Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution

Chatzispyrou, Iliana A.; Guerrero–Castillo, Sergio; Held, Ntsiki M.; Ruiter, J. P. N.; Denis, Simone; IJlst, Lodewijk; Wanders, R. J. A.; Weeghel, Michel van; Ferdinandusse, Sacha; Vaz, Frédéric M.; Brandt, Ulrich; Houtkooper, Riekelt H.

doi:10.1016/j.bbadis.2018.08.041

Cited by 61 publications

(74 citation statements)

References 54 publications

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“…Depletion of either one causes mitochondrial dysfunction and atypical cristae architecture , and depletion of both cardiolipin and phosphatidylethanolamine is lethal . In humans, decreased cardiolipin levels and aberrant cardiolipin species, resulting from mutant variants of the cardiolipin remodelling enzyme tafazzin, cause Barth syndrome, a cardiomyopathy with muscle weakness (Table ) .…”

Section: Nonbilayer‐forming Phospholipidsmentioning

confidence: 99%

Shaping the mitochondrial inner membrane in health and disease

et al. 2020

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Colina-Tenorio L, Horten P, Pfanner N, Rampelt H (University of Freiburg, Freiburg, Germany). Shaping the mitochondrial inner membrane in health and disease (Review Symposium). J Intern Med 2020; 287: 645-664.Mitochondria play central roles in cellular energetics, metabolism and signalling. Efficient respiration, mitochondrial quality control, apoptosis and inheritance of mitochondrial DNA depend on the proper architecture of the mitochondrial membranes and a dynamic remodelling of inner membrane cristae. Defects in mitochondrial architecture can result in severe human diseases affecting predominantly the nervous system and the heart. Inner membrane morphology is generated and maintained in particular by the mitochondrial contact site and cristae organizing system (MICOS), the F 1 F o -ATP synthase, the fusion protein OPA1/Mgm1 and the nonbilayer-forming phospholipids cardiolipin and phosphatidylethanolamine. These protein complexes and phospholipids are embedded in a network of functional interactions. They communicate with each other and additional factors, enabling them to balance different aspects of cristae biogenesis and to dynamically remodel the inner mitochondrial membrane. Genetic alterations disturbing these membrane-shaping factors can lead to human pathologies including fatal encephalopathy, dominant optic atrophy, Leigh syndrome, Parkinson's disease and Barth syndrome.

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Section: Nonbilayer‐forming Phospholipidsmentioning

confidence: 99%

Shaping the mitochondrial inner membrane in health and disease

et al. 2020

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“…Our findings, however, are contradictory to the studies with other cellular models. Li et al report reduced carbon flux from glucose to Krebs cycle intermediates in TAZ-KO mouse C2C12 myoblast cell line [54], while Chatzispyrou et al demonstrate that the fractional contribution of glucose to the Krebs cycle intermediates is unaffected in TAZ-deficient skin fibroblasts [55]. The discrepancy between studies can be explained by differences in genotype and cellular metabolism for different types of cells.…”

Section: Alteration In Substrate Preferencesmentioning

confidence: 99%

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

et al. 2019

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Barth syndrome (BTHS) is an X-linked recessive multisystem disorder caused by mutations in the TAZ gene (TAZ, G 4.5, OMIM 300394) that encodes for the acyltransferase tafazzin. This protein is highly expressed in the heart and plays a significant role in cardiolipin biosynthesis. Heart disease is the major clinical manifestation of BTHS with a high incidence in early life. Although the genetic basis of BTHS and tetralinoleoyl cardiolipin deficiency in BTHS-affected individuals are well-established, downstream metabolic changes in cardiac metabolism are still uncovered. Our study aimed to characterize TAZ-induced metabolic perturbations in the heart. Control (PGP1-TAZWT) and TAZ mutant (PGP1-TAZ517delG) iPS-CM were incubated with 13C6-glucose and 13C5-glutamine and incorporation of 13C into downstream Krebs cycle intermediates was traced. Our data reveal that TAZ517delG induces accumulation of cellular long chain acylcarnitines and overexpression of fatty acid binding protein (FABP4). We also demonstrate that TAZ517delG induces metabolic alterations in pathways related to energy production as reflected by high glucose uptake, an increase in glycolytic lactate production and a decrease in palmitate uptake. Moreover, despite mitochondrial dysfunction, in the absence of glucose and fatty acids, TAZ517delG-iPS-CM can use glutamine as a carbon source to replenish the Krebs cycle.

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“…CL abnormalities have been implicated in cardiac dysfunction, and are seen in ischemic heart disease and aging [ 29 ]. The mechanisms that lead from abnormal CL biogenesis to cardiomyopathy are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

Petit

Ardilla-Osorio

Penalvia

et al. 2020

Cells

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Tafazzin is a phospholipid transacylase that catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mutations of the tafazzin gene cause Barth syndrome, which is characterized by mitochondrial dysfunction and dilated cardiomyopathy, leading to premature death. However, the molecular mechanisms underlying the cause of mitochondrial dysfunction in Barth syndrome remain poorly understood. We again highlight the fact that the tafazzin deficiency is also linked to defective oxidative phosphorylation associated with oxidative stress. All the mitochondrial events are positioned in a context where mitophagy is a key element in mitochondrial quality control. Here, we investigated the role of tafazzin in mitochondrial homeostasis dysregulation and mitophagy alteration. Using a HeLa cell model of tafazzin deficiency, we show that dysregulation of tafazzin in HeLa cells induces alteration of mitophagy. Our findings provide some additional insights into mitochondrial dysfunction associated with Barth syndrome, but also show that mitophagy inhibition is concomitant with apoptosis dysfunction through the inability of abnormal mitochondrial cardiolipin to assume its role in cytoplasmic signal transduction. Our work raises hope that pharmacological manipulation of the mitophagic pathway together with mitochondrially targeted antioxidants may provide new insights leading to promising treatment for these highly lethal conditions.

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Barth syndrome cells display widespread remodeling of mitochondrial complexes without affecting metabolic flux distribution

Cited by 61 publications

References 54 publications

Shaping the mitochondrial inner membrane in health and disease

Shaping the mitochondrial inner membrane in health and disease

Barth Syndrome: Exploring Cardiac Metabolism with Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Tafazzin Mutation Affecting Cardiolipin Leads to Increased Mitochondrial Superoxide Anions and Mitophagy Inhibition in Barth Syndrome

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