Abstract
A mismatch between β-oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP-derived carnitine-lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster.
Highlights
Carnitine is an important molecule that regulates mitochondrial long-chain fatty acid β-oxidation and enables the import of fatty acid intermediates from the cytosol to the mitochondria via the carnitine cycle [1]
We found that 3-(2,2,2-trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD)
There is increasing experimental evidence that mutant Htt aggregates play an important role in the pathogenesis of HD in human and model organisms [45,46]
Summary
Carnitine is an important molecule that regulates mitochondrial long-chain fatty acid β-oxidation and enables the import of fatty acid intermediates from the cytosol to the mitochondria via the carnitine cycle [1]. The inhibition of carnitine palmitoyltransferase 1 (CPT1), the key rate-limiting enzyme of the carnitine carrier system, decreases fatty acid oxidation with a parallel increase in glucose oxidation [3]. CPT1 inhibition limits the carnitine shuttle for the oxidation of long-chain lipids in the mitochondria, carnitine allows the system to work through the peroxisomal synthesis of short- and medium-chain acylcarnitine. These carnitine derivatives can enter into the mitochondrial matrix independently by CPT1, still leading to mitochondria oversupply and dysfunction. As carnitines are important for mitochondrial β-oxidation, a disturbance in plasma membrane carnitine transport and/or liver carnitine synthesis can significantly affect fatty acid oxidation
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