ACOT8

ACOT8 Full Name

acyl-CoA thioesterase 8

ACOT8 Introduction

Acyl-CoA Thioesterase 8 (ACOT8), also known as acyl-CoA thioesterase MTE-2 or mitochondrial acyl-CoA thioesterase 2, is a unique member of the acyl-CoA thioesterase (ACOT) family, exclusively specialized in regulating medium-chain and long-chain acyl-CoA ester metabolism within mitochondria. Distinguished from other ACOT family members (including ACOT9 with dual localization), ACOT8 is strictly localized to the mitochondrial matrix, where it fulfills a critical role in maintaining mitochondrial lipid homeostasis and supporting energy metabolism. ACOT8 catalyzes the hydrolysis of medium-chain (C8-C14) and long-chain (C16-C20) acyl-CoA esters to free fatty acids and coenzyme A (CoA), preventing the toxic buildup of these intermediates that would impair mitochondrial function. It is predominantly expressed in tissues with high mitochondrial density and energy demand, including the heart, skeletal muscle, and liver, where its function is essential for sustaining mitochondrial fatty acid oxidation and overall cellular energy homeostasis. Today, ACOT8 is recognized not only as a mitochondria-specific acyl-CoA thioesterase but also as a key regulator of mitochondrial lipid metabolism, with profound implications for mitochondrial biology, metabolic disorders, and cardiac health research.

Figure 1.The structure of ACOT8.

ACOT8 Gene and Protein Features
The ACOT8 gene is located on human chromosome 11q13.1, encoding a approximately 42 kDa protein that is exclusively targeted to the mitochondrial matrix. Unlike ACOT9 (which lacks a classic targeting signal), ACOT8 contains a conserved N-terminal mitochondrial targeting sequence (MTS) that mediates its import into mitochondria—this targeting is critical for its function, as its substrates are primarily generated within the mitochondrial matrix during fatty acid oxidation. The protein contains a conserved thioesterase domain, which is responsible for its catalytic activity, with highest specificity toward medium-chain and long-chain acyl-CoA esters, including lauroyl-CoA (C12:0) and palmitoyl-CoA (C16:0). Structurally, ACOT8 shares a core thioesterase domain with other ACOT family members but contains unique amino acid residues in its active site that enhance its affinity for mitochondrial acyl-CoA substrates. Additionally, ACOT8 is stabilized by interactions with mitochondrial inner membrane proteins, ensuring its proper localization and catalytic efficiency within the mitochondrial matrix.

ACOT8 in Disease and Therapeutic Relevance
Genetic variations and dysregulation of ACOT8 are closely associated with mitochondrial disorders and metabolic diseases linked to impaired energy metabolism. Reduced ACOT8 expression or activity leads to the accumulation of medium-chain and long-chain acyl-CoA esters in the mitochondrial matrix, disrupting fatty acid oxidation and mitochondrial function. This is linked to cardiac myopathy, where impaired mitochondrial energy production causes muscle weakness, arrhythmias, and heart failure. In skeletal muscle, ACOT8 dysregulation contributes to exercise intolerance, myopathy, and muscle wasting. Additionally, ACOT8 deficiency is associated with non-alcoholic fatty liver disease (NAFLD), as impaired mitochondrial fatty acid oxidation promotes hepatic lipid accumulation and inflammation. Common genetic polymorphisms in the ACOT8 gene have been linked to increased susceptibility to metabolic syndrome and cardiovascular disease. ACOT8 holds therapeutic potential for these conditions: modulating its activity could restore mitochondrial fatty acid metabolism, improve energy production, and alleviate symptoms of mitochondrial and metabolic disorders. Ongoing research focuses on developing targeted therapies to enhance ACOT8 function in diseased tissues.

Alternate Names for ACOT8

ACOT8; acyl-CoA thioesterase 8; hTE; PTE1; PTE2; PTE-1; PTE-2; HNAACTE; hACTE-III; acyl-coenzyme A thioesterase 8