Impaired Acetyl-CoA Compartmentalization Drives a Futile Lipogenic–Oxidative Cycle in N88S Seipinopathy

TL;DR

A mutation in seipin disrupts acetyl-CoA use, causing harmful lipid production and oxidative stress in motor neuron disease.

Contribution

The study identifies a futile lipogenic-oxidative cycle caused by acetyl-CoA misrouting in N88S seipinopathy.

Findings

N88S seipin disrupts acetyl-CoA compartmentalization, limiting mitochondrial and glyoxylate cycle pathways.

Misrouted acetyl-CoA increases cytosolic lipogenesis and oxidative stress in N88S seipinopathy.

Intervening at multiple metabolic control points offers novel therapeutic strategies for seipinopathies.

Abstract

What are the main findings?
The N88S seipin mutation disrupts acetyl-CoA compartmentalization, limiting its proper utilization through mitochondrial and glyoxylate cycle consuming pathways.Misrouting of acetyl-CoA promotes cytosolic lipogenesis and potentiates oxidative stress.

The N88S seipin mutation disrupts acetyl-CoA compartmentalization, limiting its proper utilization through mitochondrial and glyoxylate cycle consuming pathways.

Misrouting of acetyl-CoA promotes cytosolic lipogenesis and potentiates oxidative stress.

What are the implications of the main findings?
Defective peroxisome–mitochondria metabolic coupling fuels a futile lipogenic–oxidative cycle that amplifies cellular dysfunction in N88S seipinopathy.Intervening at multiple metabolic control points, by enhancing mitochondrial acetyl-CoA utilization, promoting phospholipid biosynthetic flux, modulating lipogenic transcriptional programs, and optimizing peroxisomal metabolic capacity, offers novel therapeutic avenues to treat seipinopathies and related motor neuron diseases.

Defective peroxisome–mitochondria metabolic coupling fuels a futile lipogenic–oxidative cycle that amplifies cellular dysfunction in N88S seipinopathy.

Intervening at multiple metabolic control points, by enhancing mitochondrial acetyl-CoA utilization, promoting phospholipid biosynthetic flux, modulating lipogenic transcriptional programs, and optimizing peroxisomal metabolic capacity, offers novel therapeutic avenues to treat seipinopathies and related motor neuron diseases.

The N88S mutation in human seipin causes a dominant motor neuron disease marked by ER stress and inclusion body formation, lipid imbalance, and oxidative damage. However, the metabolic mechanisms connecting these defects remain poorly understood. Previous proteomic profiling in our yeast model of N88S human seipinopathy revealed decreased protein levels of enzymes involved in the tricarboxylic acid cycle, fatty acid and carboxylic acid metabolism, and the glyoxylate cycle, suggesting impaired downstream utilization of peroxisome-derived acetyl-CoA. Guided by these findings, we investigated how peroxisomal function contributes to cellular dyshomeostasis. N88S seipin-expressing cells exhibited increased peroxisome abundance but defective routing of acetyl-CoA into mitochondrial and glyoxylate pathways, resulting in elevated reactive oxygen species (ROS), impaired glyoxylate cycle activation, and reduced metabolic adaptability to non-fermentable carbon sources. Loss of peroxisomes or forced cytosolic redirection of acetyl-CoA further exacerbated ER stress, ROS accumulation, lipid peroxidation, and the growth defect on N88S seipin-expressing cells, whereas inhibition of fatty acid synthesis mitigated oxidative damage. These findings demonstrate that N88S seipin triggers a futile cycle in which misrouted cytosolic acetyl-CoA drives lipogenesis, amplifying oxidative damage and ER stress. We conclude that defective peroxisome–mitochondria metabolic coupling and acetyl-CoA misrouting may represent central pathogenic mechanisms driving cellular dysfunction in N88S-linked seipinopathy.

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