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TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes (part-I)

ABSTRACT: Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome (SIDS) with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via a novel, engineered MicroRNA Maturation Cocktail (MiMaC) that upregulated the epigenetic regulator, HOPX. Fatty acid challenged MiMaC treated HADHA mutant cardiomyocytes manifested the disease phenotype: defective calcium dynamics and repolarization kinetics which resulted in a pro-arrhythmic state. Single cell RNA-seq revealed a novel cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gave rise to mature-like cardiomyocytes in control cells but, mutant cells transitioned to a pathological state with reduced fatty acid beta-oxidation (FAO), reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that TFPa/HADHA, a MLCL-AT-like enzyme, is required for FAO and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Sudden Infant Death Syndrome

SUBMITTER: Megan Showalter

PROVIDER: ST001246 | MetabolomicsWorkbench | Mon Aug 26 00:00:00 BST 2019

REPOSITORIES: MetabolomicsWorkbench

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TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes

Project description:Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.

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Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

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Metabolic reprogramming from fatty acid oxidation to glycolysis in a patient mutation knock-in mouse model of Barth Syndrome. [human]

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Project description:Mitochondria are central for cellular metabolism and energy supply. Barth Syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patient. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid driven OXPHOS and protects mice against cardiac failure.

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Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

Project description:Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

| PRJNA490270 | ENA

Characterisation of a novel CRLS1 variant in multi-system mitochondrial disease pathogenesis identifies mitochondrial and endoplasmic reticular stress responses to cardiolipin dysfunction

Project description:Mitochondrial diseases (MD) are a group of inherited diseases with highly varied and complex clinical presentations and their molecular diagnosis has been improved through next generation sequencing. Here, we report four individuals, two of whom are siblings, affected by a progressive mitochondrial encephalopathy who carry biallelic variants in the cardiolipin biosynthesis gene CRLS1. Using patient fibroblasts, we characterised defects in mitochondrial function that were reflective of CRLS1 dysfunctions, providing functional evidence that the CRLS1 I109N variant causes the MD phenotype observed in this patient. Lipid profiling highlighted that the CRLS1 variants reduced cardiolipin levels, altered its acyl-chain composition and caused a significant increase in phosphatidylglycerol, the substrate of cardiolipin synthase. Proteomic profiling of patient cells and Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. Our findings support that deleterious variants in CRLS1 cause a novel autosomal recessive MD, presenting as a severe encephalopathy with multisystemic involvement. Furthermore, we have identified key changes in cardiolipin and proteome profiles across various degrees of cardiolipin dysfunction, facilitating future advances in diagnostic technologies based on curated signatures in high-throughput datasets.

2023-03-06 | PXD029861 | Pride

Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

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