[5] Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid-lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acyltransferases).
A 30 residue hydrophobic stretch at the N terminus may function as a membrane anchor, which does not exist in the shortest forms of tafazzins.
[15] The half-life of tafazzin is just 3–6 hours, considerably shorter than most mitochondrial proteins, which may explain research difficulties in studying its structure.
[17] In addition, tafazzin localizes to the membrane leaflets facing the intermembrane space (IMS), which is crucial for remodeling.
Tafazzin transacylase activity is responsible for cardiolipin remodeling, critical to maintaining mitochondrial inner membrane structure and function.
Tafazzin, an acyl-specific transferase, catalyzes the acyl transfer reaction between phospholipids and lysophospholipids in a CoA-independent manner.
The remodeling process of cardiolipin involves reaching a final acyl composition that is primarily linoleoyl residues.
[26] MLCL is reacylated by tafazzin in a single-step reaction which transfers a linoleic acid group from phosphatidylcholine (PC), completing the CL deacylation-reacylation cycle.
[19] Cardiolipin is a complex glycerophospholipid which contains four acyl groups linked to three glycerol moietie localized in the mitochondrial inner membrane.
Properly formed CL is critical in maintaining mitochondrial shape, energy production, and protein transport within cells,[9] and remodeling by tafazzin aids in removing and replacing acyl chains damaged by oxidative stress.
[36] During apoptosis and similar processes, CL is known to act as a platform for proteins and other machinery involved with its interactions with members of the Bcl-2 family, caspases, Bid, Bax, and Bak.
As a result, linoleic acid is not added to cardiolipin, which disrupts normal mitochondrial shape and function, including energy production and protein transport.
[citation needed] Additionally, affected white blood cells have abnormally shaped mitochondria, which could impair their ability to grow (proliferate) and mature (differentiate), leading to a weakened immune system and recurrent infections.
[9] Phenotypes of Barth Syndrome encompass a wide range, with cardiovascular, musculoskeletal, neurological, metabolic, and hematologic consequences.
[45][46][47] Common clinical manifestations include:[9][38] Additional features include hypertrophic cardiomyopathy, isolated noncompaction of left ventricular myocardium (INVM), ventricular arrhythmia, motor delay, poor appetite, fatigue and exercise intolerance, hypoglycemia, lactic acidosis, hyperammonemia, and dramatic late catch-up growth after growth delay throughout childhood.
The change in acyl chain composition and lipid peroxidation caused by defective tafazzin can cause defective sarcomeric action, which may lead to an insufficient power stroke, severely weakened tissue, enlarged left ventricle, partial or incomplete contraction, and decreased ejection volume.
Such consequences contribute to the cardiomyopathic phenotypes of Barth syndrome, marked by a weakened heart and diminished contractility.
[35][55] Alternatively, reactive oxygen species (ROS) has been suggested as the primary cause of cardiovascular impairments in BTHS.
LVNC is a condition in which the left ventricle, characterized by a spongy structure on the ventricular wall, exhibits prominent trabeculations and deep intertrabecular recesses.
[60] Additional symptoms of musculoskeletal pathology include hypotonia, delayed motor development, short stature, and facial dysmorphia in varying degrees.
[citation needed] Treatment for developmental delays have included cornstarch supplementation as an alternative source of glucose.
[47] Metabolic deficiencies have been treated by oral arginine and carnitine supplementation, which has been shown to ameliorate cardiac function and muscle weakness in some patients.
[61] This shows the limited neurologic involvement in BTHS, despite tafazzin's crucial roles in brain mitochondrial respiration and normal cognitive function.
[69] The major hematologic pathology for BTHS patients is neutropenia, a condition characterized by a decline in total number of neutrophils in circulation with an increase in monocytes and eosinophils and no fluctuations in lymphocytes.
This resistance was identified to be due to the acquired ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT).
[12] In a study of 140 Swedish rectal cancer patients, TAFAZZIN overexpression was associated with an increase in the expression of oncogenes (FXYD-3 and Livin).
[15] Owing to the complex procedure required for the identification of tafazzin, the protein was named after Tafazzi, an Italian comedy character played by Giacomo Poretti who enthusiastically beats his groin with a plastic bottle, this as a symbol of masochism for the strenuous will to find it by the group of researchers.