TAZ encodes tafazzin, a transacylase essential for cardiolipin formation and central to the etiology of Barth syndrome

Garlid, Anders O.; Schaffer, Calvin T.; Kim, JaeWoo; Bhatt, Hirsh; Guevara-Gonzalez, Vladimir; Ping, Peipei

doi:10.1016/j.gene.2019.144148

Cited by 16 publications

(11 citation statements)

References 190 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Taffazin protein is an acyltransferase located in the inner mitochondrial membrane responsible for remodeling monolysocardiolipin (MLCL) to its mature form of cardiolipin (CL) (Fig. 2 ) [ 22 ]. The unique structure of cardiolipin enables the curvature of the inner mitochondrial membrane to form cristae and stabilizes the individual complexes of the ETC, facilitating oxidative phosphorylation [ 22 ].…”

Section: Pre-clinical Studies On Aav Vector-based Gene Replacement Th...mentioning

confidence: 99%

“…2 ) [ 22 ]. The unique structure of cardiolipin enables the curvature of the inner mitochondrial membrane to form cristae and stabilizes the individual complexes of the ETC, facilitating oxidative phosphorylation [ 22 ]. BTHS mitochondria have an increased MLCL/CL ratio that causes instability of the inner mitochondrial membrane, ultimately resulting in a decreased efficiency in ATP production [ 22 ].…”

Section: Pre-clinical Studies On Aav Vector-based Gene Replacement Th...mentioning

confidence: 99%

See 1 more Smart Citation

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Hanaford

Cho

Nakai

2022

Orphanet J Rare Dis

View full text Add to dashboard Cite

Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.

show abstract

Section: Pre-clinical Studies On Aav Vector-based Gene Replacement Th...mentioning

confidence: 99%

Section: Pre-clinical Studies On Aav Vector-based Gene Replacement Th...mentioning

confidence: 99%

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Hanaford

Cho

Nakai

2022

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…This disease has been mainly described by mutations in the nuclear-encoded tafazzin ( Bione et al, 1996 ). Barth syndrome presents a unique pathophysiological mechanism: in detail, mutated tafazzin primary promotes an aberrant cardiolipin maturation process due its role in the transacylation process showing preference for the transfer of a linoleic acid group from phosphatidylcholine to monolysocardiolipin, resulting in depletion of mature cardiolipin and accumulation of an immature form and thereby in a deleterious mitochondrial metabolism ( Garlid et al, 2020 ). Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition and affects many aspects of mitochondrial structure and function, including MRC complex formation/interaction, mitochondrial dynamics, and apoptosis ( Dudek, 2017 ).…”

Section: Modeling Mitochondrial Cardiomyopathies Using Ipsc-derived Cardiomyocytesmentioning

confidence: 99%

Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Pavez‐Giani

Cyganek

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Around one third of patients with mitochondrial disorders develop a kind of cardiomyopathy. In these cases, severity is quite variable ranging from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. ATP is primarily generated in the mitochondrial respiratory chain via oxidative phosphorylation by utilizing fatty acids and carbohydrates. Genes in both the nuclear and the mitochondrial DNA encode components of this metabolic route and, although mutations in these genes are extremely rare, the risk to develop cardiac symptoms is significantly higher in this patient cohort. Additionally, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac symptoms. At this point, the mechanisms behind cardiac disease progression related to mitochondrial gene mutations are poorly understood and current therapies are unable to substantially restore the cardiac performance and to reduce the disease burden. Therefore, new strategies are needed to uncover the pathophysiological mechanisms and to identify new therapeutic options for mitochondrial cardiomyopathies. Here, human induced pluripotent stem cell (iPSC) technology has emerged to provide a suitable patient-specific model system by recapitulating major characteristics of the disease in vitro, as well as to offer a powerful platform for pre-clinical drug development and for the testing of novel therapeutic options. In the present review, we summarize recent advances in iPSC-based disease modeling of mitochondrial cardiomyopathies and explore the patho-mechanistic insights as well as new therapeutic approaches that were uncovered with this experimental platform. Further, we discuss the challenges and limitations of this technology and provide an overview of the latest techniques to promote metabolic and functional maturation of iPSC-derived cardiomyocytes that might be necessary for modeling of mitochondrial disorders.

show abstract

“…Newly generated PE can either be accumulated in the mitochondrion or exported to the ER where it is trimethylated to PC by PE specific methyltransferase CHO2 and PL methyltransferase OPI3 [55]. End products of this synthesis machinery can be modulated by mitochondrial transacylases, such as tafazzin (TAZ1) [56].…”

Section: Manipulating Components Of Pl Biosynthesis Modulates Mitochondrial Lipid Composition and Affects Lifespanmentioning

confidence: 99%

Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging

Löser

Joppe

Hamann

et al. 2021

Cells

View full text Add to dashboard Cite

Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature.

show abstract

TAZ encodes tafazzin, a transacylase essential for cardiolipin formation and central to the etiology of Barth syndrome

Cited by 16 publications

References 190 publications

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging

Contact Info

Product

Resources

About