additional phenotype of mtFAS dysfunction.…”

“…Gait abnormalities were observed in these conditional KO mice around 7 months of age. Detailed characterization of this model revealed functional and cellular ultrastructural changes preceding progressive loss of PCs and ataxic symptoms (Nair and others 2018). Reduction of the PC lining is already detectable in cerebellar sections of 6-month-old mice, where concomitant microgliosis and astrogliosis indicated ongoing neuron damage, progressing to almost complete loss of PCs by 11 months of age.…”

Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

“…Inducible knockout of the mitochondrial malonyl CoA-acyl carrier protein transacylase ( Mcat ) using a Cre driver that expresses in most tissues in mice results in a severe phenotype characterized by weight loss, reduced muscle strength, and shortened lifespan despite the persistence of residual MCAT protein ( Smith et al, 2012 ). Knockout of the mitochondrial 2-enoyl thioester reductase, Mecr , is lethal in mice due to a placental defect ( Nair et al, 2017 ), while the inducible knockout of Mecr specifically in Purkinje cells leads to loss of this cell population and recapitulates many phenotypes of MePaN syndrome, the human disease caused by Mecr mutation ( Gorukmez et al, 2019 ; Heimer et al, 2016 ; Nair et al, 2018 ). Similarly, Mecr knockdown has been shown to inhibit the growth of hepatocellular carcinoma cells ( Cai et al, 2019 ).…”

Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism

“…Inducible knockout of the mitochondrial malonyl CoA-acyl carrier protein transacylase (Mcat) using a Cre driver that expresses in most tissues in mice results in a severe phenotype characterized by weight loss, reduced muscle strength, and shortened lifespan despite the persistence of residual MCAT protein (Smith et al, 2012). Knockout of the mitochondrial 2-enoyl thioester reductase, Mecr, is lethal in mice due to a placental defect (Nair et al, 2017), while the inducible knockout of Mecr specifically in Purkinje cells leads to loss of this cell population and recapitulates many phenotypes of MePaN syndrome, the human disease caused by Mecr mutation (Gorukmez et al, 2019;Heimer et al, 2016;Nair et al, 2018). Similarly, Mecr knockdown has been shown to inhibit the growth of hepatocellular carcinoma cells (Cai et al, 2019).…”